CN117203208A - Inhibitors targeting activated and inactivated KRAS G12D - Google Patents

Abstract

A pyridopyrimidine compound, a pharmaceutical composition containing the same, and a preparation method and application thereof, wherein the compound can be targeted to activated and inactivated KRAS G12D and can be used as a reversible inhibitor of KRAS G12D mutant proteins.

Description

Inhibitors targeting activated and inactive KRAS G12D Technical field

The present invention relates to the field of medicine. Specifically, the present invention provides compounds capable of reversibly inhibiting KRAS G12D mutant protein and preparation methods and applications thereof.

Background technique

Rat sarcoma homologous gene (rat sarcoma, RAS) is the first oncogene discovered and has the highest mutation frequency. RAS protein serves as a "molecular switch" and regulates multiple signaling pathways related to cell proliferation and differentiation.

Common mutation sites in KRAS include G12, G13 and Q61, of which the vast majority are mutations at the G12 site, accounting for approximately 83%. Common mutation types of KRAS G12 include G12D, G12V and G12C, among which the number of cancer patients carrying KRAS G12D mutations is the largest. In pancreatic ductal carcinoma, colorectal cancer and lung adenocarcinoma, KRAS G12D mutations account for 51%, 45% and 17% respectively (Schirripa, M., et al., KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. Clin Colorectal Cancer 19, (2020) 219-225). One statistical estimate shows that in the United States and Europe, there are as many as 180,000 new cancer patients carrying KRAS G12D mutations each year (Baldus, S.E., et al., Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 16, (2010) 790-799).

In the past thirty years, all RAS-targeted drug development has failed. The main difficulty lies in the fact that the guanylate-binding pocket of the RAS protein is not suitable for drug synthesis and there are no other deeper binding pockets on the surface. Since scientists discovered an allosteric pocket in the KRAS G12C mutant protein that can be induced by small molecules in 2013, there has been an upsurge in the pharmaceutical industry to develop covalent inhibitors of KRAS G12C. However, the mutant protein KRAS G12D has greater clinical significance. inhibitors, but there are few successful cases reported.

Therefore, there is an urgent need in this field for safe and effective inhibitors of KRAS G12D mutant protein.

Contents of the invention

Unlike KRAS G12C, the carboxyl group of Asp 12 of KRAS G12D cannot add to the double bond of acrylamide. Therefore, although covalent inhibitors have been successful on the KRAS G12C protein, this type of small molecule is obviously unable to bind to KRAS G12D. Faced with this technical problem, the present invention designed and synthesized an inhibitor that can form non-covalent bonds with KRAS G12D, and proved that the compound of the present invention can effectively inhibit the activity of KRAS G12D.

In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:

in,

X is -N(R)- or -CH(R*)-;

Wherein R is selected from H, -(CH ₂ ) _1-3 -halogen, -(CH ₂ ) _1-3 -OH, -(CH ₂ ) _1-3 -CN, -(CH ₂ ) _{1- 3} -NH ₂ , C _1-6 alkyl or C _1-6 haloalkyl;

R* is selected from -(CH ₂ ) _0-3 -halogen, -(CH ₂ ) _0-3 -OH, -(CH ₂ ) _0-3 -CN or -(CH ₂ ) _0-3 -NH ₂ ;

Y is N or CH;

Y ₁ is CR _Y1a R _Y1b ;

Y ₂ is CR _Y2a R _Y2b ;

Y ₃ is CR _Y3a R _Y3b or NR _Y3c ;

r=1 or 2;

s=0 or 1;

Wherein R _Y1a , R _Y1b , R _Y2a , R _Y2b , R _Y3a and R _Y3b are independently selected from H, halogen, _{C 1-6 alkyl or C 1-6 haloalkyl ;}

R _Y3c is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Or a double bond can be formed between Y ₃ and the adjacent Y ₂ ;

R _A is selected from H, C _6-10 aryl or 5-14 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R _A1 ;

Wherein each R _{A1 is} independently selected from _{H ,} halogen _{, -CN , -OR} C _2-6 alkynyl;

L is selected from chemical bond, -O-, -S- or -NH-;

_{R B is} selected _{from H} , _{halogen , -CN} , _-OR Alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; which is optionally substituted by 1, 2, 3 or 4 R#;

Wherein R# is selected from H, -C _0-6 alkylene-halogen, -C _0-6 alkylene-CN, C _{1-6 alkyl, C 1-6 haloalkyl} , C _2-6 alkenyl, _{C 2-6 alkynyl , -C 0-6} alkylene -OR _X , -C _0-6 alkylene _-SR Alkylene _{- C} (O) _RX , _{-C 0-6 alkylene} -C( _O ) _{OR 6} -alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3-10-membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl or -C _{0- 6} alkylene-5-14 membered heteroaryl; and R# is optionally replaced by halogen, -OH, -OC _1-6 alkyl, -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , C _1-6 alkyl or C _1-6 haloalkyl substitution _;

_{Wherein R _ _ _}

R _Y and R _Z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _Y and _{R Z} and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclic groups;

R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R';

R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R”;

R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group;

Or any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -;

p=0, 1, 2 or 3;

q=0, 1, 2 or 3;

Wherein R _a is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _b is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _c is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _d is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R' is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e , -C(O)NR _f R _g , C _{2- 6} alkenyl or C _2-6 alkynyl;

R” is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e , -C(O)NR _f R _g , C _{2- 6} alkenyl or C _2-6 alkynyl;

m=0, 1, 2, 3, 4, 5 or 6;

n=0, 1, 2, 3, 4, 5 or 6;

Wherein R _e is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl;

R _f and R _g are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _f and R _g and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclyl groups.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.

In another aspect, the invention provides pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.

In another aspect, the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prevention of diseases mediated by KRAS G12D mutant protein.

In another aspect, the invention provides a method of treating and/or preventing a KRAS G12D mutein-mediated disease in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.

In another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of KRAS G12D mutant protein-mediated diseases.

In specific embodiments, diseases treated by the present invention include cancers selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancers (e.g., lymphoma and kaposi sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterus Endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastric cancer Intestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular Melanoma, islet cell tumor, pancreatic neuroendocrine tumor, renal cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary tumor, Midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasia, multiple myeloma, Meck's disease Myeloid cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of the bone, nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), Oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary Central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cellular lymphoma , testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare cancers in children, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer .

Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

Description of the drawings

Figure 1 Analysis of binding sites between KRAS G12D protein and TH-Z 816.

Figure 2 Analysis of the binding mode of TH-Z 816 and KRAS G12D protein.

Figure 3 Structural analysis of the protein cavity around the piperazine ring of TH-Z 816.

definition

chemical definition

Definitions of specific functional groups and chemical terms are described in more detail below.

When numerical ranges are listed, each value and subrange within the stated range is intended to be included. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , _{C 5} , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and _{C 5 -6} alkyl.

"C _1-6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C _1-4 alkyl and C _1-2 alkyl are preferred. Examples of C _1-6 alkyl groups include: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl base (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl ( C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-pentyl (C ₅ ) and n-hexyl (C ₆ ). The term "C _1-6 alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH ₃ ), Et(-CH ₂ CH ₃ ), iPr(-CH(CH ₃ ) ₂ ), nPr(-CH ₂ CH ₂ CH ₃ ), n-Bu(-CH ₂ CH ₂ CH ₂ CH ₃ ) or i-Bu(-CH ₂ CH(CH ₃ ) ₂ ).

"C _2-6 alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 alkenyl is preferred. Examples of C _2-6 alkenyl groups include: vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), etc. The term "C _2-6 alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Alkenyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"C _2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C _2-4 alkynyl is preferred. Examples of C _2-6 alkynyl groups include, but are not limited to: ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-Butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), etc. The term "C _2-6 alkynyl" also includes heteroalkynyl groups in _which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"C _1-6 alkylene" refers to a divalent group formed by removing another hydrogen of C _1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C _1-4 alkylene, C _2-4 alkylene, and C _1-3 alkylene are preferred. The unsubstituted alkylene group includes, but is not limited to: methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), ethylene Base (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) ,etc. Exemplary substituted alkylene groups, for example, the alkylene groups substituted by one or more alkyl (methyl) include, but are not limited to: substituted methylene (-CH(CH ₃ )- , -C(CH ₃ ) ₂ -), substituted ethylene (-CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) _2- ), substituted propylene (-CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH(CH ₃ ) -, -C(CH ₃ ) ₂ CH ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH ₂ C(CH ₃ ) ₂ -), etc.

"C _0-6 alkylene" refers to a chemical bond as well as the above-mentioned "C _1-6 alkylene".

"C _2-6 alkenylene" refers to a divalent group formed by removing the other hydrogen of the C _2-6 alkenyl group, and may be substituted or unsubstituted. In some embodiments, C _2-4 alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to: vinylene (-CH=CH-) and propenylene (eg, -CH= _CHCH2- , _-CH2 -CH=CH-). Exemplary substituted alkenylene groups, such as alkenylene groups substituted by one or more alkyl (methyl) groups, include but are not limited to: substituted ethylene (-C(CH ₃ )=CH- , -CH＝C(CH ₃ )-), substituted propenylene (-C(CH ₃ )＝CHCH ₂ -, -CH＝C(CH ₃ )CH ₂ -, -CH＝CHCH(CH ₃ )- , -CH＝CHC(CH ₃ ) ₂ -, -CH(CH ₃ )-CH＝CH-, -C(CH ₃ ) ₂ -CH＝CH-, -CH ₂ -C(CH ₃ )＝CH-, -CH ₂ -CH=C(CH ₃ )-), etc.

"C _2-6 alkynylene" refers to a divalent group formed by removing the other hydrogen of the C _2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C _2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH ₂ -), and the like.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

Therefore, "C _1-6 haloalkyl" refers to the above-mentioned "C _1-6 alkyl" which is substituted by one or more halogen groups. In some embodiments, C _1-4 haloalkyl is particularly preferred, with C _1-2 haloalkyl being more preferred. Exemplary haloalkyl groups include, but are not limited to: -CF ₃ , -CH ₂ F, -CHF ₂ , -CHFCH ₂ F, -CH ₂ CHF ₂ , -CF ₂ CF ₃ , -CCl ₃ , -CH ₂ Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Haloalkyl groups may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"C _3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C _4-7 cycloalkyl and C _3-6 cycloalkyl are particularly preferred, with C _5-6 cycloalkyl being more preferred. Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues as indicated The number of carbons in a cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl ( C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptene group (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptadienyl (C ₇ ), etc. A cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"3-12 membered heterocyclyl" refers to a group of 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. In some embodiments, 4-12 membered heterocyclyl is preferred, which is a 4-12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-10 membered is preferred Heterocyclyl, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8-membered heterocyclyl is preferred, which is a 3- to 8-membered heterocyclic ring system having ring carbon atoms and 1 to 5 ring heteroatoms. A 3- to 8-membered non-aromatic ring system with 1 to 4 ring heteroatoms; preferably a 3-6-membered heterocyclic group, which is a 3- to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; Preferred are 4-7-membered heterocyclyl groups, which are 4-7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferred are 5-6-membered heterocyclyl groups, which are 4- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. 5-6 membered non-aromatic ring system with 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above-described heterocyclyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or in which the above-described heterocyclyl ring is fused with one or more aryl groups or Heteroaryl fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxirinyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolyl, oxasulfuranyl, disulfuranyl, and oxalanyl. Azolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxpanyl, and thipanyl. Exemplary 5-membered heterocyclyl fused to a _C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to: indolyl, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclyl fused to a _C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to: tetrahydroquinolyl, tetrahydroisoquinolyl, etc. Heterocyclyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"C _6-10 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having a Shared 6 or 10 π electrons) group. In some embodiments, an aryl group has six ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C ₁₀ aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. Aryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having a 6, 10 or 14 π electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the heteroaryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom Number continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. . Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepantrienyl, oxetapyltrienyl, and thioheptantrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indazinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl . Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc. are defined herein as optionally substituted groups.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(＝O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa ,- Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(＝O) ₂ R ^aa , -P(＝O)(R ^aa ) ₂ , -OP(＝O)(R ^aa ) ₂ , -OP(＝O)(OR ^cc ) ₂ , -P( ＝O) ₂ N(R ^bb ) ₂ , -OP(＝O) ₂ N(R ^bb ) ₂ , -P(＝O)(NR ^bb ) ₂ , -OP(＝O)(NR ^bb ) ₂ ,- NR ^bb P(＝O)(OR ^cc ) ₂ , -NR ^bb P(＝O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R ^dd groups substituted;

Or two bihydrogen groups on carbon atoms =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , = NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc substituted;

Each R ^aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ^aa groups are combined to form heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R ^dd groups group replacement;

Each of R ^bb is independently selected from: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) _2. -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O ) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkene radical, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ^bb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne Base, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each R ^cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^cc groups are combined to form a heterocycle or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R ^dd group substitution;

Each of R ^dd is independently selected from: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N ⁽ R ^ff _{) 2} ^{, -N ( R ff )} ₃ ⁺ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff ) R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(＝O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , - SC(=S)SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle Aryl, aryl and heteroaryl groups are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal R ^dd substituents may be combined to form =O or =S;

Each R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R ^gg groups;

Each R ^ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ^ff groups combine to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R ^gg group substitution;

Each of R ^gg is independently: halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 Alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ ⁽ _{C 1-6} ^{alkyl ) +} _{_ _ _ _} ), -NH(OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (=O) (C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC (=O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (=O)NH ₂ , -C (=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , - NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _{1- 6} alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl) , -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _{1-6 alkyl} , -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C (=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl , -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(= O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two R ^gg substituted The radicals may combine to form =O or =S; where X ^- is the counterion.

Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O )(NR ^cc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ^cc groups connected to the nitrogen atom combine to form a heterocycle or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R ^{The dd} group is substituted, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as described above.

Other definitions

The term "KRAS G12D" refers to a mutated form of the mammalian KRAS protein that contains the amino acid substitution of aspartic acid for glycine at amino acid position 12.

The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testicle, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, Cancers of tongue, oral cavity, pharynx, small intestine, colorectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, renal cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, pilocytic carcinoma, and leukemia.

As used herein, the term "treatment" refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the noun "treat" refers to the action of the verb treat, as just defined.

As used herein, the term "pharmaceutically acceptable salts" means those carboxylate salts and amino acid addition salts of the compounds of the present invention which are suitable for contact with patient tissue within the scope of reliable medical judgment and will not produce undue toxicity, Irritation effects, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

Base addition salts of acidic compounds may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to form the salt. The free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in the usual manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention the salts are nevertheless equivalent to their respective free acids.

The salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salt, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate Acid, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, lauryl sulfonate and isethionate, etc. Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylbenzoate Acid, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1- 19, incorporated by reference).

"Subjects" for administration include, but are not limited to: humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. The terms "person," "patient," and "subject" are used interchangeably herein.

"Disease," "disorder," and "condition" are used interchangeably herein.

Unless otherwise indicated, the term "treatment" or "treatment" as used herein includes an action in a subject suffering from a specific disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a condition ("therapeutic treatment"), and also includes effects that occur before a subject begins to suffer from a specific disease, disorder or condition ("preventive treatment").

Generally, an "effective amount" of a compound is an amount sufficient to elicit a target biological response. As will be understood by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age health conditions and symptoms. The effective amount includes a therapeutically effective amount and a preventive effective amount.

Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount to delay or minimize. A therapeutically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.

Unless otherwise stated, a "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of a disorder or condition. A prophylactically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.

"Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or with other therapeutic agents in a single unit dosage form.

Specific implementation plan

Herein, "compounds of the present invention" refers to the following compounds of formula (I) (including sub-general formulas, such as formula (II), formula (V-2), etc.), their pharmaceutically acceptable salts, enantiomers conformers, diastereomers, solvates, hydrates or isotopic variants, and mixtures thereof.

In this article, compounds are named using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise stated) all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention with carbon-carbon double bonds may appear in the Z and E forms. Compounds exist in different tautomeric forms, and a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.

In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:

in,

X is -N(R)- or -CH(R*)-;

Wherein R is selected from H, -(CH ₂ ) _1-3 -halogen, -(CH ₂ ) _1-3 -OH, -(CH ₂ ) _1-3 -CN, -(CH ₂ ) _{1- 3} -NH ₂ , C _1-6 alkyl or C _1-6 haloalkyl;

R* is selected from -(CH ₂ ) _0-3 -halogen, -(CH ₂ ) _0-3 -OH, -(CH ₂ ) _0-3 -CN or -(CH ₂ ) _0-3 -NH ₂ ;

Y is N or CH;

Y ₁ is CR _Y1a R _Y1b ;

Y ₂ is CR _Y2a R _Y2b ;

Y ₃ is CR _Y3a R _Y3b or NR _Y3c ;

r=1 or 2;

s=0 or 1;

Wherein R _Y1a , R _Y1b , R _Y2a , R _Y2b , R _Y3a and R _Y3b are independently selected from H, halogen, _{C 1-6 alkyl or C 1-6 haloalkyl ;}

R _Y3c is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Or a double bond can be formed between Y ₃ and the adjacent Y ₂ ;

R _A is selected from H, C _6-10 aryl or 5-14 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R _A1 ;

Wherein each R _{A1 is} independently selected from _{H ,} halogen _{, -CN , -OR} C _2-6 alkynyl;

L is selected from chemical bond, -O-, -S- or -NH-;

_{R B is} selected _{from H} , _{halogen , -CN} , _-OR Alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; which is optionally substituted by 1, 2, 3 or 4 R#;

Wherein R# is selected from H, -C _0-6 alkylene-halogen, -C _0-6 alkylene-CN, C _{1-6 alkyl, C 1-6 haloalkyl} , C _2-6 alkenyl, _{C 2-6} alkynyl _{, -C 0-6} alkylene -OR _X , -C _{0-6 alkylene -SR} Alkylene _{- C} (O) _RX , _{-C 0-6 alkylene} -C( _O ) _{OR 6} -alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3-10-membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl or -C _{0- 6} alkylene-5-14 membered heteroaryl; and R# is optionally replaced by halogen, -OH, -OC _1-6 alkyl, -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , C _1-6 alkyl or C _1-6 haloalkyl substitution _;

_{Wherein R _ _ _}

R _Y and R _Z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _Y and _{R Z} and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclic groups;

R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R';

R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R”;

R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group;

Or any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -;

p=0, 1, 2 or 3;

q=0, 1, 2 or 3;

Wherein R _a is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _b is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _c is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _d is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R' is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e , -C(O)NR _f R _g , C _{2- 6} alkenyl or C _2-6 alkynyl;

R” is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e , -C(O)NR _f R _g , C _{2- 6} alkenyl or C _2-6 alkynyl;

m=0, 1, 2, 3, 4, 5 or 6;

n=0, 1, 2, 3, 4, 5 or 6;

Wherein R _e is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl;

R _f and R _g are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _f and R _g and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclyl groups.

X

In one specific embodiment, X is -N(R)-; in another specific embodiment, X is -NH-; in another specific embodiment, X is -NMe-; in one specific embodiment , X is -CH(R*)-; in another embodiment, X is -CH(NH ₂ )-; in another embodiment, X is -CH(CH ₂ NH ₂ )-; in In another embodiment, X is -CH(CH ₂ CH ₂ NH ₂ )-; in another embodiment, X is -CH(OH)-; in another embodiment, X is -CH (CH ₂ OH)-; in another specific embodiment, X is -CH(CH ₂ CH ₂ OH)-.

Y

In one specific embodiment, Y is N; in another specific embodiment, Y is CH.

(Y ₁ ) _r

In one specific embodiment, Y ₁ is CR _Y1a R _Y1b ; in another specific embodiment, Y ₁ is CH ₂ ; in another specific embodiment, (Y ₁ ) _r is CH ₂ ; in another specific embodiment In embodiments, (Y ₁ ) _r is CH ₂ CH ₂ .

(Y ₂ ) _s

In one specific embodiment, Y ₂ is CR _Y2a R _Y2b ; in another specific embodiment, Y ₂ is CH ₂ ; in another specific embodiment, (Y ₂ ) _s is CH ₂ ; in another specific embodiment In embodiments, (Y ₂ ) _s is a chemical bond.

Y ₃

In one specific embodiment, Y ₃ is CR _{Y3a RY3b} ; in another specific embodiment, Y ₃ is CH ₂ ; in another specific embodiment, Y ₃ is NR _Y3c ; in another specific embodiment , Y ₃ is NH; in another specific embodiment, (Y ₂ ) _s -Y ₃ is CH ₂ CH ₂ ; in another specific embodiment, (Y ₂ ) _s -Y ₃ is CH=CH; in In another specific embodiment, (Y ₂ ) _s -Y ₃ is CH ₂ NH; in another specific embodiment, (Y ₂ ) _s -Y ₃ is CH=N.

In a more specific embodiment, Selected from the following mother cores: In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for In another more specific embodiment, for

R _A

In one embodiment, R _A is selected from H, C _6-10 aryl or 5-14 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R _A1 ; in another embodiment In this embodiment, R _A is H; in another specific embodiment, R _A is C _6-10 aryl, which is optionally substituted by 1, 2, 3 or 4 R _A1 ; in another specific embodiment , R _A is phenyl, which is optionally substituted by 1, 2, 3 or 4 R _A1 ; in another specific embodiment, R _A is naphthyl, which is optionally substituted by 1, 2, 3 or 4 R _A1 substituted; in another specific embodiment, R _A is a 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3 or 4 R _A1 .

In a specific _embodiment , R _A1 is _{H , halogen , -CN} , _-OR group or C _2-6 alkynyl; in another specific embodiment, R _A1 is H; in another specific embodiment, R _A1 is halogen; in another specific embodiment, R _A1 is -CN; in _{In another specific} embodiment, _{R A1 is -OR} In one embodiment, R _A1 is C _1-6 alkyl; in another specific embodiment, R _A1 is C _1-6 haloalkyl; in another specific embodiment, R _A1 is C _2-6 alkenyl; In another specific embodiment, R _A1 is C _2-6 alkynyl.

In a more specific embodiment, _RA is selected from the following groups: preferred More preferred In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is In another more specific embodiment, R _A is

L

In one embodiment, L is a chemical bond; in another embodiment, L is -O-; in another embodiment, L is -S-; in another embodiment, L is - NH-.

R _B

In _a specific embodiment, R _B is selected _from H _{, halogen} , _{-CN , -OR} Alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl, which is optionally replaced by 1, 2, 3 Or 4 R# substitutions; in another specific embodiment, R _B is H; in another specific embodiment, R _B is halogen; in another specific embodiment, R B is -CN; in another specific embodiment, R _B is -CN; _{In a} specific _{embodiment , RB is -OR} In, R _B is C _1-6 alkyl, which is optionally substituted by 1, 2, 3 or 4 R#; in another specific embodiment, R _B is C _1-6 haloalkyl, which is optionally substituted by 1, 2, 3 or 4 R# substituted; in another specific embodiment, R _B is C _2-6 alkenyl, which is optionally substituted with 1, 2, 3 or 4 R#; in another specific embodiment In embodiments, R _B is C _2-6 alkynyl, which is optionally substituted by 1, 2, 3 or 4 R#; in another specific embodiment, R _B is C _3-10 cycloalkyl, which optionally substituted by 1, 2, 3 or 4 R#; in another specific embodiment, R _B is a 3-10 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R#; In another specific embodiment, R _B is a C _6-10 aryl group, which is optionally substituted by 1, 2, 3 or 4 R#; in another specific embodiment, R _B is a 5-14 membered hetero Aryl, optionally substituted by 1, 2, 3 or 4 R#.

In a more specific embodiment, -LR _B is selected from H, Preferably H, In another more specific embodiment, -LR _B is H; in another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is In another more specific embodiment, -LR _B is

R ₁ and R ₂

In one specific embodiment, R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN, or -(CR _c R _d ) _m -R'; in another specific embodiment, R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN, -CH ₃ or -CH ₂ -OH; in another specific embodiment, R ₁ and R ₂ are independently selected from -CH ₃ or -CH ₂ -OH; in another embodiment, one of R ₁ and R ₂ is -CH ₃ or -CH ₂ -OH; in another embodiment, one of R ₁ and R ₂ One is -CH ₃ or -CH ₂ -OH in R configuration.

R _2'

In one specific embodiment, R _2' is H; in another specific embodiment, R ₂ , R _2' together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group.

R ₃ and R ₄

In one specific embodiment, R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN, or -(CR _c R _d ) _m -R”; in another specific embodiment, R ₃ and R ₄ are independently selected from H, -CH ₂ -Cl, -CH ₂ -F, -CH ₂ -CN, -CH ₂ CH ₂ -Cl, -CH ₂ CH ₂ -F, -CH ₂ CH ₂ -CN; In another specific embodiment, R ₃ and R ₄ are independently selected from H or -CH ₂ -CN.

In a more specific embodiment, R ₁ and R ₂ are joined to form -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, preferably -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, more preferably -CH ₂ CH ₂ -; in another more specific embodiment, R ₃ and R ₄ are joined to form -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, preferably -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, more preferably -CH ₂ CH ₂ -; in another more specific embodiment, R ₁ and R ₄ are joined to form -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, preferably -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, more preferably -CH ₂ CH ₂ -; in another more specific embodiment, R ₂ and R ₃ joins to form -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, preferably -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -, more preferably -CH ₂ CH ₂ - .

p and q

In one embodiment, p=0; in another embodiment, p=1; in another embodiment, p=2; in another embodiment, p=3.

In one embodiment, q=0; in another embodiment, q=1; in another embodiment, q=2; in another embodiment, q=3.

Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. _{For example , any technical solution of _ _} , R ₄ , p and q, etc., or any combination thereof. The present invention is intended to include combinations of all these technical solutions, and due to space limitations, they will not be listed one by one.

In a more specific embodiment, the invention provides the above-mentioned compound (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof , which has the following structure:

Wherein, each group is as defined above.

In a more specific embodiment, the invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotopic variant thereof :

in,

X is -N(R)- or -CH(R*)-;

Wherein R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R* is selected from -(CH ₂ ) _0-3 -NH ₂ or -(CH ₂ ) _0-3 -OH;

R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R';

R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R”;

R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group;

p=0, 1, 2 or 3;

q=0, 1, 2 or 3;

Wherein R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R' is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e or -C(O)NR _e R _f ;

R” is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e or -C(O)NR _e R _f ;

m=0, 1, 2, 3, 4, 5 or 6;

Wherein R _e is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl;

R _f and R _g are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _f and R _g and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclyl groups.

In a more specific embodiment, the invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof. body, among which,

X is -N(R)- or -CH(R*)-;

Wherein R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R* is selected from -(CH ₂ ) _0-1 -NH ₂ or -(CH ₂ ) _0-1 -OH;

R ₁ and R ₂ are independently selected from H or -(CR _c R _d ) _m -R';

R ₃ and R ₄ are independently selected from H or -(CR _c R _d ) _m -R”;

R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group;

p=0, 1 or 2;

q=0, 1 or 2;

where R _c is H;

R _d is H;

R' is selected from H, halogen or -OH;

R” is selected from H, halogen, -OH, -NH ₂ or -CN;

m=0, 1, 2, 3, 4, 5 or 6.

In a more specific embodiment, the invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotopic variant thereof :

in,

R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d )-R';

R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -CN;

p=0, 1, 2 or 3;

q=0, 1, 2 or 3;

Where R _c is selected from H or halogen;

R _d is selected from H or halogen;

R' is selected from H, halogen, -OH, -SH, -NH ₂ or -CN;

m=1 or 2.

In a more specific embodiment, the present invention provides the compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotopic variant thereof. body, among which,

R ₁ and R ₂ are independently selected from H or -(CR _c R _d )-R';

R ₃ and R ₄ are independently selected from H or -(CR _c R _d )-CN;

p=1 or 2;

q=1 or 2;

where R _c is H;

R _d is H;

R' is selected from H or -OH.

In a more specific embodiment, the invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotopic variant thereof :

in,

One of R ₁ and R ₂ is -(CR _c R _d )-R', and the other is selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d )-R';

R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d )-R”;

R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

p=0, 1, 2 or 3;

q=0, 1, 2 or 3;

Wherein R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R' is selected from H, halogen, -OH, -SH, -NH ₂ or -CN;

R" is selected from halogen, -OH, -SH, _-NH2 or -CN.

In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate or isotopic variant thereof. body, among which,

One of R ₁ and R ₂ is -(CR _c R _d )-R', and the other is H;

R ₃ and R ₄ are independently selected from H or -(CR _c R _d )-R”;

R is selected from H, C _1-2 alkyl or C _1-2 haloalkyl;

p=1 or 2;

q=1 or 2;

where R _c is H;

R _d is H;

R' is selected from H or -OH;

R” is -CN.

In a more specific embodiment, the invention provides compounds of formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, enantiomers, diastereoisomers thereof body, solvate, hydrate or isotopic variant:

in,

Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ and R ₂ are independently selected from H or -(CR _c R _d ) _m -R', the remaining R ₃ and R ₄ are independently selected from H or -(CR _c R _d ) _m -R”;

R is H, C _1-6 alkyl or C _1-6 haloalkyl;

wherein R _a is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _b is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R' is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl;

R” is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl;

n=0, 1, 2, 3 or 4;

m=0, 1, 2 or 3.

In a more specific embodiment, the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, enantiomers, diastereomers thereof conformation, solvate, hydrate or isotopic variant, where,

Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ is H, halogen, -CN, -OH or -NH ₂ respectively;

R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

wherein R _a is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _b is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

n=0, 1, 2, 3 or 4.

In a more specific embodiment, the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, enantiomers, diastereomers thereof conformation, solvate, hydrate or isotopic variant, where,

Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ is H;

R is selected from H, C _1-2 alkyl or C _1-2 haloalkyl;

where R _a is H;

R _b is H;

n=1, 2 or 3.

In a more specific embodiment, the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, enantiomers, diastereomers thereof conformation, solvate, hydrate or isotopic variant, where,

Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ and R ₂ are independently selected from H or -(CR _c R _d ) _m -R', the remaining R ₃ and R ₄ are independently selected from H or -(CR _c R _d ) _m -R”;

R is H;

wherein R _a is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _b is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl;

R' is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl;

R” is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl;

m=0, 1, 2 or 3;

n=2, 3 or 4.

In a more specific embodiment, the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, enantiomers, diastereomers thereof conformation, solvate, hydrate or isotopic variant, where,

Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ are independently selected from H, halogen, -CN, -OH or -NH ₂ ;

R is H;

wherein R _a is selected from H, halogen or C _1-4 alkyl;

R _b is selected from H, halogen or C _1-4 alkyl;

n=2, 3 or 4.

In a more specific embodiment, the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, enantiomers, diastereomers thereof conformation, solvate, hydrate or isotopic variant, where,

Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ is H;

R is H;

where R _a is H;

R _b is H;

n=2 or 3.

In a more specific embodiment, the invention provides the following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, wherein said The compounds mentioned above are selected from:

The compounds of the present invention may contain one or more asymmetric centers and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Included are racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by Prepared by asymmetric synthesis.

Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate." This invention encompasses all solvates of the compounds of the invention.

The term "solvate" refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolating, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methoxides.

The term "hydrate" refers to a compound combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound may be represented, for example, by the general formula _R.xH2O , where R is the compound and x is a number greater than zero. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R·0.5H ₂ O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R·2 H ₂ O) and hexahydrate (R·6 H ₂ O)).

The compounds of the invention may be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), except that one or more atoms are surrounded by atoms having an atomic mass or mass number different from that common in nature. replaced. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ respectively. O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the invention containing the above-mentioned isotopes and/or other isotopes of other atoms, prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes (eg, ³ H and ¹⁴ C), may be used in drug and/or substrate tissue distribution assays. Tritium, ie ³ H, and carbon-14, ie ¹⁴ C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes, such as deuterium, i.e. ² H, may be preferred in some cases as greater metabolic stability may provide therapeutic benefits, such as increased half-life in vivo or reduced dosage requirements. The isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotopes with readily available isotope-labeled reagents when performing the following processes and/or the processes disclosed in the Examples and Preparation Examples. Labeled reagents.

Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced This article serves as a reference.

A prodrug is any covalently bonded compound of the invention that releases the parent compound in the body when administered to a patient. Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved by conventional manipulations or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino or thiol group is bonded to any group that can be cleaved to form a hydroxyl, amino or thiol group when administered to a patient. Accordingly, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxyl, thiol and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, etc. can be used. The ester itself may be reactive and/or hydrolyzable under human body conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily break down in the human body to release the parent acid or salt thereof.

The present invention also provides pharmaceutical preparations, comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.

Pharmaceutical compositions and kits

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of the invention. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical compositions comprise a prophylactically effective amount of a compound of the invention.

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds with which they are formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols, and lanolin.

The present invention also includes kits (eg, pharmaceutical packaging). Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packaging or other) containing the compounds of the invention, other therapeutic agents. suitable container). In some embodiments, provided kits may also optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.

Give medication

The pharmaceutical composition provided by the present invention can be administered through many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration drugs, administered via implants or other methods of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal membrane drug administration, intralesional drug administration, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .

When used to prevent a condition described herein, a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice of and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or those who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.

The pharmaceutical compositions provided herein can also be administered over a long period of time ("chronic administration"). Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may be continued indefinitely, For example, the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, a pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic levels of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, whereas a bolus dose delivered directly into the vein (e.g., via an IV drip) ) can be delivered more quickly, allowing the concentration of active ingredients in the blood to quickly increase to effective levels. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions, or bulk powders. More typically, however, the compositions are provided in unit dosage form to facilitate precise dosing. The term "dosage unit form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material in association with a suitable pharmaceutical excipient suitable to produce the desired therapeutic effect. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.

For oral dosing, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.

In order to provide similar blood levels, or lower blood levels than with injectable doses, a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

Injectable dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially from 24 to 96 hours. To achieve adequate steady state levels, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds of similar nature: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricant, for example, magnesium stearate; glidant, for example, colloidal silicon dioxide; sweetener, for example, sucrose or saccharin; or flavoring agent, for example, mint, water Methyl glycolate or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As stated previously, in such compositions the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredients. When formulated as an ointment, the active ingredients are typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and often include other ingredients to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by this invention.

The compounds of the present invention may also be administered via transdermal devices. Thus, transdermal administration may be achieved using reservoir or porous membrane types, or a variety of solid matrix patches.

The foregoing components of compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which document is incorporated herein by reference.

The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation includes water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units respectively, optionally including a or multiple substituents including, but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).

drug combination

Many chemotherapeutic agents currently known in the art can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, Antihormones, angiogenesis inhibitors, and antiandrogens.

Example

The starting materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art.

Synthesis of intermediate 1-bromo-8-methylnaphthalene

Dissolve compound 1,8-dibromonaphthalene (1g, 3.5mmol) in 20mL tetrahydrofuran, add 2.6mL 1.6M methyllithium ether solution, and react at 0°C for 30min under nitrogen protection. Then slowly add 1 mL of methyl iodide dropwise, and react at room temperature for 3 hours. The reaction mixture was then quenched with ice water and extracted twice with petroleum ether. The organic phase was dried and purified by silica gel column separation (eluent: petroleum ether) to obtain compound 1-bromo-8-methylnaphthalene (386 mg, 50 % yield).

Synthesis of intermediate compound 7

Step 1: Dissolve metallic sodium (23 mg, 1 mmol) in 2 mL of anhydrous methanol, react at room temperature for 15 min, and then slowly add the sodium methoxide solution to the tetrahydrofuran solution of raw material 1 (purchased from Shanghai Zhuoyin Biotechnology Co., Ltd., 294 mg, 1 mmol) (5mL), react at room temperature for 2h. Then saturated NH ₄ Cl was added for quenching, and extracted twice with ethyl acetate. The organic phase was dried and purified by silica gel column separation (eluent: petroleum ether: ethyl acetate = 5:1) to obtain compound 2 (260 mg, 90% yield).

Step 2: Add sodium hydride (80 mg, 60% purity, 2 mmol) to anhydrous tetrahydrofuran, and add N-methyl-L-prolinol (230 mg, 2 mmol) dropwise under nitrogen protection at 0°C. After stirring for 30 min, compound 2 (290 mg, 1 mmol) was added dropwise. After the temperature was raised to room temperature, it was heated to 70°C for 12 hours. Then slowly add 1 mL of NH ₄ Cl saturated solution dropwise at 0°C. After stirring for 15 min, add 20 mL of NaHCO ₃ saturated solution, extract twice with ethyl acetate, concentrate the organic phase, and separate through a silica gel column (eluent: dichloride Methane: methanol = 10:1) was purified to obtain compound 3 (294 mg, 80% yield).

Step 3: Dissolve compound 3 (368 mg, 1 mmol) in 10 mL methanol, add 30 mg Pd/C, and react under H ₂ and 40°C for 12 h. Pd/C was removed by filtration, the organic phase was concentrated, and purified through silica gel column separation (dichloromethane:methanol=5:1) to obtain compound 4 (250 mg, 90% yield).

Step 4: Dissolve Pd ₂ (dba) ₃ (137 mg, 0.15 mmol) and BINAP (187 mg, 0.3 mmol) in 4 mL of toluene, react under nitrogen protection at 100°C for 30 min, and then cool to room temperature. Compound 4 (278 mg, 1 mmol), 1-bromo-8-methylnaphthalene (331 mg, 1.5 mmol) and sodium tert-butoxide (240 mg, 2.5 mmol) were first dissolved in 10 mL of toluene. Under nitrogen protection, the catalyst and The ligand solution was reacted at 100°C for 18 hours. Then cool to room temperature, add 40 mL of water, extract twice with ethyl acetate, concentrate the organic phase, and purify through silica gel column separation (eluent: dichloromethane: methanol = 15:1) to obtain compound 5 (293 mg, 70% yield) Rate).

Step 5: Add sodium hydride (80 mg, 60% purity, 2 mmol) into 4 mL of anhydrous DMF, slowly add ethyl mercaptan (124 mg, 2 mmol) dropwise at 0°C, and after reacting for 30 min, add compound 5 (418 mg, 1 mmol) dropwise. ) in 5mL DMF solution. Then the temperature was raised to 60°C for 1 h, and then 1 mL of NH ₄ Cl saturated solution was slowly added dropwise at 0°C. After the reaction was stirred for 15 minutes, 20 mL of water was added to the mixture for quenching, and then extracted once with ethyl acetate and dichloromethane respectively. The organic phases were combined, and an appropriate amount of anhydrous magnesium sulfate was added for drying. The solution was then filtered and concentrated, and the crude product was purified by silica gel column separation (eluent: dichloromethane: methanol = 10:1) to obtain compound 6 (384 mg, 95% yield).

Step 6: Dissolve compound 6 (404 mg, 1 mmol) in 20 mL anhydrous dichloromethane, add N-phenylbis(trifluoromethanesulfonyl)imide (428 mg, 1.2 mmol) and cesium carbonate (423 mg, 1.3 mmol) ), reacted at room temperature for 2 hours under nitrogen protection. Then, the solid was removed by filtration, and the organic phase was concentrated and purified through silica gel column separation (petroleum ether: ethyl acetate = 2:1) to obtain compound 7 (428 mg, 80% yield).

Synthesis of intermediate compound 12

Step 1: Dissolve compound 8 (9.8g, 146mmol) in a mixed solution of tBuOH/PE (15mL/57.5mL), then dissolve 23.3g Br ₂ in 15mL tBuOH, and slowly add it dropwise to the above mixed solution, 15 React at ℃ for 30 minutes to obtain intermediate 9.

Step 2: Dissolve metallic sodium (3.36g, 146mmol) in 85 mL of EtOH, slowly drop it into the reaction mixture of Intermediate 9, and react at 15°C for 2 hours. The mixture was quenched by adding water, and extracted twice with ethyl acetate. The organic phase was concentrated and purified through column to obtain compound 10 (10.6 g, 50%).

Step 3: Dissolve N,N-dibenzylethylenediamine (5.75g, 24mmol) in 50mL toluene, add 4.85g triethylamine, and then add compound 10 dropwise at 0°C, then return to room temperature, and react for 12h. After filtration, the solvent was removed, and compound 11 (3.2 g, 45%) was obtained through column purification.

Step 4: Dissolve compound 11 (1.64g, 5.36mmo) in 15mL DCE, add 1-chloroethyl chloroformate (3.06g, 21.4mmol) dropwise at 0°C, then raise the temperature to 84°C, and react for 2 days. Then add 15 mL of methanol and react at 65°C for 1 hour. After the solvent was removed by rotary evaporation under negative pressure, the solid was washed with methyl tert-butyl ether and filtered to obtain compound 12 (0.6 g, 56%).

Synthesis of Examples 1-38

Compounds of the invention were synthesized using the following reaction scheme. For the compounds TH-Z 808, TH-Z 814, TH-Z 815, TH-Z 830, TH-Z 831 and TH-Z 832, intermediate compound 7 was used as the starting material, and the final compound was obtained after one step of reaction. product. Other compounds also need to undergo a one-step reaction to remove the protecting group to obtain the final product.

The general synthesis steps are as follows:

Step 1: Dissolve compound 7 (536 mg, 1 mmol) in 5 ml anhydrous DMF, add DIPEA (258 mg, 2 mmol), and various N-Boc protected amine fragments or amine fragments without N-Boc protection (1.05 mmol) , react under nitrogen protection and 100°C for 1 to 10 hours. After cooling, add 20 mL of water, extract twice with ethyl acetate, concentrate the organic phase, and purify through column to obtain the N-Boc protected compound and the target compound without N-Boc protection (30-90% yield).

Step 2: Dissolve the N-Boc protected compound (1 mmol) in 2 mL of methylene chloride, add 1 mL of trifluoroacetic acid, and react at room temperature for 1 hour. Add 10 mL of Na ₂ CO ₃ saturated solution, extract twice with dichloromethane, concentrate the organic phase, and purify through column to obtain the target compound (80% yield).

Bioactivity testing

KRAS protein expression and purification

(1)Protein expression and sample processing

Transfer the plasmid containing the target gene (KRAS4b G12D, with His tag, truncated sequence 1-169) into BL21 (DE3) competent E.coli, and transfer it to LB medium containing ampicillin resistance. Cultivate at 37°C and 220rpm. When the OD 600nm of the bacterial solution is approximately 0.6, cool down to 16°C, add 0.5mM IPTG (isopropyl-β-D-thiogalactopyranoside) to the large bottle culture medium, and culture at 16°C and 220 rpm for about 24 hours. . Centrifuge the fermentation broth at 4°C and 6000g for 10 min, and discard the supernatant. Resuspend the bacterial cells in Buffer A (25mM Tris, 150mM NaCl, 10mM imidazole, pH 8.5). The resuspended bacterial solution was crushed in a high-pressure homogenizer at 4°C, and then centrifuged at high speed at 16,000g for 1 hour at 4°C. The supernatant was taken, and the sample was filtered with a filter membrane with a pore size of 0.22 μm.

(2) Affinity chromatography separation

First use 0.1M NiSO ₄ to regenerate the Ni-NTA column, balance with Buffer A to wash away excess Ni ions, and start loading the sample after the column is balanced, with a flow rate of 3 mL/min. After loading, use Buffer A to wash away unbound proteins and impurities until the A280 value returns to a stable baseline. Use a linear elution strategy to add Buffer A and Buffer B (25mM Tris, 150mM NaCl, 500mM imidazole, pH 8.5) Mix and collect 6 mL of eluate in each tube for protein electrophoresis analysis.

(3) Tev enzyme digestion and secondary affinity chromatography separation

Add an appropriate amount of Tev enzyme to the eluate containing KRAS G12D to cleave the N segment of thioredoxin containing His tag, and dialyze it in Buffer C (25mM Tris, 150mM NaCl, pH 8.5). Pass through the Ni-NTA column for the second time. Since the Tev enzyme has cleaved the thioredoxin containing the His tag, the target protein cannot bind to the affinity chromatography column. Therefore, when passing through the Ni column for the second time, the unbound fraction is collected. The eluate was analyzed by protein electrophoresis.

(4)Concentration, purity and concentration testing of KRAS G12D

The protein sample buffer contains 25mM Tris, pH 8.5 and 150mM NaCl. First try two kits, Crystal Screen I and Crystal Screen II, to spot crystals to observe the ratio of precipitation, determine the protein concentration to 40mg/mL, and conduct electrophoresis on the concentrated protein. Analyze to verify purity.

(5) Preliminary screening and optimization of crystallization conditions for KRAS G12D protein

Crystals were grown on a 96-well plate using the sitting drop vapor diffusion method in a constant temperature incubation room at a constant temperature of 22°C. All more than 1,000 conditions were initially screened and observed every two days to see if crystals had grown and relevant records were made. It was found that the crystallization conditions of KRAS G12D are 0.2M sodium acetate, 0.1M Tris, pH 8.5, 26% (w/v) PEG 3350. Related reagents were prepared and the crystallization condition concentration and protein concentration were optimized.

(6) Collection and data processing of diffraction data of KRAS G12D

Collect X-ray diffraction data of regular-shaped KRAS G12D crystals. The crystals are immersed in compound TH Z 816 with a concentration of 2mM for 6 hours, then dipped in antifreeze. Add 10% glycerol to the crystallization conditions, perform X-ray diffraction and Collect data and process it with HKL2000 and other related software.

SOS ^cat- catalyzed nucleotide exchange experiment

Different concentrations of compounds (final DMSO concentration 4%) were mixed with reaction buffer (40mM HEPES-KOH, 10mM MgCl ₂ , 1mM DTT, pH 8.5) in black flat-bottomed 96-well plates (Corning, #3686), followed by Add KRAS G12D mantGDP (2′/3′-O-(N-methylanthranilinyl)guanosine 5′-diphosphate), mix and incubate for 10 min. After premixing the SOS ^cat protein and GDP solution, add it to the KRAS protein solution to start the reaction. The total system is 100μL, and the final concentration of each component is KRAS G12D mantGDP 2μM, SOS ^cat 2μM, and GDP 1mM.

TH-Z 835 inhibits the nucleotide substitution experiment of KRAS G12D mantGCP (polypyridone film synthesized by pyromellitic dianhydride and diphenyltetramine) catalyzed by SOS ^cat . The reaction buffer remains unchanged, the total system is 100μL, and the final concentration of each component is KRAS G12C mantGCP 3μM, SOS ^cat 4μM, GCP 2mM, and TH-Z 835500μM.

Nucleotide replacement experiments for TH-Z 835 inhibiting SOS ^cat -catalyzed KRAS G12D GCP. The reaction buffer remains unchanged, the total system is 100 μL, and the final concentration of each component is KRAS G12C GCP 3 μM, SOS ^cat 2 μM, mantGCP 4 μM, and TH-Z 835 500 μM.

After the reaction was started, the fluorescence value was read with a microplate reader (PerkinElmer, EnVision) (excitation wavelength 355nm, emission wavelength 460nm, reading every 30s, continuous reading for 1h). The obtained kinetic data were fitted using the One phase decay equation or One phase association in GraphPad Prism 7.0 software, the rate k value was calculated, and plotted corresponding to the compound concentration gradient to obtain the IC ₅₀ curve.

The experimental results are shown in the following table:

Killing of KRAS G12D mutated tumor cells by the compound of the present invention

We tested the killing effect of three representative compounds on pancreatic cancer-derived PANC-1 cells and Panc 04.03 cells, as well as p53.2.1.1 cells. Both cells are heterozygous for the KRAS gene, meaning that only one allele is the G12D mutation.

PANC-1, Panc 04.03 and p53.2.1.1 cells were purchased from ATCC (American Type Culture Collection). In a 96-well plate (Nest, #701001), 5000 cells (PANC-1 or Panc 04.03) were seeded in each well in DMEM (10% fetal calf serum, 1% penicillin/streptomycin). After the cells were plated, they were cultured in the incubator for 24 hours, and then different concentrations of drugs were added to continue culturing for 24 hours. Then CCK-8 reagent (Beyotime, C0042) was added and incubated for 1 hour. Use a microplate reader to measure the absorbance value at 450nm. The data was fitted using the [Inhibitor] vs. response --Variable slope (four parameters) model in GraphPad Prism 7.0 software, and the IC ₅₀ value was calculated.

Killing effects of two KRAS G12D inhibitors on three types of cells

Crystal structure analysis of TH-Z 816

We tried to conduct crystallographic experiments on TH-Z 816 and KRAS G12D protein in order to study the structure-activity relationship of the compounds.

We used the soaking method to obtain complex crystals of small molecules and KRAS G12D protein (Figure 1) and analyzed them. Observing the crystal structure at the binding site, it can be found that TH-Z 816 binds in the pocket formed under switch II (RAS protein residues 60-76), that is, switch II pocket (SIIP). This is an allosteric site adjacent to the binding site for guanylate (GDP or GTP). Displaying the electron cloud density (2F _o -F _c , 1σ) near the compound, you can see that it completely covers the small molecule skeleton. We aligned the crystal of KRAS G12D-TH-Z 816 with the crystal of KRAS G12C-MRTX849 (PDB: 6UT0). We can find that the overall conformation of the two proteins is very similar, and the RMSD of Cα is

Analyzing the binding mode of TH-Z 168 and KRAS G12D protein, it can be found that there are four groups of polar interactions: the salt bridge formed by the carboxyl group of Asp 12 and the secondary amine at the piperazine terminal; the O atom of the main chain of Gly 60 and the piperazine terminal The hydrogen bond formed by the N atom at the end of the azine; the electrostatic attraction between the carboxyl group of Glu 62 and the positively charged N-methylpyrrolidine in the side chain; the N atom of His 95 and the N atom of the core skeleton pyrimidine ring. of hydrogen bonds. Nonpolar interactions mainly include hydrophobic interactions between small molecules and surrounding residues (Figure 2).

It is worth noting that these polar interactions are directional, especially the hydrogen bonds and salt bridge interactions formed by the N atom at the end of the piperazine and the surrounding amino acids, which have strong directionality, so for better activity For small molecules, the positions of the N atoms at both ends of piperazine are relatively fixed, and its conformation (TH-Z 816-position twisted boat) and the angle with the pyrimidine ring have certain restrictions.

Figure 3 shows the spatial characteristics of the binding pocket: the spatial characteristics of the binding pocket around the piperazine ring are that the upper space is smaller, while the lower space is larger, the proximal space is larger, and the distal space is smaller, so the piperazine ring The methyl group on it points downward.

The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be concluded that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, and all of them should be regarded as belonging to the protection scope of the present invention.

Claims (27)

Compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof: in, X is -N(R)- or -CH(R*)-; Wherein R is selected from H, -(CH ₂ ) _1-3 -halogen, -(CH ₂ ) _1-3 -OH, -(CH ₂ ) _1-3 -CN, -(CH ₂ ) _{1- 3} -NH ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R* is selected from -(CH ₂ ) _0-3 -halogen, -(CH ₂ ) _0-3 -OH, -(CH ₂ ) _0-3 -CN or -(CH ₂ ) _0-3 -NH ₂ ; Y is N or CH; Y ₁ is CR _Y1a R _Y1b ; Y ₂ is CR _Y2a R _Y2b ; Y ₃ is CR _Y3a R _Y3b or NR _Y3c ; r=1 or 2; s=0 or 1; Wherein R _Y1a , R _Y1b , R _Y2a , R _Y2b , R _Y3a and R _Y3b are independently selected from H, halogen, _{C 1-6 alkyl or C 1-6 haloalkyl ;} R _Y3c is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; Or a double bond can be formed between Y ₃ and the adjacent Y ₂ ; R _A is selected from H, C _6-10 aryl or 5-14 membered heteroaryl, which is optionally substituted by 1, 2, 3 or 4 R _A1 ; Wherein each R _{A1 is} independently selected from _{H ,} halogen _{, -CN , -OR} C _2-6 alkynyl; L is selected from chemical bond, -O-, -S- or -NH-; _{R B is} selected _{from H} , _{halogen , -CN} , _-OR Alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; which is optionally substituted by 1, 2, 3 or 4 R#; Wherein R# is selected from H, -C _0-6 alkylene-halogen, -C _0-6 alkylene-CN, C _{1-6 alkyl, C 1-6 haloalkyl} , C _2-6 alkenyl, _{C 2-6 alkynyl , -C 0-6} alkylene -OR _X , -C _0-6 alkylene _-SR Alkylene _{- C} (O) _RX , _{-C 0-6 alkylene} -C( _O ) _{OR 6} -alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-3-10-membered heterocyclyl, -C _0-6 alkylene-C _6-10 aryl or -C _{0- 6} alkylene-5-14 membered heteroaryl; and R# is optionally replaced by halogen, -OH, -OC _1-6 alkyl, -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , C _1-6 alkyl or C _1-6 haloalkyl substitution _{; Wherein R _ _ _} R _Y and R _Z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _Y and _{R Z} and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclic groups; R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R'; R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R”; R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group; Or any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -; p=0, 1, 2 or 3; q=0, 1, 2 or 3; Wherein R _a is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R _b is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R _c is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R _d is selected from H, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R' is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e , -C(O)NR _f R _g , C _{2- 6} alkenyl or C _2-6 alkynyl; R” is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e , -C(O)NR _f R _g , C _{2- 6} alkenyl or C _2-6 alkynyl; m=0, 1, 2, 3, 4, 5 or 6; n=0, 1, 2, 3, 4, 5 or 6; Wherein R _e is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R _f and R _g are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _f and R _g and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclyl groups. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, in Selected from the following mother cores: A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, where R _A is selected from the following groups: The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, Where -LR _B is selected from H, The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , X is -N(R)-, and wherein R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl, X is preferably -NH-. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , R ₁ or R ₂ is selected from H, halogen, -OH, -NH ₂ , -CN, -CH ₃ or -CH ₂ -OH, preferably -CH ₃ or -CH ₂ -OH; preferably, R ₁ and R One of ₂ is -CH ₃ or -CH ₂ -OH; preferably, one of R ₁ and R ₂ is -CH ₃ or -CH ₂ -OH in R configuration. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ - , preferably -CH ₂ CH ₂ - or -CH ₂ CH ₂ CH ₂ -. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein , R ₃ and R ₄ are independently selected from H, -CH ₂ -Cl, -CH ₂ -F, -CH ₂ -CN, -CH ₂ CH 2 -Cl, -CH _{2 CH 2 -F} , -CH ₂ CH ₂ -CN, preferably H or _-CH2 -CN. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, Has the following structure: Wherein, each group is as defined in any one of claims 1-8. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof: in, X is -N(R)- or -CH(R*)-; Wherein R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; R* is selected from -(CH ₂ ) _0-3 -NH ₂ or -(CH ₂ ) _0-3 -OH; R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R'; R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -R”; R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group; p=0, 1, 2 or 3; q=0, 1, 2 or 3; Wherein R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R' is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e or -C(O)NR _e R _f ; R” is selected from H, halogen, -OH, -SH, -NH ₂ , -CN, -C(O)R _e , -C(O)OR _e or -C(O)NR _e R _f ; m=0, 1, 2, 3, 4, 5 or 6; Wherein R _e is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R _f and R _g are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl, or R _f and R _g and the nitrogen to which they are attached. Atoms form 3-10 membered heterocyclyl groups. The compound of formula (II) of claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein, X is -N(R)- or -CH(R*)-; Wherein R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; R* is selected from -(CH ₂ ) _0-1 -NH ₂ or -(CH ₂ ) _0-1 -OH; R ₁ and R ₂ are independently selected from H or -(CR _c R _d ) _m -R'; R ₃ and R ₄ are independently selected from H or -(CR _c R _d ) _m -R”; R _2' is H, or R ₂ and R _2' together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl group; p=0, 1 or 2; q=0, 1 or 2; where R _c is H; R _d is H; R' is selected from H, halogen or -OH; R” is selected from H, halogen, -OH, -NH ₂ or -CN; m=0, 1, 2, 3, 4, 5 or 6. The compound of formula (III) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof: in, R ₁ and R ₂ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d )-R'; R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d ) _m -CN; p=0, 1, 2 or 3; q=0, 1, 2 or 3; Where R _c is selected from H or halogen; R _d is selected from H or halogen; R' is selected from H, halogen, -OH, -SH, -NH ₂ or -CN; m=1 or 2. The compound of formula (III) of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein, R ₁ and R ₂ are independently selected from H or -(CR _c R _d )-R'; R ₃ and R ₄ are independently selected from H or -(CR _c R _d )-CN; p=1 or 2; q=1 or 2; where R _c is H; R _d is H; R' is selected from H or -OH. The compound of formula (IV) according to claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof: in, One of R ₁ and R ₂ is -(CR _c R _d )-R', and the other is selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d )-R'; R ₃ and R ₄ are independently selected from H, halogen, -OH, -NH ₂ , -CN or -(CR _c R _d )-R”; R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; p=0, 1, 2 or 3; q=0, 1, 2 or 3; Wherein R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R' is selected from H, halogen, -OH, -SH, -NH ₂ or -CN; R" is selected from halogen, -OH, -SH, _-NH2 or -CN. The compound of formula (IV) of claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein, One of R ₁ and R ₂ is -(CR _c R _d )-R', and the other is H; R ₃ and R ₄ are independently selected from H or -(CR _c R _d )-R”; R is selected from H, C _1-2 alkyl or C _1-2 haloalkyl; p=1 or 2; q=1 or 2; where R _c is H; R _d is H; R' is selected from H or -OH; R” is -CN. The compound of formula (V), (V-1) or (V-2) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or hydrate thereof or isotopic variants: in, Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ and R ₂ are independently selected from H or -(CR _c R _d ) _m -R', the remaining R ₃ and R ₄ are independently selected from H or -(CR _c R _d ) _m -R”; R is H, C _1-6 alkyl or C _1-6 haloalkyl; wherein R _a is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _b is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R' is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl; R” is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl; n=0, 1, 2, 3 or 4; m=0, 1, 2 or 3. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or hydrate thereof or isotopic variants, where, Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ is H, halogen, -CN, -OH or -NH ₂ respectively; R is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; wherein R _a is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _b is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; n=0, 1, 2, 3 or 4. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or hydrate thereof or isotopic variants, where, Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ is H; R is selected from H, C _1-2 alkyl or C _1-2 haloalkyl; where R _a is H; R _b is H; n=1, 2 or 3. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or hydrate thereof or isotopic variants, where, Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ and R ₂ are independently selected from H or -(CR _c R _d ) _m -R', the remaining R ₃ and R ₄ are independently selected from H or -(CR _c R _d ) _m -R”; R is H; wherein R _a is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _b is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _c is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R _d is selected from H, halogen, C _1-4 alkyl or C _1-4 haloalkyl; R' is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl; R” is selected from H, halogen, -CN, -OH, -NH ₂ , C _2-4 alkenyl or C _2-4 alkynyl; m=0, 1, 2 or 3; n=2, 3 or 4. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or hydrate thereof or isotopic variants, where, Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ are independently selected from H, halogen, -CN, -OH or -NH ₂ ; R is H; wherein R _a is selected from H, halogen or C _1-4 alkyl; R _b is selected from H, halogen or C _1-4 alkyl; n=2, 3 or 4. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or hydrate thereof or isotopic variants, where, Any group of R ₁ and R ₂ , R ₃ and R ₄ , R ₁ and R ₄ , R ₂ and R ₃ are connected to form -(CR _a R _b ) _n -, and the remaining R ₁ , R ₂ , R ₃ or R ₄ is H; R is H; where R _a is H; R _b is H; n=2 or 3. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein the compound is selected from: Pharmaceutical compositions containing a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof , and pharmaceutically acceptable excipients; preferably, it also contains other therapeutic agents. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof in the preparation for use in the treatment and/or or use in drugs to prevent diseases mediated by KRAS G12D mutant protein. A method of treating and/or preventing KRAS G12D mutant protein-mediated diseases in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 22 or a pharmaceutical agent thereof. Acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants or the pharmaceutical composition of claim 23. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof or the pharmaceutical combination of claim 23 Drugs for the treatment and/or prevention of diseases mediated by KRAS G12D mutant protein. The use of claim 24 or the method of claim 25 or the use of a compound or composition of claim 26, wherein the disease mediated by the KRAS G12D mutein is selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia, juvenile cancer , childhood adrenocortical cancer, AIDS-related cancers (such as lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone Carcinoma, brainstem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, Childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma , extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cells Tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, Heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS) , lung cancer, lymphoma, metastatic squamous neck cancer with occult primary site, midline tract cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myeloid dysplasia syndrome Myelodysplasia/myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma tumour, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, thyroid cancer Paraadenocarcinoma, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cellular lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, rare diseases in children Cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.