Compounds as PKMYT1 inhibitors

Abstract

The invention provides a compound. Specifically, the invention provides a compound with a structure as shown in a formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate of the compound. The compound can effectively inhibit PKMYT1, and is used for treating or preventing diseases or symptoms related to the activity or expression quantity of PKMYT1. # imgabs0 #

Description

Compounds that act as PKMYT1 inhibitors Technical Field

[0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel compound, a synthesis method thereof and its use as a PKMYT1 inhibitor in the preparation of drugs for treating various diseases such as tumors. Background Art

[0002] In cancer cells, amplification of the CCNE1 gene is a hallmark of difficult-to-treat ovarian, endometrial, and gastroesophageal cancers. CCNE1, located on chromosome 9q12, encodes Cyclin E1, a cyclin protein that forms a complex with CDK2 to promote cell progression from G1 to S phase. CCNE1 amplification and dysregulation of Cyclin E1 promote premature S phase entry, leading to replication stress and DNA damage. When p53 is inactivated, cells enter division carrying unrepaired DNA damage, causing genomic instability.

[0003] CDK1 forms a complex with the cyclin B protein, promoting cell entry into the M phase. PKMYT1 (Protein kinase, membrane associated tyrosine / threonine 1) can phosphorylate CDK1. PKMYT1 is a serine-threonine kinase belonging to the WEE1 family. It inhibits CDK1 function by phosphorylating it at threonine 14. In an unperturbed cell cycle, PKMYT1 function is not essential. However, in certain tumor types, such as those with CCNE1 amplification and dysregulation of Cyclin E1, loss of PKMYT1 function leads to overactivation of CDK1, uncontrolled mitosis, catastrophic DNA damage, and ultimately cell death. Therefore, loss of PKMYT1 and CCNE1 amplification constitute a synthetic lethal relationship.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a new type of PKMYT1 inhibitor.

[0006] The first aspect of the present invention provides a compound having a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0007] In formula (I):

[0008] X is selected from N or CRa ; Among them, R a Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkynyl, or C 3-6 Cycloalkyl;

[0009] R 1 Selected from hydrogen or NR b R b ; Among them, each R b are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 Cycloalkyl; or two R b Together with the nitrogen atom to which it is attached, it forms a 3- to 6-membered ring structure;

[0010] R 2 Selected from C(O)NHR c or C(O)R g ; Among them, R c Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 Cycloalkyl; R g Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl;

[0011] Each R 3 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, hydroxyl, or C 1-4 alkoxy;

[0012] R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, C 3-6 Cycloalkyl C 2-4 Alkynyl, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic group C 1-4Alkyl, 3- to 6-membered heterocyclic group C 2-4 Alkynyl, aryl, heteroaryl, OR f SR f NR d R d , CN, or formula (Ia):

[0013] represents the site where the fragment of formula (Ia) is connected to the rest of the structure of formula (I);

[0014] The prerequisite is R 4 and R 5 At least one of them is selected from formula (Ia);

[0015] or R 4 and R 5 Together with the carbon atom to which it is attached, it forms a 4- to 8-membered ring structure, which is substituted with =M;

[0016] Z is selected from N or CR e ; Among them, R e Selected from hydrogen, halogen, or C 1-4 alkyl;

[0017] M is selected from CR h R i ; Among them, R h and R i are each independently selected from hydrogen, halogen, or C 1-4 Alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d 、OC(O)NR d R d NR d C(O)OR f 、OC(O)OR f 、S(O)2NR d R d NRd S(O)2R g NR d S(O)2NR d R d ; or R h and R i Together with the carbon atom to which it is attached, it forms a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S;

[0018] The above R d are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R f are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R g are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl;

[0019] R 6 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, or CN;

[0020] m and n are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

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

[0022] Each q independently selects 0, 1, 2, 3, or 4;

[0023] wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic structure, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR f SR f NRd R d 、C(O)R g 、C(O)OR f 、C(O)NR d R d NR d C(O)R g NR d S(O)2R g , or S(O)2R g , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R d 、R f 、R g The definition of is as above;

[0024] Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

[0025] In another preferred embodiment, the formula (I) is formula (IIa), formula (IIb), or formula (IIc):

[0026] The definitions of the groups in formula (IIa), (IIb) or (IIc) are as described above.

[0027] In another preferred embodiment, the formula (I) is formula (III):

[0028] Each R 3 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0029] The remaining groups in formula (III) are as defined above.

[0030] In another preferred embodiment, the formula (I) is formula (IV):

[0031] X is selected from N or CR a ; Among them, R a Selected from hydrogen, halogen, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0032] Z is selected from N or CR e ; Among them, R e Selected from hydrogen, halogen, or C 1-4 alkyl;

[0033] R5 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, OR f SR f NR d R d ,CN;

[0034] M is selected from CR h R i ; Among them, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 Alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d 、OC(O)NR d R d NR d C(O)OR f 、OC(O)OR f 、S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or R h and R i Together with the carbon atom to which it is attached, it forms a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S;

[0035] The above R d are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkoxy C 2-4 Alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R f are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R g are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl;

[0036] m and n are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0037] In another preferred embodiment, the formula (I) is formula (V):

[0038] Each R 3 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0039] The remaining groups in formula (V) are as defined above.

[0040] In another preferred embodiment, the formula (I) is formula (VI):

[0041] R 4 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, OR f SR f NR d R d ,CN;

[0042] R d 、R f , and the definitions of the remaining groups in formula (VI) are as described above.

[0043] In another preferred embodiment, the formula (I) is formula (VII):

[0044] The definitions of the groups in formula (VII) are as described above.

[0045] In another preferred embodiment, the formula (I) is formula (VIII):

[0046] The definitions of the groups in formula (VIII) are as described above.

[0047] In another preferred embodiment, in the formula (IV):

[0048] X is selected from N or CH;

[0049] Z is selected from N or CH;

[0050] R 5 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, CN;

[0051] M is selected from CR h R i ; Among them, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 Alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g ;

[0052] The above R d are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 haloalkyl; each R f are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R g Each independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl;

[0053] m and n are each independently selected from 1 or 2;

[0054] In another preferred embodiment, in the formula (VI):

[0055] X is selected from N or CH;

[0056] Z is selected from N or CH;

[0057] R 4 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, CN;

[0058] M is selected from CR h R i ; Among them, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 Alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g ;

[0059] The above R d are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 haloalkyl; each R f are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R g Each independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl;

[0060] m and n are each independently selected from 1 or 2;

[0061] In another preferred embodiment, the compound is selected from the following group:

[0062] A is selected from hydrogen, methyl, or chlorine;

[0063] X is selected from N or CH.

[0064] The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

[0065] The third aspect of the present invention provides a use of a compound as described in the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof, for preparing a pharmaceutical composition for treating diseases, disorders, or conditions associated with PKMYT1 activity or expression.

[0066] In another preferred embodiment, the disease, disorder or condition is selected from the following group: breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, pancreatic cancer, prostate cancer, glioma, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B cell lymphoma, T cell lymphoma, monocytic leukemia, hypereosinophilic syndrome, multiple myeloma and other solid tumors and blood tumors. DETAILED DESCRIPTION

[0067] After extensive and in-depth research, the inventors unexpectedly discovered a class of novel PKMYT1 inhibitors, as well as their preparation methods and uses. These compounds can be used to treat various diseases associated with PKMYT1 activity. Based on these discoveries, the inventors completed the present invention.

[0068] the term

[0069] Unless otherwise specified, "or" mentioned in this document has the same meaning as "and / or" (referring to "or" and "and").

[0070] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may be optionally in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0071] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched hydrocarbon groups. 1-10 ), it means that the alkyl group contains 1 to 10 carbon atoms. For example, C 1-8 The alkyl group refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0072] As used herein, the term "alkenyl" when used alone or as part of another substituent refers to a straight or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms in the alkenyl group is limited (e.g., C 2-8 ), it means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0073] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of another substituent. The alkynyl group may be straight-chain or branched, or a combination thereof. 2-8 When the term "alkynyl" is used, it means that the alkynyl contains 2 to 8 carbon atoms. 2-8 The term "alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0074] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated ring, bicyclic or polycyclic (fused, bridged or spiro) ring system group when used alone or as part of another substituent. 3-10 ) refers to a cycloalkyl group containing 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Fused cycloalkyl" refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.

[0075] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.

[0076] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity containing one or more heteroatoms (selectively selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by condensing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur) with an aryl group, wherein the attachment point is located on the aryl group. The heteroaryl group may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.

[0077] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyls refer to heterocyclyls including spirocyclic, fused, and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with the other rings in the system, in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group contains both saturated and aromatic rings (for example, a saturated ring and an aromatic ring are fused together), the point of attachment to the parent group must be on the saturated ring. Note: When the point of attachment to the parent group is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.

[0078] As used herein, the term "halogen," by itself or as part of another substituent, refers to F, Cl, Br, and I.

[0079] As used herein, the term "substituted" (with or without the "arbitrarily" modifier) ​​refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described accordingly in the preceding text, or the substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents are, for example (but not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C2-10 Ester group, amino group.

[0080] For the sake of convenience and in accordance with common understanding, the term "arbitrary substitution" or "optionally substituted" only applies to sites that can be substituted by substituents, and does not include those substitutions that are chemically unfeasible.

[0081] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without producing undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt of the compound of the present invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

[0082] use:

[0083] The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if any), hydrates, pharmaceutically acceptable carriers or excipients for use in inhibiting PKMYT1.

[0084] The compound of the present invention is useful as a PKMYT1 inhibitor.

[0085] The present invention is a single inhibitor of PKMYT1, which prevents, alleviates, or cures diseases by modulating the activity of PKMYT1. These diseases include, but are not limited to, breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, pancreatic cancer, prostate cancer, glioma, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, monocytic leukemia, hypereosinophilic syndrome, multiple myeloma, and other solid tumors and hematological tumors.

[0086] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present), or hydrates thereof, and / or compositions thereof, can be formulated with pharmaceutically acceptable excipients or carriers. The resulting compositions can be administered to mammals, such as men, women, and animals, in vivo for the treatment of conditions, symptoms, and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions, sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, cross-linked sodium carboxymethyl cellulose, complex silicates, and high molecular weight polyethylene glycols), granulation binders (such as polyvinyl pyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound of the present invention or the pharmaceutical composition administered to the patient is not fixed and is usually administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by the physician based on actual conditions, including the condition being treated, the selected route of administration, the actual compound administered, the individual condition of the patient, etc. The dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the patient's condition, and the physician's judgment. The ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration, etc.

[0087] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions.

[0088] Pharmaceutical compositions and methods of administration

[0089] Since the compounds of the present invention have excellent inhibitory activity against PKMYT1, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to PKMYT1 activity or expression.

[0090] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0091] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0092] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0093] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0094] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0095] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0096] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0097] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0098] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0099] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0100] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0101] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0102] The main advantages of the present invention include:

[0103] 1. Provided is a compound as shown in formula I.

[0104] 2. Provided is a novel PKMYT1 inhibitor, as well as its preparation and use. The inhibitor can inhibit the activity of PKMYT1 at extremely low concentrations.

[0105] 3. Provides a PKMYT1 inhibitor with good oral absorption.

[0106] 4. Provides a pharmaceutical composition for treating diseases related to PKMYT1 activity.

[0107] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0108] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structure of the compound of the present invention is disclosed, the above selection can be made by those skilled in the art based on the knowledge in the art.

[0109] abbreviation

[0110] Boc = tert-butyloxycarbonyl

[0111] Et = Ethyl

[0112] Me = methyl

[0113] H2O2=hydrogen peroxide

[0114] L-Methionine=L-methionine

[0115] Ph = phenyl

[0116] TFA = trifluoroacetic acid

[0117] Example 1: Preparation of Compound 1

[0118] Compound 1-a (200 mg, 1.18 mmol) (the synthetic route of compound 1-a is prepared according to the synthetic route of patent WO 2022 / 122044) was dissolved in tetrahydrofuran (10 mL), and cesium carbonate (1.2 g, 3.54 mmol) was added. The mixture was stirred at room temperature for 3 hours and filtered to obtain a tetrahydrofuran solution containing 1-b, which was used directly in the next step.

[0119] Compound 1-c (20 mg, 0.05 mmol) (intermediate 1-c synthesis route reference patent WO 2021 / 195781A1 synthesis route) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (5 mg, 0.01 mmol) were dissolved in tetrahydrofuran (1 mL). Under nitrogen protection, a tetrahydrofuran solution of lithium bistrimethylsilylamide (0.1 mL, 0.1 mmol, 1 M) and a tetrahydrofuran solution of 1-b (13 mg, 0.1 mmol) were added sequentially. The reaction system was heated at 65 ° C for 2 hours, quenched with water, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was concentrated under reduced pressure. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:2) to give a light yellow solid compound 1-d (5.0 mg, yield 22%). MS m / z 442.2 [M+H] + .

[0120] Compound 1-d (4 mg, 0.01 mmol) was dissolved in dichloromethane (1.0 mL) and cooled to -50°C. A dichloromethane solution of boron tribromide (0.1 mL, 0.1 mmol, 1.0 M) was then added. After addition, the reaction mixture was heated to -20°C and stirred for 3 hours. After completion, the reaction was quenched with methanol, followed by addition of an appropriate amount of water. The mixture was extracted with ethyl acetate (3 × 10 mL), and the organic phase was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (ethyl acetate 100%) to afford Compound 1 (2 mg, 51% yield) as a light blue solid. 1 H NMR (500MHz, DMSO-d6) δ9.45(s,1H),7.65(d,J=2.3Hz,1H),7.48(d,J=2.3Hz,1H),7.04(d,J=8.3Hz,1H ),6.94-6.83(m,3H),6.74(s,2H),3.16(t,J=5.6Hz,4H),2.33-2.26(m,4H),1.74(s,3H),1.66(s,3H). MS m / z 428.1[M+H] + .

[0121] Example 2: Preparation of Compound 2

[0122] Dissolve compound 2-a (500 mg, 2.25 mmol) in tetrahydrofuran (20 mL), add cesium carbonate (2199 mg, 6.75 mmol), and stir at room temperature for 3 hours. Filter the mixture to obtain a tetrahydrofuran solution containing 2-b, which is used directly in the next step.

[0123] Compound 2-c (150 mg, 0.32 mmol) (intermediate 2-c synthesis route is prepared according to the synthesis route of patent WO 2021 / 195781A1), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (15 mg, 0.03 mmol) and sodium tert-butoxide (92 mg, 0.96 mmol) were dissolved in N,N-dimethylacetamide (5 mL), and a tetrahydrofuran solution of 2-b (80 mg, 0.64 mmol) was added under nitrogen protection. After the addition, the reaction system was heated at 100 ° C for 1 hour, quenched with water, extracted with ethyl acetate (3×10 mL), the organic phases were combined, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a light yellow solid compound 2-d (50.0 mg, yield 30%). MS m / z 516.2 [M+H] + .

[0124] Compound 2-d (50 mg, 0.1 mmol) was dissolved in ethanol (2 mL), and 6 M hydrochloric acid (1 mL) was added. The reaction mixture was stirred at 80°C for 30 minutes. After cooling to room temperature, an appropriate amount of triethylamine was added to make the system alkaline. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to afford compound 2-e (35.0 mg, 87% yield) as a pale yellow solid. MS m / z 416.2 [M+H] + .

[0125] Compound 2-e (35 mg, 0.08 mmol) was dissolved in dimethyl sulfoxide (2 mL). Potassium carbonate (35 mg, 0.08 mmol) and 30% hydrogen peroxide (1 mL) were added at 0°C. The system was stirred at this temperature for 30 minutes, then warmed to room temperature and stirred for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain a light yellow solid compound 2-f (20.0 mg, yield 55%). MS m / z 434.1 [M+H] + .

[0126] Compound 2-f (12 mg, 0.03 mmol) was dissolved in methanesulfonic acid (1.0 mL) and L-methionine (45 mg, 0.3 mmol) was added. The reaction mixture was heated to 70°C and stirred for 8 hours. After completion of the reaction, the system was cooled to 0°C and aqueous ammonia was added. The system was adjusted to a weak alkaline state, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by reverse phase preparative chromatography (water and acetonitrile, 5%-95%) to obtain a gray solid compound 2 (2 mg, yield 17%). MS m / z 420.1 [M+H]+ .

[0127] Example 3: Preparation of Compound 3

[0128] Compound 1-c (185 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (22 mg, 0.03 mmol), cesium carbonate (469 mg, 1.44 mmol), and 3-a (255 mg, 0.96 mmol) were dissolved in a mixture of dioxane (4 mL) and water (1 mL). Under nitrogen, the reaction was heated at 100°C for 1 hour. After completion, the reaction was quenched with water and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 3-b (180.0 mg, 84% yield) as a pale yellow solid. MS m / z 449.1 [M+H] + .

[0129] Compound 3-b (180 mg, 0.40 mmol) was dissolved in methanol (5 mL), and palladium on carbon (10%, 100 mg) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 3-c (180.0 mg, yield 99%) as a pale yellow solid. MS m / z 451.1 [M+H] + .

[0130] Compound 3-c (180 mg, 0.40 mmol) was dissolved in dioxane (5 mL), and methanesulfonic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. After completion, an appropriate amount of saturated sodium carbonate solution was added to make the reaction alkaline. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to afford compound 3-d (50.0 mg, 31% yield) as a pale yellow solid. MS m / z 407.1 [M+H]+.

[0131] Compound 3-d (33 mg, 0.08 mmol) and difluoromethyl (2-pyridyl) sulfone (31 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction system was cooled to -45°C, and a solution of potassium tert-butoxide in N,N-dimethylformamide (27 mg, 1 mL) was slowly added. The reaction system was stirred for 2 hours, followed by the addition of 3 mL of 2M hydrochloric acid solution. The reaction was stirred at room temperature for 30 minutes. Water and ethyl acetate were then added for extraction, and the organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to afford compound 3-e (20.0 mg, 56% yield) as a pale yellow solid. MS m / z 441.1 [M+H]+.

[0132] Compound 3-e (20 mg, 0.05 mmol) was dissolved in dichloromethane (1.0 mL). A 1.0 M solution of boron tribromide in dichloromethane (0.2 mL, 0.2 mmol) was added at -50°C and stirred at -50°C for 30 minutes. After completion, the reaction was quenched with methanol, followed by addition of an appropriate amount of water and extraction with ethyl acetate (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (ethyl acetate 100%) to afford compound 3 (8 mg, 41% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),7.91(d,J=1.7Hz,1H),7.63(d,J=1.7Hz,1H),7.04(d,J=8.3Hz,1H), 6.95-6.85(m,3H),6.75(s,2H),2.67-2.61(m,1H),2.05-1.78(m,6H),1.73(s,3H),1.71-1.61(m,5H).MS m / z 427.1[M+H] + .

[0133] Example 4: Preparation of Compounds 4, 4A and 4B

[0134] The synthesis of compound 4-a refers to the synthesis route in patent WO 2021 / 195781.

[0135] Compound 4-a (60 mg, 0.15 mmol), XPhos Pd G4 (9 mg, 0.01 mmol), a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (0.6 mL, 0.6 mmol), and 1-a (40 mg, 0.3 mmol) were dissolved in dioxane (4 mL) and heated at 100°C for 2 hours under nitrogen. Upon completion, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) to afford compound 4-b (10.0 mg, 15% yield) as a pale yellow solid. MS m / z 456.2 [M+H]+.

[0136] Compound 4-b (10 mg, 0.02 mmol) was dissolved in dichloromethane (1.0 mL). A 1.0 M solution of boron tribromide in dichloromethane (0.1 mL, 0.1 mmol) was added at -50°C, and the mixture was heated to -20°C and stirred for 3 hours. Methanol was added to quench the mixture, followed by an appropriate amount of water and extraction with ethyl acetate. The organic phase was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:formic acid = 20:1:1) to afford Compound 4 (4 mg, 41% yield) as a pink solid. 1 H NMR (500MHz, DMSO-d6) δ9.48 (s, 1H), 7.73 (s, 1H), 7.04 (d, J = 8.3 Hz,1H),6.90(d,J=8.3Hz,1H),6.80-6.64(m,4H),2.91(t,J=5.4Hz,4H),2.34-2.23(m,7H),1.74(s,3H),1.66(s,3H). MS m / z 442.0[M+H] + .

[0137] Compound 4 (48 mg) was subjected to chiral separation (IG column_20% MeOH / CO2 mobile phase, flow rate 2 mL / min) to give compounds 4A (t=3.72 min) and 4B (t=4.08 min) (the stereochemical structures of 4A and 4B are tentative).

[0138] Compound 4A: pink solid, MS m / z 442.1[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.50(s,1H),7.73(s,1H),7.04(d,J=8.3Hz,1H),6.90(d,J=8.3Hz, 1H), 6.73 (d, J = 21.1Hz, 4H), 2.91 (t, J = 5.4Hz, 4H), 2.30 (s, 7H), 1.74 (s, 3H), 1.66 (s, 3H).

[0139] Compound 4B: pink solid, MS m / z 442.1[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.50(s,1H),7.73(s,1H),7.04(d,J=8.3Hz,1H),6.90(d,J=8.2Hz, 1H), 6.73 (d, J = 21.0Hz, 4H), 2.91 (t, J = 5.4Hz, 4H), 2.30 (s, 7H), 1.74 (s, 3H), 1.66 (s, 3H).

[0140] Example 6: Preparation of Compound 6

[0141] Compound 4-a (100 mg, 0.25 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (22 mg, 0.03 mmol), cesium carbonate (244 mg, 0.75 mmol), and 6-a (133 mg, 0.50 mmol) were dissolved in a mixture of dioxane (4 mL) and water (1 mL) and heated at 100°C for 1 hour under nitrogen. After completion, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 6-b (110.0 mg, 97% yield) as a pale yellow solid. MS m / z 463.1 [M+H] + .

[0142] Compound 6-b (80 mg, 0.17 mmol) was dissolved in methanol (5 mL), and palladium on carbon (100 mg) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a light yellow solid compound 6-c (35.0 mg, yield 44%). MS m / z 465.1 [M+H] + .

[0143] Compound 6-c (35 mg, 0.08 mmol) was dissolved in dioxane (5 mL), and methanesulfonic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes. After cooling to room temperature, an appropriate amount of saturated sodium carbonate solution was added to make the system alkaline. Water and ethyl acetate were added for extraction, and the organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to afford compound 6-d (17.0 mg, 54% yield) as a pale yellow solid. MS m / z 421.1 [M+H] + .

[0144] Compound 6-d (17 mg, 0.04 mmol) and difluoromethyl (2-pyridyl) sulfone (16 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (2 mL). A solution of potassium tert-butoxide in N,N-dimethylformamide (14 mg, 1 mL) was added at -45°C. The mixture was stirred at this temperature for 2 hours. 3 mL of 2M hydrochloric acid solution was added, and the reaction was stirred at room temperature for another 30 minutes. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain compound 6-e (10.0 mg, 54% yield) as a light yellow solid. MS m / z 455.1 [M+H] + .

[0145] Compound 6-e (10 mg, 0.02 mmol) was dissolved in dichloromethane (1.0 mL). A 1.0 M solution of boron tribromide in dichloromethane (0.2 mL, 0.2 mmol) was added at -50°C. The reaction was stirred at -50°C for 30 minutes. Methanol was added to quench the reaction, followed by an appropriate amount of water. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by medium-pressure preparative chromatography (acetonitrile / water 5% to 95%, 0.1% formic acid) to afford the formate salt of compound 6 as a white solid (3 mg, 28% yield). 1 H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.44(s,1H,FA salt),7.80(s,1H),7.04(d,J=8.3Hz,1H),6.90(d,J=8.3Hz,1H),6.81-6.66(m,4H), 2.85-2.78(m,1H),2.34(s,3H),2.04-1.96(m,2H),1.88-1.67(m,9H),1.65(s,3H).MS m / z441.1[M+H] + .

[0146] Example 7: Inhibition of PKMYT1 enzyme activity by compounds

[0147] The ADP-Glo ​​method was used to test the enzyme activity of PKMYT1. The compound was diluted with DMSO in a 4-fold gradient, with a total of ten concentrations. Use Echo to transfer 0.1 μL of the diluted compound to a 384-well plate, and the maximum final concentration of the compound test was 1000 nM. Add 5 μL of enzyme working solution, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes. Add 5 μL of ATP and substrate solution to start the reaction, and incubate at 25°C for 180 minutes. Add 5 μL of ADP-Glo ​​solution to a 384-well plate, incubate at 25°C for 40 minutes, add 10 μL of detection solution, incubate at 25°C for 40 minutes, and read the fluorescence value using BMG. Calculate according to the following formula: Inhibition rate (%) = (DMSO well control reading - compound well reading) / (DMSO well control reading - blank control reading) × 100%. The blank control well is DMSO and buffer, and the DMSO well is DMSO and enzyme solution. The IC of each compound 50 The values ​​were analyzed by nonlinear regression method using XLFit 5.5.0 software, and the formula was: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 =X)*HillSlope). Y is the inhibition rate, and X is the Log value of the compound concentration. The enzyme inhibition activity data of some representative compounds are shown in Table 1.

[0148] Table 1: Inhibitory activity of compounds against PKMYT1 enzyme

[0149] Example 8: Pharmacokinetic study in mice

[0150] Instrument: SCIEX Triple Quad 6500+ triple quadrupole liquid chromatography-mass spectrometry (LC-MS / MS), operating software: Analyst 1.7.2 (Applied Biosystems, Inc.); ExionLC liquid chromatography system; data were calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNolin 8.2 software using the statistical moment method. These parameters included Tmax, T1 / 2, Cmax, and AUC0-24h. Chromatographic column: Synergi 4μm Fusion-RP Luna C18 2mm*50mm, 4μm; column temperature 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate 0.8 mL / min, gradient elution: 0.10 min: 15% B; 1.6 min: 95% B; 1.90 min: 95% B; 1.91 min: 15% B; 2.20 min: 15% B. Injection volume: 1 μL.

[0151] Animals: Six female ICR mice weighing 25-30 g were purchased and housed in the laboratory of the Experimental Animal Center for three days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at the designated times after oral gavage and intravenous injection.

[0152] The oral administration vehicle was 0.5% methylcellulose, and the intravenous injection vehicle was 5% DMSO + 5% Solutol + 90% Saline. The mice were administered at a dose of 5 mg / kg by oral administration and 1 mg / kg by intravenous injection, respectively, with three mice in each group.

[0153] Cheek blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after oral administration; and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after intravenous administration. 20 μL of plasma sample (blank sample and internal standard blank sample plus 20 μL of blank plasma) was transferred to a 1.5 mL centrifuge tube, and 200 μL of internal standard (50% methanol in acetonitrile (concentration 100 ng / mL)) solution was added (double blank sample plus 200 μL of 50% methanol in acetonitrile). The sample was vortexed for 5 minutes and centrifuged at 6000g at 4°C for 3 minutes. 80 μL of the sample was added to 80 μL of water, mixed thoroughly, and analyzed by LC-MS / MS.

[0154] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including kinetic parameters Tmax, T 1 / 2 , Cmax, AUC 0-24h The pharmacokinetic data of some representative compounds are shown in Table 2.

[0155] Table 2 Pharmacokinetic parameters in mice

[0156] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure represented by the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof: In formula (I): X is selected from N or C R a ; wherein, R a selected from hydrogen, a halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, or C 3-6 cycloalkyl; R 1 selected from hydrogen or NR b R b ; wherein each R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; or two Rs b together with the nitrogen atom to which they are attached form a 3- to 6-membered ring structure; R 2 selected from C(O)NHR c or C(O)R g ; wherein, R c is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; R g is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, or heteroaryl; Each R 3 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy, or C 1-4 alkoxy; R 4 and R 5 each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4 alkyl, C 3-6 cycloalkylC 2-4 alkynyl, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic groupC 1-4 alkyl, 3- to 6-membered heterocyclic groupC 2-4 alkynyl, aryl, heteroaryl, OR f , SR f , NR d R d , CN, or formula (Ia): represents the site where the fragmentary (Ia) is connected to other parts of the structure of formula (I); The prerequisite is R 4 and R 5 at least one of which is selected from formula (Ia); or R 4 and R 5 together with the carbon atom to which it is attached form a 4- to 8-membered ring structure which is substituted by =M; Z is selected from N or CR e ; wherein, R e is selected from hydrogen, halogen, or C 1-4 alkyl; M is selected from CR h R i ; wherein, R h and R i are each independently selected from hydrogen, halogen, or C 1-4 alkyl; said alkyl is optionally substituted with one or more groups selected from the group consisting of: halogen, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)OR f , S(O)2NR d R d , NR d S(O)2R g , NR d S(O)2NR d R d ; or R h and R i together with the carbon atom to which they are attached form a 3- to 8-membered ring structure, which ring structure optionally contains 0, 1, or 2 heteroatoms selected from N, O, S; Each of the above Rs d is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R f is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R g is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, aryl, or heteroaryl; R 6 selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, or CN; m and n each independently select 0, 1, 2, 3, 4, 5, or 6; each p independently selects 0, 1, 2, 3, 4, or 5; each q independently selects 0, 1, 2, 3, or 4; Wherein, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents independently selected from the group consisting of: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, CN, NO2, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , NR d S(O)2R g , or S(O)2R g , provided that the chemical structure formed is stable and meaningful; wherein, R d , R f , R g are as defined above; Unless otherwise specified, the above-mentioned aryl is an aromatic group containing 6-12 carbon atoms; heteroaryl is a 5- to 15-membered heteroaromatic group; the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

2. The compound according to claim 1, characterized in that, Formula (I) is Formula (IIa), Formula (IIb), or Formula (IIc): The definitions of the groups in formula (IIa), (IIb), or formula (IIc) are as described in claim 1.

3. The compound according to any one of claims 1-2, characterized in that Formula (I) is Formula (III): Each R 3 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl; The definitions of the remaining groups in formula (III) are as described in claim 1.

4. The compound according to any one of claims 1-3, characterized in that Formula (I) is Formula (IV): X is selected from N or CR a ; wherein, R a is selected from hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; Z is selected from N or CR e ; wherein, R e is selected from hydrogen, halogen, or C 1-4 alkyl; R 5 selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, OR f , SR f , NR d R d , CN; M is selected from CR h R i ; wherein, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d C(O)NR d R d , OC(O)NR d R d , NR d C(O)OR f , OC(O)OR f , S(O)2NR d R d , NR d S(O)2R g , or NR d S(O)2NR d R d ; or R h and R i together with the carbon atom to which they are attached form a 3- to 8-membered ring structure, which ring structure optionally contains 0, 1, or 2 heteroatoms selected from N, O, S; Each of the above Rs d is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 2-4 alkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R f is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R g is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, aryl, or heteroaryl; m and n each independently select 0, 1, 2, 3, 4, 5, or 6.

5. The compound according to any one of claims 1-2, characterized in that, Formula (I) is Formula (V): Each R 3 is independently selected from hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl; The definitions of the remaining groups in formula (V) are as described in claim 1.

6. The compound according to any one of claims 1-2 and 5, characterized in that, Formula (I) is Formula (VI): R 4 selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, OR f 、SR f 、NR d R d 、CN; R d and R f and the definitions of the remaining groups in formula (VI) are as described in claim 4.

7. The compound according to any one of claims 1-2, characterized in that, Formula (I) is Formula (VII): The definitions of the groups in formula (VII) are as described in claim 1.

8. The compound according to any one of claims 1-2 and 7, characterized in that, Formula (I) is Formula (VIII): The definitions of the groups in formula (VIII) are as described in claim 4.

9. The compound according to claim 4, wherein In formula (IV): X is selected from N or CH; Z is selected from N or CH; R 5 Selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, CN; M is selected from CR h R i ; wherein, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g ; Each of the above Rs d is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl; each R f is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R g is independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, aryl, or heteroaryl; m and n each independently select 1 or 2.

10. The compound according to claim 6, characterized in that, In formula (VI): X is selected from N or CH; Z is selected from N or CH; R 4 selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, CN; M is selected from CR h R i ; wherein, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of: halogen, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g ; Each of the above Rs d is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl; each R f is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R g is independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, aryl, or heteroaryl; m and n each independently select 1 or 2.

11. The compound according to claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, selected from one of the following groups: A is selected from hydrogen, methyl, or chlorine; X is selected from N or CH.

12. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 11, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate, and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, characterized in that, For preparing a pharmaceutical composition for treating diseases, disorders or conditions related to PKMYT1 activity or expression level.

14. The use according to claim 13, characterized in that The diseases, disorders or conditions are selected from the following group: breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, laryngeal cancer, pancreatic cancer, prostate cancer, glioblastoma, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, renal cancer, skin cancer, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, monocytic leukemia, eosinophilic leukocytosis syndrome, multiple myeloma and other various solid tumors and hematological tumors.

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