CN116891468A - Thiazole compound and application thereof - Google Patents

Abstract

Thiazole compounds and pharmaceutically acceptable salts thereof are described as inhibitors of RAD51, said compounds having the structure of formula (I) and having the substituents and structural features described herein. The application also describes a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound of formula (I) or the pharmaceutically acceptable salt thereofUse in the manufacture of a medicament for the prevention or treatment of a RAD51 related disorder.

Description

Thiazole compound and application thereof

The present application claims priority from a prior application entitled "thiazole Compounds and their use", filed on China State intellectual Property office at 4/2/2022, patent application number 202210343109.X, which is incorporated herein by reference in its entirety.

Technical Field

The application belongs to the field of medicines, and particularly relates to a thiazole compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the thiazole compound or the pharmaceutically acceptable salt thereof, and application of the thiazole compound or the pharmaceutically acceptable salt thereof in preventing or treating RAD51 related diseases.

Background

RAD51 is a eukaryotic gene. The protein encoded by this gene is a member of the RAD51 protein family, which can help repair DNA double strand breaks. RAD51 family members are homologous to bacterial RecA, archaea RadA and yeast RAD 51. From yeast to humans, this protein is highly conserved in most eukaryotic cells. In humans, RAD51 is a protein consisting of 339 amino acids and possesses DNA-dependent ATP kinase activity. During repair of DNA Double Strand Breaks (DSBs), it plays an important role in homologous recombination. RAD51 is involved in the reciprocal transfer of the disrupted sequence to the intact homologous sequence, allowing the re-synthesis of the disrupted region.

The DNA damage response plays an important role in maintaining cell genomic stability and cell survival. DNA double strand breaks (Double strand breaks, DSBs) are the most severe form of DNA damage. Homologous recombination repair is one of the important mechanisms involved in repair of DSBs damage in vivo, where RAD51 is a key factor involved in repair of homologous recombination DNA in vivo. RAD51 is highly expressed in various human tumor tissues, such as breast cancer, non-small cell lung cancer, prostate cancer, etc., and is associated with metastasis and exacerbation of tumors (Klein et al, DNA Repair (Amst). 20080May 3;7 (5): 686-693). How to effectively reduce the level of RAD51 in tumor tissues and reduce the DNA damage repair capability of tumor cells, thereby improving the curative effect of tumor treatment and having potential clinical application value.

Homologous recombination has multiple roles in DNA damage repair, including repair of DNA double strand breaks and recovery of damage caused by DNA cross-linking agents that block DNA replication. Homologous recombination repairs DNA double strand breaks by locating homologous fragments of DNA and copying the missing genetic information from the homologous templates. Numerous studies have shown that homologous recombination is critical in maintaining genomic stability. Studies have shown that defects in proteins in cells that promote homologous recombination repair are associated with the sensitivity of certain DNA damage treatments. This sensitivity is particularly pronounced for DNA cross-linking chemotherapeutics and ionizing radiation (Takata et al, mol Cell biol.2001apr,21 (8): 2858-2866;Godthelp et al, nucleic Acids res.2002May 15,30 (10): 2172-2182).

Recently, it has been demonstrated by the research team that the sensitivity of cells to DNA damaging therapies can be further enhanced by partial inhibition of homologous recombination. For example, XRCC3 (paralog protein of RAD 51) may be inhibited using a synthetic peptide corresponding to another paralog protein. The synthetic peptide made the intermediate Hua Cangshu ovarian (CHO) cells more sensitive to cisplatin and inhibited RAD51 foci formation due to DNA damage (Connell et al, cancer res.2004may 1,64 (9): 3002-3005).

Therefore, in view of the fact that defects in proteins associated with DNA homologous recombination repair can increase the sensitivity of cells to DNA damage treatment, there is a need to develop small molecules capable of inhibiting RAD51 activity. Currently, WO2019014315A1, WO2019051465A1, WO2020186006A1, WO2021164746A1, etc. disclose a series of RAD51 inhibitors of novel structure.

Although certain progress is made in the current treatment of tumor, autoimmune diseases and other fields, a large number of patients still need better and more effective clinical treatment drugs and schemes. In view of the huge unmet clinical demands and the potential application value of RAD51 inhibitors in the field of diseases such as tumors, the RAD51 inhibitors with novel structure, better drug effect, high bioavailability and strong patentability still need to be provided.

Disclosure of Invention

The present application relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof,

wherein, the liquid crystal display device comprises a liquid crystal display device,

a is selected from phenyl or a six membered heteroaryl group, said six membered heteroaryl group being substituted with one or more R ¹ Substituted, said phenyl optionally substituted with one or more R ² Substitution;

each R is ¹ And R is ² Are independently selected from deuterium, halogen, CN, NO ₂ Amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkyloxy, 4-7 membered heterocyclyl or 4-7 membered heterocyclyloxy, said amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkyloxy, 4-7 membered heterocyclyl or 4-7 membered heterocyclyloxy optionally substituted with one or more R ^a Substitution;

or two adjacent R ¹ Or R is ² And the atoms to which they are attached together form a benzene ring, a 5-6 membered heteroaromatic ring or a 4-7 membered heterocyclic ring, said benzene ring, 5-6 membered heteroaromatic ring or 4-7 membered heterocyclic ring optionally being substituted with one or more R ^b Substitution;

each R is ^a And R is ^b Independently of each other selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkyl or C _3-6 Cycloalkyl; the amino group, C _1-6 Alkyl or C _3-6 Cycloalkyl is optionally substituted withOne or more R ^c Substitution;

each R is ^c Independently selected from deuterium, halogen, OH or CN;

the conditions are as follows: the compounds of formula (I) do not comprise

In some embodiments, a is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, said pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl being substituted with one or more R ¹ Substituted, said phenyl optionally substituted with one or more R ² And (3) substitution.

In some embodiments, A is selected from phenyl or pyridinyl, said pyridinyl being substituted with one or more R ¹ Substituted, the phenyl optionally substituted with one or more R ² And (3) substitution.

In some embodiments, A is selected fromOr->Said->Is/are R ¹ Substitution, said->Optionally by one or more R ² And (3) substitution.

In some embodiments, R ¹ Selected from deuterium, halogen, CN, NO ₂ Amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl, said amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one or more R ^a And (3) substitution.

In some embodiments, R ¹ Selected from halogen, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl or 4-6 membered heterocyclyl, said amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl or 4-6 membered heterocyclyl optionally substituted with one or more R ^a And (3) substitution.

In some embodiments, R ¹ Selected from halogen, amino, C _1-3 Alkyl, C _1-3 Alkoxy, cyclopropyl or azetidinyl groups, said amino, C _1-3 Alkyl, C _1-3 Alkoxy, cyclopropyl or azetidinyl optionally substituted with one or more R ^a And (3) substitution.

In some embodiments, R ^a Selected from halogen, OH, amino, CN, C _1-3 Alkyl or C _3-6 Cycloalkyl, the amino group, C _1-3 Alkyl or C _3-6 Cycloalkyl optionally substituted with one or more R ^c And (3) substitution.

In some embodiments, R ^a Selected from halogen, OH, amino or C _1-3 Alkyl, said amino or C _1-3 Alkyl is optionally substituted with one or more R ^c And (3) substitution.

In some embodiments, R ^a Selected from halogen or C _1-3 An alkyl group.

In some embodiments, R ^a Selected from F or methyl.

In some embodiments, R ¹ Selected from F, cl, br, methyl, CF ₃ Ethyl, CH ₂ CH ₂ F、OCH ₃ Cyclopropyl, NHCH ₃ 、N(CH ₃ ) ₂ 、

In some embodiments, R ² Selected from deuterium, halogen, CN, NO ₂ Amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl, said amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one or more R ^a Substitution; or two adjacent R ² And the atoms to which they are attached together form a benzene ring, a 5-6 membered heteroaromatic ring or a 4-7 membered heterocyclic ring, said benzene ring, 5-6 membered heteroaromatic ring or 4-7 membered heterocyclic ring optionally being substituted with one or more R ^b And (3) substitution.

In some embodiments, R ² Selected from halogen, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl, said amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one or more R ^a Substitution; or two adjacent R ² And the atoms to which they are attached together form a group optionally substituted with one or more R ^b Substituted 5-6 membered heteroaryl rings.

In some embodiments, R ² Selected from halogen, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl, said amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one or more R ^a And (3) substitution.

In some embodiments, R ² Selected from halogen or optionally by one or more R ^a Substituted C _1-3 An alkyl group.

In some embodiments, R ² Selected from halogen or C _1-3 An alkyl group.

In some embodiments, two adjacent R ² And the atoms to which they are attached together form a group optionally substituted with one or more R ^b Substituted 5-6 membered heteroaryl rings.

In some embodiments, two adjacent R ² Together with the atoms to which they are attached form a five membered heteroaromatic ring, optionally substituted with one or more R ^b And (3) substitution.

In some embodiments, R ² Selected from halogen or optionally by one or more R ^a Substituted C _1-3 Alkyl, or two adjacent R ² And the atoms to which they are attached together form a group optionally substituted with one or more R ^b Substituted five membered heteroaromatic rings.

In some embodiments, R ² Selected from halogen or optionally by one or more R ^a Substituted C _1-3 Alkyl, or two adjacent R ² Together with the atoms to which they are attached form a pyrrole or pyrazole ring, optionally substituted with one or more R ^b And (3) substitution.

In some embodiments, two adjacent R ² Together with the atoms to which they are attached form a pyrrole or pyrazole ring, optionally substituted with one or more R ^b And (3) substitution.

In some embodiments, R ^b Selected from deuterium, halogen, OH, amino, CN or optionally substituted with one or more R ^c Substituted C _1-3 An alkyl group.

In some embodiments, R ^b Selected from OH, halogen or optionally substituted with one or more R ^c Substituted C _1-3 An alkyl group.

In some embodiments, R ² Selected from F or methyl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia):

wherein: n is selected from 1, 2, 3 or 4; r is R ¹ As defined in formula (I), provided that the compound of formula (Ia) does not comprise

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia'):

Wherein: n is selected from 1, 2, 3 or 4; r is R ¹ As defined in formula (I), provided that the compound of formula (Ia') does not comprise

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib):

wherein: n is selected from 1, 2, 3 or 4; r is R ¹ As defined in formula (I), provided that the compound of formula (Ib) does not comprise

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib'):

wherein: n is selected from 1, 2, 3 or 4; r is R ¹ As defined in formula (I), provided that the compound of formula (Ib') does not comprise

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ic):

wherein: m is selected from 0, 1, 2, 3, 4 or 5; r is R ² As defined in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ic'):

wherein: m is selected from 0, 1, 2, 3, 4 or 5; r is R ² As defined in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.

In another aspect, the application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a RAD 51-related disorder.

In another aspect, the application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a tumor.

In another aspect, the application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of RAD 51-related disorders.

In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a tumor.

In another aspect, the present application provides a compound of formula (i) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of RAD 51-related disorders.

In another aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a tumor.

In another aspect, the application provides a method of treating a RAD 51-associated disorder comprising administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (i) or a pharmaceutically acceptable salt thereof as described herein.

In another aspect, the application provides a method of treating a tumor comprising administering to a patient a therapeutically effective amount of a pharmaceutical formulation comprising a compound of formula (i) or a pharmaceutically acceptable salt thereof as described herein.

In some embodiments, the RAD 51-associated disease is selected from a tumor.

In some embodiments, the RAD 51-associated disease is selected from small cell lung cancer or breast cancer.

Definition and description of terms

Unless otherwise indicated, the terms used in the present application have the following meanings, and the groups and term definitions recited in the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and combined with each other. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

Herein, a method of manufacturing a semiconductor deviceRepresenting the ligation site.

The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985,62:114-120. Unless otherwise indicated, wedge keys and virtual wedge keys are usedRepresenting the absolute configuration of a stereogenic center, using the black real and virtual keys +.>Representing the relative configuration of a stereocenter (e.g., the cis-trans configuration of a alicyclic compound).

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present application may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present application encompasses all tautomeric forms of the compounds.

The term "stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers and diastereomers.

The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present application may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the application. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the definition of compounds of the application. The asymmetric atom-containing compounds of the present application may be isolated in optically pure form or in racemic form, which may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH ₂ CH ₃ ) Monosubstituted (CH) ₂ CH ₂ F、CH ₂ CH ₂ Cl, etc.), polysubstituted (CHFCH ₂ F、CH ₂ CHF ₂ 、CHFCH ₂ Cl、CH ₂ CHCl ₂ Etc.) or fully substituted (CF) ₂ CF ₃ 、CF ₂ CCl ₃ 、CCl ₂ CCl ₃ Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

When any variable (e.g. R ^a 、R ^b ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. For example, if a group is substituted with 2R ^b Substituted, each R ^b There are independent options.

When the number of one substituent is 0, for example- (R) ² ) ₀ Indicating that the substituent is absent.

When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural unitsR represents ¹ Substitution may occur at any position on the pyridine ring.

C herein _i-j Refers to having an integer number of carbon atoms in the range of i-j. For example "C _1-10 By "is meant that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

The term "alkyl" refers to a compound of the formula C _n H _2n+1 The alkyl group may be linear or branched. The term "C _1-6 Alkyl "is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C _1-3 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1 to 3 carbon atoms. The "C _1-6 The alkyl group may further comprise "C _1-3 An alkyl group.

The term "alkoxy" refers to a monovalent group generated by the loss of a hydrogen atom on a hydroxyl group of a straight or branched chain alcohol, and is understood to be "alkyloxy" or "alkyl-O-". The term "C _1-6 Alkoxy "is understood to mean" C _1-6 Alkyloxy "or" C _1-6 alkyl-O- ". The "C _1-6 Alkoxy "may contain" C _1-3 An alkoxy group.

The term "cycloalkyl" refers to fully saturatedAnd in the form of a single ring, a parallel ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C _3-6 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms, specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkyloxy" is understood as "cycloalkyl-O-".

The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic in nature as a whole) monovalent monocyclic, bicyclic, spiro, or bridged ring radical containing from 1 to 5 heteroatoms or groups of heteroatoms (i.e., groups of heteroatoms) in the ring atoms, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), S (=o) ₂ -S (=o) (=nh) -, -C (=o) NH-, -C (=nh) -, -S (=o) ₂ NH-, S (=o) NH-, or-NHC (=o) NH-, etc. The term "4-7 membered heterocyclic group" refers to a heterocyclic group having 4,5, 6 or 7 ring atoms and containing 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from those described above. "4-7 membered heterocyclyl" includes "4-6 membered heterocyclyl", wherein specific examples of 4 membered heterocyclyl include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydro-oxazolyl, or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H- [1,3,4 ]]Thiadiazinyl; specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepinyl. The heterocyclic group may also be a bicyclic group. "4-7 membered heterocyclic group" may further include "4-6 membered heterocyclic group", "5-7 membered heterocyclic group", "4-or 5 membered heterocyclic group", "5-or 6 membered heterocyclic group", "6-or 7 membered heterocyclic group" and the like, "4-6 membered heterocyclic group" may further include "4-or 5 membered heterocyclic group", and the like Heterocyclyl "," 5-or 6-membered heterocyclyl ", and the like. In the present application, although some bicyclic heterocyclic groups contain a benzene ring or a heteroaryl ring in part, the heterocyclic groups as a whole are not aromatic.

The term "heterocyclyloxy" is understood to mean "heterocyclyl-O-".

The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being aromatic ring groups of C. The term "six membered heteroaryl" is understood to be a monovalent monocyclic ring system having 6 ring atoms and which comprises 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2 heteroatoms independently selected from N, O and S. In particular, the "six membered heteroaryl" is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to an-OH group.

The term "cyano" refers to a-CN group.

The term "amino" refers to-NH ₂ A group.

The term "nitro" refers to-NO ₂ A group.

The term "therapeutically effective dose" means an amount of a compound of the application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective dose" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

The application also includes isotopically-labeled compounds of the application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I and ³⁶ cl, and the like.

Certain isotopically-labeled compounds of the application (e.g., with ³ H is H ¹⁴ C-tag) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e ³ H) And carbon-14 (i.e ¹⁴ C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O、 ¹³ N、 ¹¹ C and C ¹⁸ F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is from 0.01mg/kg to 200mg/kg body weight, preferably from 0.05mg/kg to 50mg/kg body weight, more preferably from 0.1mg/kg to 30mg/kg body weight, either alone or in divided doses.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.

The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.

Detailed Description

The present application is described in detail below by way of examples, but is not meant to be limiting in any way. The present application has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the application without departing from the spirit and scope of the application. All reagents used in the present application are commercially available and can be used without further purification.

Unless otherwise indicated, the ratio of the mixed solvent is a volume mixing ratio. Unless otherwise indicated,% refers to wt%.

The compounds being obtained by hand or by handSoftware naming, commercial compounds are referred to by vendor catalog names.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvent for NMR measurement was deuterated dimethyl sulfoxide (DMSO-d ₆ ) Deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); IC (integrated circuit) ₅₀ "means half inhibition concentration" means concentration at which half of the maximum inhibition effect is achieved.

The eluent below can be a mixed eluent formed by two or more solvents, the ratio of which is the volume ratio of the solvents, for example, 0-10% methanol/dichloromethane represents the volume ratio of methanol to dichloromethane in the mixed eluent in the gradient elution process, which is 0:100-10:100.

The application employs the following abbreviations:

OXONE: potassium peroxomonosulphonate; b (B) ₂ Pin ₂ : duplex pinacol borates; pd (dppf) ₂ Cl ₂ :1, 1-bis (diphenylphosphorus) ferrocene palladium chloride; pd (PPh) ₃ ) ₄ : tetraphenylphosphine palladium; xantphos:4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; pd (Pd) ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium; EA: ethyl acetate; NBS: n-bromosuccinimide; DMF is N, N-dimethylformamide; DCM: dichloromethane; meOH: methanol; etOH: ethanol; dioxane:1, 4-dioxane; KOAc, potassium acetate; boc, t-butyloxycarbonyl; ACN: acetonitrile.

Example 1: synthesis of isopropyl trans- (4- (5- (4-amino-2- (cyclopropylsulfonyl) phenyl) thiazol-2-yl) cyclohexyl) carbamate (intermediate 1)

The synthetic route is as follows:

step 1: synthesis of 1-bromo-2-cyclopropylsulfanyl benzene

2-Bromothiophenol (40.0 g,211.56 mmol) was dissolved in N, N-dimethylformamide (400 mL), potassium carbonate (87.59 g,634.69 mmol) was added, and then cyclopropyl bromide (51.19 g,423.12 mmol) was added dropwise at 25 ℃. The reaction mixture was stirred at 120℃for 12 hours. TLC (silica, petroleum ether: ethyl acetate=1:0, ultraviolet (UV, 254 nm)) monitored the reaction was complete. The reaction was filtered and the filter cake was washed 3 times with ethyl acetate (200 ml x 3). The filtrate was concentrated to dryness under reduced pressure to give a crude 1-bromo-2-cyclopropylsulfanyl benzene (41 g).

Step 2: synthesis of 1-bromo-2-cyclopropylsulfonyl benzene

1-bromo-2-cyclopropylsulfanyl benzene (40.0 g,174.57 mmol) was dissolved in anhydrous methanol (300 ml), and then potassium peroxomonosulphonate (321.56 g,523.71 mol) was dissolved in water (300 ml), and the mixture was slowly stirred at 0 ℃. The reaction solution was stirred at 25℃for 12 hours. After the completion of the reaction, LC-MS was carried out, a saturated sodium sulfite solution (1.0L) at 0℃was slowly poured into the reaction solution, and the completion of the quenching was detected by starch potassium iodide paper. Then, the mixture was directly filtered, the cake was washed four times with methanol (100 mL), the filtrate was concentrated under reduced pressure to remove a large amount of methanol, and then extracted with ethyl acetate (500 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-bromo-2-cyclopropylsulfonylbenzene (38.0 g).

Step 3: synthesis of 1-bromo-2- (cyclopropylsulfonyl) -4-nitrobenzene

1-bromo-2-cyclopropylsulfonyl benzene (30.0 g,114.88 mmol) was dissolved in sulfuric acid (300 mL), and nitric acid (21.72 g,344.65mmol,15.5 mL) was slowly added dropwise to the reaction solution over 30 minutes, maintaining the temperature of the system at 0℃in an ice-salt bath environment. After the completion of the dropwise addition, the clear reaction solution was stirred at 10℃for 2 hours. TLC (PE/ea=10/1) detected completion of the reaction. The reaction solution was slowly added to ice water (2.5L). A white solid precipitated under stirring. The white solid was filtered and then washed with water (0.75 l,0.25l x 3) and dried to give the solid compound 1-bromo-2- (cyclopropylsulfonyl) -4-nitrobenzene (30 g).

Step 4: synthesis of 4-bromo-3- (cyclopropylsulfonyl) aniline

1-bromo-2- (cyclopropylsulfonyl) -4-nitrobenzene (27.0 g,88.2 mmol) was dissolved in ethanol (600 mL) and water (100 mL), and reduced iron powder (49.3 g,882.0 mmol) and ammonium chloride (47.2 g,882.0 mmol) were added. The reaction mixture was stirred at 90℃for 4 hours. LC-MS detection reaction was completed. The reaction solution is filtered out with suction to remove iron powder. The mother liquor was concentrated to dryness under reduced pressure, water (200 mL) was added and extracted with 600mL (300 mL x 2) of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude solid compound, i.e., 4-bromo-3- (cyclopropylsulfonyl) aniline (23 g).

MS m/z(ESI):275.8；277.8[M+H] ⁺ .

Step 5: synthesis of 3- (cyclopropylsulfonyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

4-bromo-3- (cyclopropylsulfonyl) aniline (10.0 g,36.21 mmol) was dissolved in anhydrous N, N-dimethylformamide (200 mL), and bis-pinacolato borate (18.39 g,72.42 mmol) and potassium acetate (10.65 g,108.64 mmol) were added. 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride dichloromethane mixture (2.65 g,3.62 mmol) was added to the reaction solution under nitrogen. The dark red reaction solution was stirred at 100℃for 16 hours under nitrogen. LC-MS detection reaction was completed. The reaction mixture was filtered under reduced pressure, water (300 mL) was added to the filtrate, and extracted with ethyl acetate (300 mL x 2) to give crude oil, 3- (cyclopropylsulfonyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (10.0 g).

MS m/z(ESI):324.2[M+H] ⁺ .

Step 6: synthesis of isopropyl trans- (4- (5- (4-amino-2- (cyclopropylsulfonyl) phenyl) thiazol-2-yl) cyclohexyl) carbamate (intermediate 1)

3- (cyclopropylsulfonyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (10.00 g,30.94 mmol) and isopropyl trans- (4- (5-bromothiazol-2-yl) cyclohexyl) carbamate (8.95 g,25.78 mmol) were dissolved in ethanol (70 mL) and dioxane (70 mL), and aqueous sodium carbonate (2M, 10 mL), potassium fluoride (1.50 g,25.78 mmol) was added. The reaction mixture was charged with tetrakis triphenylphosphine palladium (2.98 g,2.58 mmol) under nitrogen. The reaction solution was stirred at 100℃for 12 hours under nitrogen protection. LC-MS detection reaction was completed. The reaction mixture was concentrated to dryness under reduced pressure, water (500 mL) was added to the reaction mixture, extracted three times with ethyl acetate (200 mL x 3), the organic phase was dried over anhydrous magnesium sulfate, suction filtered, the filtrate was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography to give a solid compound i.e. isopropyl trans- (4- (5- (4-amino-2- (cyclopropylsulfonyl) phenyl) thiazol-2-yl) cyclohexyl) carbamate (5.6 g).

MS m/z(ESI):464.1[M+H] ⁺ .

Example 2: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((6-fluoropyridin-3-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 004)

The synthetic route is as follows:

intermediate 1 (40 mg, 86.28. Mu. Mol), 3-iodo-6-fluoropyridine (23.09 mg, 103.53. Mu. Mol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 8.63. Mu. Mol), xantphos (9.98 mg, 17.26. Mu. Mol) and cesium carbonate (56.25 mg, 172.56. Mu. Mol) were weighed out under nitrogen and dissolved in N, N-dimethylformamide (1 mL) and reacted at 60℃for two hours. Saturated saline (5 mL), ethyl acetate (5 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentrating the organic phase, the organic phase was purified by column chromatography (gradient elution of petroleum ether/ethyl acetate), concentrated again, and the crude product was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:50% -70%, B was acetonitrile, flow rate 20 mL/min)), freeze-dried to give the title compound (14.14 mg).

MS m/z(ESI):559.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(s,1H),8.07-8.06(m,1H),7.84-7.79(m,1H),7.67(s,1H),7.60(d,J＝2.6Hz,1H),7.38(d,J＝8.4Hz,1H),7.29-7.25(m,1H),7.19-7.16(m,1H),7.02-7.00(m,1H),4.77-4.71(m,1H),3.30-3.28(m,1H),2.96-2.88(m,1H),2.45–2.38(m,1H),2.17–2.09(m,2H),1.96–1.87(m,2H),1.63–1.50(m,2H),1.40–1.28(m,2H),1.16(d,J＝6.3Hz,6H),0.99-0.93(m,2H),0.90-0.83(m,2H).

Example 3: synthesis of isopropyl trans- (4- (5- (4- ((5-chloropyridin-2-yl) amino) -2- (cyclopropylsulfonyl) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 005)

The synthetic route is as follows:

intermediate 1 (40 mg, 86.28. Mu. Mol), 2-iodo-5-chloropyridine (22.72 mg, 94.91. Mu. Mol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 8.63. Mu. Mol), xantphos (9.98 mg, 17.26. Mu. Mol) and cesium carbonate (56.25 mg, 172.56. Mu. Mol) were weighed out under nitrogen and dissolved in N, N-dimethylformamide (1 mL) and reacted at 60℃for two hours to completion. Saturated saline (5 mL), ethyl acetate (5 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentrating the organic phase, the organic phase was purified by column chromatography (gradient elution of petroleum ether/ethyl acetate), concentrated again, and the crude product was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:60% -80%, B was acetonitrile, flow rate 20 mL/min)), freeze-dried to give the title compound (9.59 mg).

MS m/z(ESI):575.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.86(s,1H),8.30(d,J＝2.4Hz,1H),8.25(d,J＝2.7Hz,1H),8.15-8.12(m,1H),7.75-7.69(m,1H),7.70(s,1H),7.47-7.45(m,1H),7.02-7.00(m,1H),6.93-6.91(m,1H),4.77-4.71(m,1H),3.30-3.28(m,1H),2.97-2.89(m,1H),2.45-2.40(m,1H),2.15-2.12(m,2H),1.93-1.90(m,2H),1.62–1.50(m,2H),1.40–1.28(m,2H),1.16(d,J＝6.3Hz,6H),1.01-0.96(m,2H),0.94–0.86(m,2H).

Example 4: synthesis of isopropyl trans- (4- (5- (4- ((5-bromopyridin-2-yl) amino) -2- (cyclopropylsulfonyl) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 006)

The synthetic route is as follows:

intermediate 1 (40 mg, 86.28. Mu. Mol), 2-iodo-5-bromopyridine (29.39 mg, 103.51. Mu. Mol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 8.63. Mu. Mol), xantphos (9.98 mg, 17.26. Mu. Mol) and cesium carbonate (56.25 mg, 172.56. Mu. Mol) were weighed out under nitrogen and dissolved in N, N-dimethylformamide (1 mL) and reacted at 60℃for two hours to completion. Saturated saline (5 mL), ethyl acetate (5 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentrating the organic phase, the organic phase was purified by column chromatography (gradient elution of petroleum ether/ethyl acetate), concentrated again, and the crude product was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:50% -70%, B was acetonitrile, flow rate 20 mL/min)), freeze-dried to give the title compound (7.32 mg).

MS m/z(ESI):619.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.88(s,1H),8.32-8.28(m,2H),8.16-8.13(m,1H),7.85-7.82(m,1H),7.70(s,1H),7.47(d,J＝8.5Hz,1H),7.05(d,J＝7.8Hz,1H),6.88(d,J＝8.9Hz,1H),4.77-4.71(m,1H),3.33-3.31(m,1H),2.96–2.90(m,1H),2.46–2.40(m,1H),2.19–2.09(m,2H),1.93-1.90(m,2H),1.61-1.52(m,2H),1.38-1.29(m,2H),1.16(d,J＝6.3Hz,6H),1.01-0.97(m,2H),0.91-0.88(m,2H).

Example 5: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((5- (trifluoromethyl) pyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 007)

Synthetic route

2-iodo-5- (trifluoromethyl) pyridine (94.21 mg, 345.12. Mu. Mol), intermediate 1 (80 mg, 172.56. Mu. Mol), cesium carbonate (112.44 mg, 345.12. Mu. Mol), tris (dibenzylideneacetone) dipalladium (15.80 mg, 17.26. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (19.97 mg, 34.51. Mu. Mol), N, N-dimethylformamide (1 mL) were added to a bottle, argon-protected, reacted at 60℃for 5h, LCMS was monitored to end point, water (5 mL) was added, ethyl acetate (5 mL) was extracted, split, concentrated, and column chromatography purified (gradient elution with petroleum ether/ethyl acetate) to give crude product (50 mg), which was purified by high pressure preparative liquid chromatography (re-HPLC (column: YMC C18; mobile phase: 0.5% aqueous ammonia; B%:40% -70%, B was acetonitrile, flow rate 25 mL/min)), and the title compound (20.3 mg) was lyophilized.

MS m/z(ESI):609.20[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ10.20(s,1H),8.60–8.56(m,1H),8.41–8.37(m,1H),8.24–

8.19(m,1H),7.99–7.94(m,1H),7.72(s,1H),7.54–7.49(m,1H),7.07–6.99(m,2H),4.78–

4.71(m,1H),3.29(s,1H),3.01–2.88(m,1H),2.48–2.40(m,1H),2.19–2.10(m,2H),1.97–

1.87(m,2H),1.62–1.53(m,2H),1.41–1.28(m,2H),1.17(d,J＝6.2Hz,6H),1.03–0.97(m,2H),0.93–0.89(m,2H)；

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-59.82.

Example 6: synthesis of isopropyl trans- (4- (5- (4- ((5-cyclopropylpyridin-2-yl) amino) -2- (cyclopropylsulfonyl) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 008)

The synthetic route is as follows:

intermediate 1 (60 mg, 129.42. Mu. Mol), 2-bromo-5-cyclopropylpyridine (28.20 mg, 142.36. Mu. Mol), tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), xantphos (14.98 mg, 25.88. Mu. Mol) and cesium carbonate (84.38 mg, 258.84. Mu. Mol) were weighed out under nitrogen and dissolved in N, N-dimethylformamide (1 mL) and reacted at 100℃for two hours to completion. Saturated saline (5 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentrating the organic phase, the organic phase was purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) and concentrated again, the crude product was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:40% -70%, B was acetonitrile, flow rate 20 mL/min)), and the title compound (28.52 mg) was obtained after lyophilization.

MS m/z(ESI):581.20[M+H] ⁺ ；

1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.33(d,J＝2.5Hz,1H),8.13-8.10(m,1H),8.07(d,J＝2.5Hz,1H),7.68(s,1H),7.42(d,J＝8.5Hz,1H),7.34-7.31(m,1H),7.01(d,J＝7.7Hz,1H),6.81(d,J＝8.6Hz,1H),4.77-4.71(m,1H),2.98-2.87(m,1H),2.45-2.38(m,1H),2.15-2.12(m,2H),1.95-1.83(m,3H),1.61-1.52(m,2H),1.42-1.28(m,2H),1.17(d,J＝6.3Hz,6H),1.00-0.95(m,2H),0.94-0.86(m,4H),0.68–0.61(m,2H).

Example 7: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- (phenylamino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 009)

The synthetic route is as follows:

intermediate 1 (40 mg, 86.28. Mu. Mol), iodobenzene (21.12 mg, 103.53. Mu. Mol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 8.63. Mu. Mol), xantphos (9.98 mg, 17.26. Mu. Mol) and cesium carbonate (56.25 mg, 172.56. Mu. Mol) were weighed out under nitrogen and dissolved in N, N-dimethylformamide (1 mL) and reacted at 60℃for two hours to completion. Saturated saline (5 mL), ethyl acetate (5 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentrating the organic phase, the organic phase was purified by column chromatography (gradient elution of petroleum ether/ethyl acetate), concentrated again, and the crude product was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:70% -90%, B was acetonitrile, flow rate 20 mL/min)), freeze-dried to give the title compound (14.04 mg).

MS m/z(ESI):540.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.87(s,1H),7.67-7.66(m,2H),7.39–7.29(m,4H),7.20–7.14(m,2H),7.04-6.97(m,2H),4.77-4.71(m,1H),3.32-3.30(m,1H),2.96-2.88(m,1H),2.45–2.37(m,1H),2.18–2.09(m,2H),1.93-1.89(m,2H),1.61-1.51(m,2H),1.38-1.28(m,2H),1.16(d,J＝6.2Hz,6H),0.97-0.94(m,2H),0.88-0.86(m,2H).

Example 8: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((2-fluorophenyl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 010)

The synthetic route is as follows:

intermediate 1 (40 mg, 86.28. Mu. Mol), 1-fluoro-2-iodobenzene (22.98 mg, 103.53. Mu. Mol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 8.63. Mu. Mol), xantphos (9.98 mg, 17.26. Mu. Mol) and cesium carbonate (56.25 mg, 172.56. Mu. Mol) were weighed out under nitrogen and dissolved in N, N-dimethylformamide (1 mL) and reacted at 60℃for two hours to completion. Saturated saline (5 mL), ethyl acetate (5 mL) was added, the organic phases were combined, dried over anhydrous sodium sulfate, and after concentrating the organic phase, the organic phase was purified by column chromatography (gradient elution of petroleum ether/ethyl acetate), concentrated again, and the crude product was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:60% -80%, B was acetonitrile, flow rate 20 mL/min)), freeze-dried to give the title compound (10.93 mg).

MS m/z(ESI):558.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(s,1H),7.67(s,1H),7.55(d,J＝2.4Hz,1H),7.41-7.34(m,2H),7.31-7.28(m,1H),7.22-7.17(m,1H),7.16-7.10(m,2H),7.04(d,J＝7.8Hz,1H),4.77-4.70(m,1H),2.96-2.88(m,1H),2.43-2.36(m,1H),2.18-2.08(m,2H),1.95-1.86(m,2H),1.63-1.50(m,2H),1.37-1.31(m,2H),1.16(d,J＝6.2Hz,6H),0.98-0.94(m,2H),0.88-0.84(m,2H).

Example 9: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3-fluorophenyl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 012)

The synthetic route is as follows:

1-fluoro-3-iodobenzene (40.22 mg, 181.19. Mu. Mol), intermediate 1 (70 mg, 150.99. Mu. Mol), cesium carbonate (98.38 mg, 301.98. Mu. Mol), tris (dibenzylideneacetone) dipalladium (13.83 mg, 15.10. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17.47 mg, 30.20. Mu. Mol), N, N-dimethylformamide (1 mL) were added to a bottle. The reaction was carried out under argon at 85℃for 2h and LCMS monitored for endpoint. Water (5 mL) was added, ethyl acetate (5 mL) was extracted, the mixture was separated, concentrated, and then purified by column chromatography (Petroleum ether/ethyl acetate gradient elution, 65% EA to give the product) to give the crude product (90 mg), which was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia solution; B%:40% -70%, B was acetonitrile, flow rate 25 mL/min)), freeze-dried to give the title compound (46 mg).

MS m/z(ESI):558.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.07(s,1H),7.72–7.69(m,1H),7.69(s,1H),7.42–7.39(m,2H),7.38–7.30(m,1H),7.04–6.97(m,2H),6.97–6.91(m,1H),6.80–6.73(m,1H),4.79–

4.69(m,1H),3.32–3.28(m,1H),2.97–2.89(m,1H),2.47–2.38(m,1H),2.19–2.08(m,2H),1.96–1.86(m,2H),1.64–1.48(m,2H),1.41–1.27(m,2H),1.17(d,J＝6.2Hz,6H),1.00–0.95(m,2H),0.93–0.83(m,2H)；

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-111.83.

Example 10: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((2, 4-difluorophenyl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 013)

The synthetic route is as follows:

2, 4-difluoro-1-iodobenzene (62.12 mg, 258.84. Mu. Mol), intermediate 1 (60 mg, 129.42. Mu. Mol), cesium carbonate (84.33 mg, 258.84. Mu. Mol), tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (14.98 mg, 25.88. Mu. Mol), N, N-dimethylformamide (1 mL) were added to the bottle. Under the protection of argon, controlling the temperature to be 60 ℃ for 2 hours, and monitoring the reaction by LCMSReaching the end point. To the reaction solution was added water (5 mL) for dilution, ethyl acetate (5 mL x 3) for extraction, separation, concentration and column chromatography purification (petroleum ether/ethyl acetate gradient elution, 80% ea to give the product) to give the crude product (70 mg), which was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:40% -70%, B was acetonitrile, flow rate 25 mL/min)), and freeze-dried to give the title compound (25 mg). MS m/z (ESI): 576.10[ M+H ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.64(s,1H),7.66(s,1H),7.48–7.45(m,1H),7.44–7.38(m,2H),7.36–7.32(m,1H),7.14–7.09(m,1H),7.04–7.01(m,2H),4.80–4.68(m,1H),2.96–

2.88(m,1H),2.42–2.36(m,1H),2.20–2.05(m,2H),1.90–1.93(m,2H),1.62–1.48(m,2H),1.39–1.28(m,2H),1.16(d,J＝6.2Hz,6H),0.98–0.93(m,2H),0.91–0.81(m,2H)；

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-115.49,-117.80.

Example 11: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((2-fluoro-4-methylphenyl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 014)

The synthetic route is as follows:

2-fluoro-1-iodo-4-toluene (61.35 mg, 258.84. Mu. Mol), intermediate 1 (60 mg, 129.42. Mu. Mol), cesium carbonate (84.33 mg, 258.84. Mu. Mol), tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (14.98 mg, 25.88. Mu. Mol) were dissolved in N, N-dimethylformamide (1 mL) under an argon atmosphere. The reaction was controlled at 100℃for 2h and LCMS monitored to endpoint. Adding water (5 mL) to the reaction, diluting, extracting with ethyl acetate (5 mL. Times.3), separating, concentrating, and purifying by column chromatography (petroleum ether/ethyl acetate)Ethyl acetate gradient elution, 80% ea yielding the crude product (65 mg), purification by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:40% -70%, B is acetonitrile, flow rate 25 mL/min)), lyophilization to afford the title compound (25 mg). MS m/z (ESI) 572.20[ M+H ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.58(s,1H),7.66(s,1H),7.48–7.44(m,1H),7.35–7.31(m,1H),7.28–7.22(m,1H),7.18–7.12(m,1H),7.05–7.01(m,3H),4.80–4.68(m,1H),3.31–3.28(m,1H),2.98–2.84(m,1H),2.43–2.35(m,1H),2.31(s,3H),2.18–2.08(m,2H),1.96–1.85(m,2H),1.61–1.51(m,2H),1.37–1.29(m,2H),1.16(d,J＝6.3Hz,6H),0.99–0.93(m,2H),0.89–0.81(m,2H)；

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-123.10.

Example 12: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- (5- (methylamino) pyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 031)

The synthetic route is as follows:

step 1: synthesis of tert-butyl trans- (6- ((3- (cyclopropylsulfonyl) -4- (2- (4- ((isopropylcarbonyl) amino) cyclohexyl) thiazol-5-yl) phenyl) amino) pyridin-3-yl) (methyl) carbamate

(6-bromopyridin-3-yl) (methyl) carbamic acid tert-butyl ester (65.03 mg, 226.48. Mu. Mol), intermediate 1 (70 mg, 150.99. Mu. Mol), cesium carbonate (98.38 mg, 301.98. Mu. Mol), tris (dibenzylideneacetone) dipalladium (13.83 mg, 15.10. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17.47 mg, 30.20. Mu. Mol) were dissolved in N, N-dimethylformamide (1 mL) under an argon atmosphere. The reaction was controlled at 100℃for 2h and LCMS monitored to endpoint. To the reaction was added water (5 mL) for dilution, ethyl acetate (5 mL x 3) for extraction, and the solution was separated and concentrated to give a residue (100 mg). The crude product was used directly in the next reaction without purification.

Step 2: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- (5- (methylamino) pyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate

Crude trans- (6- ((3- (cyclopropylsulfonyl) -4- (2- (4- ((isopropylcarbonyl) amino) cyclohexyl) thiazol-5-yl) phenyl) amino) pyridin-3-yl) (methyl) carbamic acid tert-butyl ester (100 mg) was dissolved in dichloromethane (1 mL), and 4M dioxane solution (0.5 mL) was added and stirred for 1h. LC-MS monitored the reaction to endpoint, saturated sodium bicarbonate solution (5 mL), ethyl acetate (5 mL. Times.3) was added to the reaction solution, the solution was separated, column chromatography purified (Petroleum ether/ethyl acetate gradient elution, 80% EA to give the product) after concentration gave crude (50 mg), the crude was purified by high pressure liquid chromatography (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:40% -70%, B was acetonitrile, flow rate 25 mL/min), and freeze dried to give the title compound (15.4 mg).

MS m/z(ESI):570.10[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.20(s,1H),8.22–8.18(m,1H),7.98–7.92(m,1H),7.66(s,1H),7.62–7.59(m,1H),7.37–7.32(m,1H),7.09–6.98(m,2H),6.80–6.74(m,1H),5.43–

5.40(m,1H),4.82–4.69(m,1H),3.32–3.28(m,1H),2.99–2.83(m,1H),2.68(d,J＝5.2Hz,3H),2.42–2.37(m,1H),2.18–2.09(m,2H),1.97–1.86(m,2H),1.63–1.50(m,2H),1.40–

1.27(m,2H),1.16(d,J＝6.2Hz,6H),0.98–0.95(m,1H),0.92–0.84(m,2H).

Example 13: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((5- (dimethylamino) pyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 032)

The synthetic route is as follows:

6-bromo-N, N-dimethylpyridin-3-amine (60.72 mg, 301.98. Mu. Mol), intermediate 1 (70 mg, 150.99. Mu. Mol), cesium carbonate (98.38 mg, 301.98. Mu. Mol), tris (dibenzylideneacetone) dipalladium (13.83 mg, 15.10. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17.47 mg, 30.20. Mu. Mol) were dissolved in N, N-dimethylformamide (1 mL) under an argon atmosphere. The reaction was controlled at 100℃for 16h and LCMS monitored for endpoint. To the reaction solution was added water (5 mL) for dilution, ethyl acetate (5 mL x 3) for extraction, separation, concentration and column chromatography purification (petroleum ether/ethyl acetate gradient elution, 65% ea to give the product) to give the crude product (80 mg), which was purified by high pressure liquid chromatography (re-HPLC (column: YMC 18; mobile phase: 0.5% aqueous ammonia; B%:40% -70%, B was acetonitrile, flow rate 25 mL/min)), and freeze-dried to give the title compound (29 mg).

MS m/z(ESI):584.20[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.28–8.23(m,1H),8.04–7.97(m,1H),7.82–

7.97(m,1H),7.67(s,1H),7.40–7.34(m 1H),7.30–7.23(m,1H),7.05–6.98(m,1H),6.87–

6.81(m,1H),4.80–4.68(m,1H),2.98–2.87(m,1H),2.85(s，6H),2.43–2.37(m,1H),2.19–2.07(m,2H),1.98–1.87(m,2H),1.63–1.48(m,2H),1.42–1.26(m,2H),1.17(d,J＝6.2Hz,6H),1.01–0.94(m,2H),0.94–0.83(m,2H).

Example 14: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((6-fluoropyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 052)

Synthetic route

Intermediate 1 (60 mg, 129.42. Mu. Mol) and 2-bromo-6-fluoropyridine (18.22 mg, 103.53. Mu. Mol) were dissolved in anhydrous N, N-dimethylformamide (4 mL), and tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (7.48 mg, 12.94. Mu. Mol) and cesium carbonate (126.18 mg, 388.26. Mu. Mol) were added under nitrogen. The reaction solution was in the form of a black suspension, and the reaction was stirred at 80℃for 4 hours. LC-MS detection reaction is complete, and the reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether: ethyl acetate=3:2) afforded crude (50 mg). The title compound (12.24 mg) was obtained by preparative liquid chromatography (YMC-ActusTriart C18 column, 5 μm silica, 30mm diameter, 150mm length; using a decreasing polarity mixture of water (containing 0.05% formic acid) and acetonitrile as eluent).

MS m/z(ESI):559.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.30(d,J＝2.4Hz,1H),8.15–7.97(m,1H),7.90–7.75(m,1H),7.71(s,1H),7.49(d,J＝8.5Hz,1H),7.03(d,J＝7.8Hz,1H),6.79–6.73(m,1H),6.55–6.50(m,1H),4.77–4.69(m,1H),2.98–2.89(m,1H),2.49–2.42(m,1H),2.14(d,J＝12.8Hz,2H),1.92(d,J＝12.4Hz,2H),1.63–1.51(m,2H),1.40–1.27(m,2H),1.16(d,J＝6.3Hz,6H),1.01–0.96(m,2H),0.95–0.87(m,2H).

Example 15: synthesis of isopropyl trans-4- (5- (2- (cyclopropylsulfonyl) -4- ((3-fluoropyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 054)

The synthetic route is as follows:

intermediate 1 (60 mg, 129.42. Mu. Mol) and 2-bromo-3-fluoro-pyridine (22.64 mg, 129.42. Mu. Mol) were dissolved in anhydrous N, N-dimethylformamide (2 mL), and tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (14.98 mg, 25.88. Mu. Mol) and cesium carbonate (42.17 mg, 129.42. Mu. Mol) were added under nitrogen. The reaction solution was in the form of a black suspension, and the reaction was stirred at 80℃for 2 hours. LC-MS detection reaction is complete, and the reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (silica, dichloromethane: methanol=20:1) afforded crude (30 mg). The title compound (23.66 mg) was obtained by preparative thin layer chromatography (20 x 20cm glass thin layer, 0.2±0.03mm silica gel adsorbent, petroleum ether: ethyl acetate=3:2).

MS m/z(ESI):559.1[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(d,J＝2.0Hz,1H),8.55(d,J＝2.4Hz,1H),8.23–8.19(m,1H),8.09–8.05(m,1H),7.71(s,1H),7.69–7.62(m,1H),7.47(d,J＝8.4Hz,1H),7.03(d,J＝8.0Hz,1H),6.98–6.91(m,1H),4.81–4.68(m,1H),2.98-2.90(m,1H),2.50–2.40(m,1H),2.18–2.08(m,2H),1.96–1.88(m,2H),1.60–1.50(m,2H),1.42–1.30(m,2H),1.17(d,J＝6.2Hz,6H),1.03–0.97(m,2H),0.95–0.89(m,2H)；

¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-134.63.

Example 16: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((5-fluoro-3-methylpyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 055)

The synthetic route is as follows:

intermediate 1 (40.0 mg,0.09 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.5 mL) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (9.98 mg,0.02 mmol), cesium carbonate (56.2 mg, 0.1)7 mmol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 0.01. Mu. Mol) and 2-bromo-5-fluoro-3-methylpyridine (16.4 mg,0.09 mmol) were added and stirred for 2h at 90 ℃. LC-MS monitoring showed the reaction was completed, the reaction was added to water (1 mL), EA (1 mL. Times.2) was extracted, the organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, dried by spin-drying, and purified by column chromatography (DCM/MeOH=100:1-30:1) to give crude product (40.0 mg) which was purified by high pressure liquid chromatography [ YMC-Actus Triart C18 column, 5 μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH) ₄ HCO ₃ ) And acetonitrile as eluent; acetonitrile gradient ratio of 45% -75%, eluting time of 14 min]After lyophilization, the title compound (15.53 mg) was obtained.

MS m/z(ESI):573.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.57(s,1H),8.29(s,1H),8.08–8.07(m,2H),7.70(s,1H),7.64–7.55(m,1H),7.42(d,J＝8.5Hz,1H),7.03(d,J＝7.8Hz,1H),4.97–4.56(m,1H),3.05–2.82(m,1H),2.42–2.41(m,1H),2.33(s,3H),2.19–2.10(m,2H),1.93–1.90(m,2H),1.66–1.50(m,2H),1.45–1.28(m,2H),1.17(d,J＝6.2Hz,6H),1.02–0.94(m,2H),0.92–0.89(m,2H).

Example 17: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3-fluoro-5-methylpyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 056)

The synthetic route is as follows:

intermediate 1 (60 mg, 129.42. Mu. Mol) and 2-bromo-3-fluoro-6-methylpyridine (19.67 mg, 103.53. Mu. Mol) were dissolved in anhydrous N, N-dimethylformamide (4 mL) and tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethyloxa-ne was added under nitrogenAnthracene (7.48 mg, 12.94. Mu. Mol) and cesium carbonate (126.18 mg, 388.26. Mu. Mol). The reaction solution was in the form of a black suspension, and the reaction was stirred at 80℃for 4 hours. LC-MS detection reaction is complete, and the reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether: ethyl acetate=3:2) afforded crude (50 mg). The title compound (15.63 mg) was obtained by preparative liquid chromatography (YMC-ActusTriart C18 column, 5 μm silica, 30mm diameter, 150mm length; using a decreasing polarity mixture of water (containing 0.05% formic acid) and acetonitrile as eluent). MS m/z (ESI): 573.0[ M+H ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.37(d,J＝1.9Hz,1H),8.51(d,J＝2.4Hz,1H),8.15–8.09(m,1H),7.92(d,J＝1.7Hz,1H),7.70(s,1H),7.55–7.50(m,1H),7.44(d,J＝8.5Hz,1H),7.03(d,J＝7.8Hz,1H),4.80–4.70(m,1H),2.99–2.85(m,1H),2.48–2.41(m,1H),2.25(s,3H),2.19–2.10(m,2H),1.97–1.85(m,2H),1.65–1.51(m,2H),1.39–1.28(m,2H),1.17(d,J＝6.2Hz,6H),1.03–0.95(m,2H),0.99–0.88(m,2H).

Example 18: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3, 5-dimethylpyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 057)

The synthetic route is as follows:

intermediate 1 (60 mg, 129.42. Mu. Mol) and 2-bromo-3, 5-lutidine (19.26 mg, 103.53. Mu. Mol) were dissolved in anhydrous N, N-dimethylformamide (4 mL), and tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (7.48 mg, 12.94. Mu. Mol) and cesium carbonate (126.18 mg, 388.26. Mu. Mol) were added under nitrogen. The reaction solution was in the form of a black suspension, and the reaction was stirred at 80℃for 4 hours. LC-MS detection reaction is complete, and the reaction solution is concentrated to dryness under reduced pressure. Purifying by column chromatography (silica, petroleum ether: ethyl acetate=3:2) to give a crude product (50 mg). The title compound (14.74 mg) was obtained by preparative liquid chromatography (YMC-ActusTriart C18 column, 5 μm silica, 30mm diameter, 150mm length; using a decreasing polarity mixture of water (containing 0.05% formic acid) and acetonitrile as eluent). MS m/z (ESI): 569.0[ M+H ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.45(s,1H),8.32(d,J＝2.4Hz,1H),8.12–8.07(m,1H),7.91(d,J＝2.2Hz,1H),7.69(s,1H),7.43–7.35(m,2H),7.03(d,J＝7.8Hz,1H),4.85–4.67(m,1H),2.99–2,83(m,1H),2.49–2.36(m,1H),2.27(s,3H),2.19(s,3H),2.18–2.10(m,2H),1.94–1.88(m,2H),1.64–1.51(m,2H),1.40–1.28(m,2H),1.17(d,J＝6.3Hz,6H),0.99–0.94(m,2H),0.93–0.87(m,2H).

Example 19: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((5-fluoro-3-methoxypyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 059)

The synthetic route is as follows:

intermediate 1 (60 mg, 129.42. Mu. Mol) and 2-bromo-5-fluoro-3-methoxypyridine (24.88 mg, 120.79. Mu. Mol) were dissolved in anhydrous N, N-dimethylformamide (4 mL), and tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (7.48 mg, 12.94. Mu. Mol) and cesium carbonate (126.18 mg, 388.26. Mu. Mol) were added under nitrogen. The reaction solution was in the form of a black suspension, and the reaction was stirred at 80℃for 4 hours. LC-MS detection reaction is complete, and the reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether: ethyl acetate=3:2) afforded crude (50 mg). Purification by preparative liquid chromatography (YMC-ActusTriart C18 column, 5 μm silica, 30mm diameter, 150mm length; using water (0.05% formic acid) and acetonitrile) As eluent) to give the title compound (28.14 mg). MS m/z (ESI): 589.0[ M+H ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(s,1H),8.55(d,J＝2.4Hz,1H),8.25–8.19(m,1H),7.80(d,J＝2.5Hz,1H),7.69(s,1H),7.46–7.37(m,2H),7.03(d,J＝7.8Hz,1H),4.79–4.68(m,1H),3.94(s,3H),2.99–2.86(m,1H),2.47–2.37(m,1H),2.17–2.01(m,2H),1.97–1.87(m,2H),1.59–1.46(m,2H),1.39–1.26(m,2H),1.17(d,J＝6.2Hz,6H),1.02–0.95(m,2H),0.97–0.89(m,2H).

Example 20: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3-fluoro-5-methoxypyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 060)

Synthetic route

Intermediate 1 (40.0 mg,0.09 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.5 mL), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (9.98 mg,0.02 mmol), cesium carbonate (56.2 mg,0.17 mmol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 0.01. Mu. Mol) and 2-bromo-3-fluoro-5-methoxypyridine (17.8 mg,0.09 mmol) were added, and the mixture was stirred for 2h at 90 ℃. LC-MS monitoring showed the reaction was completed, the reaction was added to water (1 mL), EA (1 mL. Times.2) was extracted, the organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, dried by spin-drying, and purified by column chromatography (DCM/MeOH=100:1-30:1) to give crude product (38.0 mg) which was purified by high pressure liquid chromatography [ YMC-Actus Triart C18 column, 5 μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH) ₄ HCO ₃ ) And acetonitrile as eluent; acetonitrile gradient ratio of 45% -70%, eluting time of 13 min ]After lyophilization, the title compound (15.82 mg) was obtained.

MS m/z(ESI):589.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.27(s,1H),8.41(s,1H),8.05–8.02(m,1H),7.88(s,1H),7.69(s,1H),7.54–7.50(m,1H),7.42(d,J＝8.5Hz,1H),7.03(d,J＝7.8Hz,1H),4.76–4.73(m,1H),3.82(s,3H),2.93–2.85(m,1H),2.47–2.34(m,1H),2.15–2.12(m,2H),1.99–1.83(m,2H),1.59–1.55(m,2H),1.45–1.31(m,2H),1.17(d,J＝6.2Hz,6H),0.98–0.96(m,2H),0.92–0.90(m,2H).

Example 21: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3, 5-dimethoxypyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 061)

Synthetic route

Step 1: synthesis of 2-bromo-3, 5-dimethoxypyridine

3, 5-Dimethoxypyridine (500 mg,3.59 mmol) was dissolved in acetonitrile (10 mL), and N-bromosuccinimide (639.53 mg,3.59 mmol) was added. The reaction mixture was stirred at 80℃for 16 hours. LC-MS detection reaction was complete. Concentrated to dryness under reduced pressure, extracted with saturated sodium carbonate (30 mL) and dichloromethane (30 mL x 3), the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to dryness under reduced pressure, and purified by column chromatography (silica, petroleum ether: ethyl acetate=5:1) to give the product 2-bromo-3, 5-dimethoxypyridine (300 mg).

MS m/z(ESI):218.0/220.0[M+H] ⁺ .

Step 2: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3, 5-dimethoxypyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate

Intermediate 1 (60 mg, 129.42. Mu. Mol) and 2-bromo-3, 5-dimethoxypyridine (26.34 mg, 120.7)9. Mu. Mol) was dissolved in anhydrous N, N-dimethylformamide (4 mL), and tris (dibenzylideneacetone) dipalladium (11.85 mg, 12.94. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (7.48 mg, 12.94. Mu. Mol) and cesium carbonate (126.18 mg, 388.26. Mu. Mol) were added under nitrogen. The reaction solution was in the form of a black suspension, and the reaction was stirred at 80℃for 4 hours. LC-MS detection reaction is complete, and the reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether: ethyl acetate=3:2) afforded crude (50 mg). The title compound (28.81 mg) was obtained by preparative liquid chromatography (YMC-ActusTriart C18 column, 5 μm silica, 30mm diameter, 150mm length; using a decreasing polarity mixture of water (containing 0.05% formic acid) and acetonitrile as eluent). MS m/z (ESI): 601.0[ M+H ] ] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ8.73(s,1H),8.53(d,J＝2.4Hz,1H),8.15–8.10(m,1H),7.67(s,1H),7.55(d,J＝2.4Hz,1H),7.37(d,J＝8.5Hz,1H),7.06–6.99(m,2H),4.79–4.66(m,1H),3.90(s,3H),3.81(s,3H),2.98–2.86(m,1H),2.48–2.37(m,1H),2.19–2.09(m,2H),1.96–1.87(m,2H),1.59–1.48(m,2H),1.38–1.26(m,2H),1.16(d,J＝6.3Hz,6H),1.02–0.94(m,2H),0.94–0.87(m,2H).

Example 22: synthesis of isopropyl trans- (4- (5- (2- (cyclopropylsulfonyl) -4- ((3, 5-dichloropyridin-2-yl) amino) phenyl) thiazol-2-yl) cyclohexyl) carbamate (Compound 063)

Synthetic route

Intermediate 1 (40.0 mg,0.09 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.5 mL), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (9.98 mg,0.02 mmol), cesium carbonate (56.2 mg,0.17 mmol), tris (dibenzylideneacetone) dipalladium (7.90 mg, 0.01. Mu. Mol) and 2-bromo-3, 5-dichloropyridine (19.6 mg,0.09 mmol) were added and the mixture was heated to 90℃and stirred2h. LC-MS monitoring showed the reaction was completed, the reaction was added to water (1 mL), EA (1 mL. Times.2) was extracted, the organic phase was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate, dried by spin-drying, and purified by column chromatography (DCM/MeOH=100:1-30:1) to give crude product (35.0 mg) which was purified by high pressure liquid chromatography [ YMC-Actus Triart C18 column, 5 μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH) ₄ HCO ₃ ) And acetonitrile as eluent; acetonitrile gradient ratio of 45% -78%, eluting time of 15 min]After lyophilization, the title compound (12.77 mg) was obtained.

MS m/z(ESI):609.1/611.1[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ9.20(s,1H),8.38(s,1H),8.23(s,1H),8.13(s,1H),8.09–8.06(m,1H),7.72(s,1H),7.48(d,J＝8.4Hz,1H),7.04(d,J＝7.8Hz,1H),4.91–4.62(m,1H),3.30–2.94(m,1H),2.48–2.38(m,1H),2.16–2.13(m,2H),2.05–1.84(m,2H),1.72–1.49(m,2H),1.44–1.29(m,2H),1.17(d,J＝6.2Hz,6H),0.98–0.97(m,2H),0.96–0.92(m,2H).

Biological Activity and related Property test cases

Test example 1: proliferation inhibition test of human small cell lung cancer cell NCI-H526 and human breast cancer cell MDA-MB-468

Brief description of the experimental principles: after incubating the RAD51 inhibitor to be tested with cancer cells for a period of time, the influence of the compound to be tested on cell proliferation is measured by adopting a cell proliferation counting method based on quantitative detection of intracellular ATP content.

Materials and cells: MDA-MB-468 and NCI-H526 cells were purchased from ATCC; fetal bovine serum, DMEM, RPMI 1640 medium and penicillin-streptomycin were purchased from Gibco corporation (usa); 96-well plates were purchased from corning corporation (usa); cell-Titer Glo reagent was purchased from Promega, inc. (USA).

Cell culture: NCI-H526 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum+1% penicillin-streptomycin; MDA-MB-468 cells were cultured with DMEM medium containing 10% fetal bovine serum+1% penicillin-streptomycin; at 37℃with 5% CO ₂ Culturing under the condition. Cells in the logarithmic growth phase can be used for experiments.

Cell proliferation activity assay: the inhibitory activity of the compounds on MDA-MB-468 and NCI-H526 Cell lines was examined using the Cell-Titer Glo reagent. Inoculating 96-well plate at 37deg.C with 5% CO ₂ Culturing for 24 hours under the condition. The test compound is serially diluted in a gradient manner by using DMSO and a culture medium and transferred into a cell plate, wherein the final concentration of the compound is 25 mu M, and the concentration of the compound is 3 times of the concentration dilution, and the total concentration is 10. The experiments were additionally set up with negative and positive controls, as Bottom and Top, respectively. The negative control group is not inoculated with cells, only the culture medium with the same volume is added, and other operations are consistent with those of the experimental group; positive control group normal seed cells, but no test compound, and only DMSO at the same volume, were added, and other procedures were consistent with experimental group. Placing at 37deg.C and 5% CO ₂ Culturing was continued for 7 days under the conditions. Cell-Titer Glo reagent was added to detect Cell activity.

Data analysis:

IC of the resulting compound was calculated as% inhibition of compound (Compound inhibition) and fitted ₅₀ ；

Percentage of inhibition of compound (% Compound inhibition) =1-100% (Signal-Bottom)/(Top-Bottom)

Signal refers to the Signal value of the experimental group, bottom refers to the average Signal value of the negative control group, and Top refers to the average Signal value of the positive control group.

Experimental results:

under the experimental conditions, the compound to be tested shows stronger proliferation inhibition activity on MDA-MB-468 and NCI-H526 cells. The corresponding anti-cell proliferation activity of the test compounds is shown in Table 1.

TABLE 1

Test example 2: pharmacokinetic test in mice

1. Test materials

CB17-SCID mice were purchased from Peking Violet laboratory animal technologies Inc.

NMP (N-methylpyrrolidone), solutol HS15 (polyethylene glycol 15-hydroxystearate), PEG400 (polyethylene glycol), vitamin E TPGS (D-alpha-tocopheryl polyethylene glycol 1000 succinate), verapamil and diclofenac were purchased from Sigma, acetonitrile and formic acid from Merck (USA). K (K) ₂ EDTA anticoagulant tubes were purchased from Jiangsu Xinkang medical instruments Inc.

2. Test method

1. Animal test

(1) Female CB17-SCID mice were divided randomly into 2 groups, 3 groups, 6 (20-30 g,4-6 weeks). The first group was given a corresponding dose of compound solution as shown in Table 2 by tail vein injection with a vehicle of 10%NMP+90%Solutol HS15 in water (10%, w/v); the second group was orally administered a corresponding dose of compound solution as shown in Table 2 in a vehicle of 30%PEG400+70%Vitamin E TPGS in water (10% w/v). Prior to the test, the animals were fed water normally. At the time of the experiment, each group of mice was subjected to intravenous blood sampling at 0.083 (intravenous injection only group), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours before and after administration. The collected whole blood sample is placed in K ₂ In EDTA anticoagulation tube, the mixture was centrifuged for 5min (4000 rpm,4 ℃ C.) to obtain plasma to be measured.

(2) Female CB17-SCID mice 3 (20-30 g,4-6 weeks) were given a mixture of the compound solutions of example 3, example 4, example 7 and example 8 (doses shown in Table 3, vehicle 10%NMP+90%Solutol HS15 in water (10%, w/v)). Prior to the test, the animals were fed water normally. At the time of the test, each mouse was subjected to intravenous blood sampling at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours before and after administration. The collected whole blood sample is placed in K ₂ In EDTA anticoagulation tube, the mixture was centrifuged for 5min (4000 rpm,4 ℃ C.) to obtain plasma to be measured.

2. Sample processing and biological analysis

A10. Mu.L sample of mouse plasma was taken, 150. Mu.L of acetonitrile solvent (containing internal standard compounds verapamil and diclofenac) was added to precipitate the protein, and after vortexing for 1min, it was centrifuged for 15min (4700 rpm,4 ℃) and the supernatant was diluted 2-fold with water containing 0.05% formic acid (v/v) and quantitatively detected using an LC-MS/MS system (AB Sciex Triple Quad 6500+). The CB17-SCID mouse plasma standard curve and quality control samples were followed in determining the sample concentration. To a 10x diluted sample, 2. Mu.L of mouse plasma sample was added with 18. Mu.L of blank plasma, after vortexing for 1min, 300. Mu.L of acetonitrile solvent (containing internal standard compounds verapamil and diclofenac) was added to precipitate the protein, after vortexing for 1min, centrifugation was performed for 15min (4700 rpm,4 ℃) and the supernatant was diluted 2-fold with water containing 0.05% formic acid (v/v) and quantitatively detected using an LC-MS/MS system (AB Sciex Triple Quad 6500+).

3. Data processing

Calculation of pharmacokinetic parameters was performed using the non-compartmental model statistical moment method of Phoenix WinNonlin 8.0.0 software (Certara, USA).

3. Test results

As shown in tables 2 and 3.

Table 2: compound of the application mouse PK experiment

Table 3: compound of the application mouse PK experiment II

Test example 3: mouse tissue distribution test

1. Test materials

CB17-SCID mice were purchased from Peking Violet laboratory animal technologies Inc.

NMP (N-methylpyrrolidone), solutol HS15 (polyethylene glycol 15-hydroxystearate), PEG400 (polyethylene glycol), vitamin E TPGS (D-alpha-tocopheryl polyethylene glycol 1000 succinate), verapamil and diclofenac were purchased from Sigma, acetonitrile and formic acid were purchased from Merck (USA), PBS (phosphate-balanced saline) was purchased from Sangon Biotech (Shangghai). K (K) ₂ EDTA anticoagulant tubes were purchased from Jiangsu Xinkang medical instruments Inc.

2. Test method

1. Animal test

Female CB17-SCID mice were divided randomly into 2 groups, 3 groups, 6 (20-30 g,4-6 weeks). The first and second groups were each given as a mixture of the compound solutions of example 7, example 8, example 10 and example 11 (doses shown in table 4, vehicle 10%NMP+90%Solutol HS15 in water (10%, w/v)) or as a compound solution of example 6 (doses shown in table 4, vehicle 30%PEG400+70%Vitamin E TPGS in water (10%, w/v)). Prior to the test, the animals were fed water normally. The animals of the first group and the second group were subjected to intravenous blood sampling at 4h and 24h after administration, respectively, and the collected whole blood samples were placed in K ₂ In EDTA anticoagulation tube, the mixture was centrifuged for 5min (4000 rpm,4 ℃ C.) to obtain plasma to be measured. The animals of the first group and the second group were subjected to CO immediately after the 4h and 24h blood sampling was completed ₂ Euthanasia, the lungs, fat, breast, muscle and/or pancreas were collected, washed with physiological saline after collection, and the tissue was weighed by blotting the water with filter paper. Weighing, storing in-20deg.C refrigerator, and storing in ultralow temperature refrigerator for long term storage. The tissue will be homogenized in a ratio of tissue weight/PBS 1:9 (m: v, g: mL) prior to analysis.

2. Sample processing and biological analysis

(1) Plasma sample processing and bioanalytical analysis

A10. Mu.L sample of mouse plasma was taken, 150. Mu.L of acetonitrile solvent (containing internal standard verapamil and diclofenac) was added to precipitate the protein, and after vortexing for 1min, it was centrifuged for 15min (4700 rpm,4 ℃) and the supernatant was diluted 2-fold with water containing 0.05% formic acid (v/v) and quantitatively detected using an LC-MS/MS system (AB Sciex Triple Quad 6500+). The CB17-SCID mouse plasma standard curve and quality control samples were followed in determining the sample concentration. For 10x dilution, 2. Mu.L of the sample was taken and added with 18. Mu.L of blank plasma, after vortexing for 1min, 300. Mu.L of acetonitrile solvent (containing internal standard verapamil and diclofenac) was added to precipitate the protein, after vortexing for 1min, centrifugation was performed for 15min (4700 rpm,4 ℃), and the supernatant was diluted 2-fold with water containing 0.05% formic acid (v/v) and quantitatively detected using an LC-MS/MS system (AB Sciex Triple Quad 6500+).

(2) Tissue sample processing and biological analysis

The mouse tissue sample was taken at 20. Mu.L, 20. Mu.L of blank plasma was added, then 600. Mu.L of acetonitrile solvent (containing internal standard verapamil and diclofenac) was added to precipitate the protein, after vortexing for 1min, centrifugation was performed for 15min (4700 rpm,4 ℃) and the supernatant was diluted 2-fold with water containing 0.05% formic acid (v/v) and quantitatively detected using an LC-MS/MS system (AB Sciex Triple Quad 6500+). Quality control samples formulated with CB17-SCID mouse plasma standard curves and mixed matrix of blank tissue and blank plasma (1:1; v/v) were followed in determining sample concentrations. For 10x dilution, 20. Mu.L of mouse tissue sample was added with 180. Mu.L of the corresponding blank tissue, vortexed and homogenized for 1min, 20. Mu.L of tissue sample was taken therefrom, 20. Mu.L of blank plasma was added, then 600. Mu.L of acetonitrile solvent (containing internal standard verapamil and diclofenac) was added to precipitate proteins, vortexed for 1min, centrifuged for 15min (4700 rpm,4 ℃) and the supernatant was taken and diluted 2-fold with water containing 0.05% formic acid (v/v) and quantitatively detected using an LC-MS/MS system (AB Sciex Triple Quad 6500+).

3. Data processing

Plasma and tissue drug concentrations were analyzed using Microsoft Office Excel 2019 (Microsoft, USA) and the tissue plasma concentration ratio was calculated.

3. Test results

As shown in table 4.

Table 4: mouse tissue distribution test

nd: the item is not detected; NA: no drug was detected.

Claims (12)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein: a is selected from phenyl or a six membered heteroaryl group, said six membered heteroaryl group being substituted with one or more R ¹ Substituted, providedThe phenyl groups optionally being substituted by one or more R ² Substitution;

each R is ¹ And R is ² Are independently selected from deuterium, halogen, CN, NO ₂ Amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkyloxy, 4-7 membered heterocyclyl or 4-7 membered heterocyclyloxy, wherein the amino group, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkyloxy, 4-7 membered heterocyclyl or 4-7 membered heterocyclyloxy optionally substituted with one or more R ^a Substitution;

or two adjacent R ¹ Or R is ² And the atoms to which they are attached together form a benzene ring, a 5-6 membered heteroaromatic ring or a 4-7 membered heterocyclic ring, said benzene ring, 5-6 membered heteroaromatic ring or 4-7 membered heterocyclic ring optionally being substituted with one or more R ^b Substitution;

each R is ^a And R is ^b Independently of each other selected from deuterium, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkyl or C _3-6 Cycloalkyl; the amino group, C _1-6 Alkyl or C _3-6 Cycloalkyl optionally substituted with one or more R ^c Substitution;

each R is ^c Independently selected from deuterium, halogen, OH or CN;

the conditions are as follows: the compounds of formula (I) do not comprise

2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the a is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, the pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl being substituted with one or more R ¹ Substituted, said phenyl optionally substituted with one or more R ² And (3) substitution.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein a is selected from the group consisting of Said->Is/are R ¹ Substitution, said->Optionally by one or more R ² And (3) substitution.

4. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from deuterium, halogen, CN, NO ₂ Amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl, said amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one or more R ^a Substitution; the R is ¹ Further preferably selected from halogen, amino, C _1-3 Alkyl, C _1-3 Alkoxy, cyclopropyl or azetidinyl groups, said amino, C _1-3 Alkyl, C _1-3 Alkoxy, cyclopropyl or azetidinyl optionally substituted with one or more R ^a And (3) substitution.

5. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from deuterium, halogen, CN, NO ₂ Amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl, said amino, C _1-6 Alkyl, C _1-6 Alkoxy group、C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one or more R ^a Substituted, or two adjacent R' s ² And the atoms to which they are attached together form a benzene ring, a 5-6 membered heteroaromatic ring or a 4-7 membered heterocyclic ring, said benzene ring, 5-6 membered heteroaromatic ring or 4-7 membered heterocyclic ring optionally being substituted with one or more R ^b Substitution; the R is ² Further preferably selected from halogen or optionally substituted with one or more R ^a Substituted C _1-3 Alkyl, or two adjacent R ² Together with the atoms to which they are attached form a pyrrole or pyrazole ring, optionally substituted with one or more R ^b And (3) substitution.

6. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^a Selected from halogen, OH, amino, CN, C _1-3 Alkyl or C _3-6 Cycloalkyl, the amino group, C _1-3 Alkyl or C _3-6 Cycloalkyl optionally substituted with one or more R ^c And (3) substitution.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (Ia):

Wherein: n is selected from 1, 2, 3 or 4; r is R ¹ As defined in claim 1, provided that the compound of formula (Ia) does not comprise

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (Ib):

wherein: n is selected from 1, 2, 3 or 4; r is R ¹ As defined in claim 1, provided that the compound of formula (Ib) does not comprise

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (Ic):

wherein: m is selected from 0, 1, 2, 3, 4 or 5; r is R ² As defined in claim 1.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

11. a pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

12. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the prevention or treatment of a RAD 51-related disease, preferably wherein the RAD 51-related disease is a tumor.