Novel compounds used as CYP11A1 inhibitors and their applications

Abstract

This invention discloses a novel compound of formula (I) that serves as a CYP11A1 inhibitor useful for treating steroid hormone receptor-mediated symptoms and diseases, including prostate cancer, such as androgen receptor (AR)-dependent symptoms and diseases. The invention further proposes methods for preparation, drug compositions, and uses. JPEG2026517927000139.jpg47170

Description

[Background technology]

[0001] (Cross-reference of related applications) This application claims priority based on the international application filed on 11 May 2023 (Application No.: PCT / CN2023 / 093491), the U.S. applications filed on 26 May 2023 (Application Nos.: 63 / 504, 611), the international application filed on 20 September 2023 (Application No.: PCT / CN2023 / 119980), the U.S. applications filed on 30 October 2023 (Application Nos.: 63 / 594, 170), the U.S. application filed on 2 January 2024 (Application Nos.: 63 / 616, 921), and the international application filed on 4 January 2024 (Application No.: PCT / CN2024 / 070542), incorporating hereby for reference the entire disclosure of these earlier applications.

[0002] Prostate cancer (PC) is one of the most frequently diagnosed cancers in men and is a leading cause of cancer-related death in men worldwide. Advanced prostate cancer has a poor prognosis, with a 5-year survival rate of 31–36%. It is widely recognized that androgens and androgen receptors (ARs) play a crucial role in the development and progression of prostate cancer. Therefore, androgen deprivation therapy (ADT), such as surgical or chemical castration, is a primary treatment strategy in the management of castration-sensitive prostate cancer (CSPC). However, even with an early, beneficial response to ADT, almost all patients inevitably progress from CSPC to a more malignant phenotype known as castration-resistant prostate cancer (CRPC) (Transl Androl Urol. 2021 Oct; 10(10): 3918-3930).

[0003] Multiple mechanisms contribute to the progression of castration-resistant disease. Current evidence supports the concept that progression from the hormonal pre-state to the castration-resistant phenotype is associated with sustained transcriptional activation of the androgen receptor (AR), and that AR remains a crucial driver in this progression. Detailed studies on CRPC have shown that even systematic androgen removal through various mechanisms is dependent on AR signaling (J Carcinog. 2011; 10: 20; Transl Androl Urol. 2015 Jun; 4(3): 365-380). These findings will accelerate the development of novel drugs that inhibit AR signaling, such as enzalutamide (Xtandi), an AR antagonist that inhibits nuclear translocation and chromatin binding, and abiraterone acetate (Zytiga), a cytochrome P450 17A1 (CYP17A1) inhibitor that suppresses androgens originating from the adrenal gland, prostate tumors, and the tumor microenvironment. While these new therapies offer additional survival opportunities, the expected resistance to abiraterone and enzalutamide remains a clinical challenge (Oncogene, 2013 (32): 5501-5511).

[0004] Preclinical studies on CRPC suggest that extragonadal steroid hormones other than androgens can maintain cancer growth by activating mutated or overexpressed ARs. Mutations in the ligand-binding domain (LBD) of ARs alter the conformation of ARs, allowing low-affinity steroid hormones to bind to ARs and promote cancer growth. Furthermore, low-affinity steroids can be converted into higher-affinity AR-binding steroids within cancer tissue. Therefore, suppression of the synthesis of most, or even all, steroid hormones may be beneficial for patients with steroid hormone-dependent cancers such as prostate cancer, even in advanced stages of the disease (Mol Cancer Ther, 2022, 21(12): 1765-1776).

[0005] Since the entire steroid hormone is produced from cholesterol, a single precursor, through a series of enzymatic reactions, and CYP11A1 is the only enzyme that catalyzes the first step in steroid hormone biosynthesis, people hypothesize that inhibition by cytochrome P450 11A1 (CYP11A1) halts the synthesis of the entire steroid hormone. Therefore, compounds with CYP11A1 inhibitory activity have the potential to suppress the biosynthesis of the entire steroid hormone, thereby inhibiting the activation of steroid hormone receptors such as AR. Consequently, CYP11A1 inhibitors may have potential applications in the treatment of steroid hormone-dependent cancers such as CRPC (Mol Cancer Ther, 2022, 21(12): 1765-1776). [Overview of the project]

[0006] The present invention relates to compounds of formula (I). These compounds are potential CYP11A1 inhibitors and are useful in treating steroid hormone-dependent symptoms and diseases. In particular, the compounds according to the present invention are useful in treating AR-dependent symptoms and diseases, including prostate cancer. Furthermore, the present invention further provides drug compositions and methods for treating steroid hormone receptor-mediated diseases.

[0007] A first aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, deuterated derivative, or stereoisomer thereof. [ka] In formula (I), ring A represents a monocyclic, bicyclic, or spirocyclic cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group, or heteroaryl group, and optionally 1 to 3 R 1 Substituted with; here, the heterocyclyl group has one or more ring-forming heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S), or nitrogen (N), and the ring-forming sulfur atom is optionally substituted with two oxo (=O) groups; Ring M represents a monocyclic or fused bicyclic ring containing 0 to 4 ring-forming heteroatoms independently selected from oxygen (O), sulfur (S), or nitrogen (N); here, the ring-forming carbon atoms are optionally substituted with oxo (=O) to form a carbonyl group; Ring B represents a 5- or 6-membered aryl group or heteroaryl group, and is optionally substituted with 1 to 3 R 5 ; X represents -CR 6 R 7 -O- or a chemical bond; n represents 1 or 2; Z represents C or N; R 1 each independently represents H, C 1-7 alkyl group, C 2-7 alkenyl group, C 2-7 alkynyl group, amino group, alkylamino group, dialkylamino group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, halogen element, haloalkyl group, -CN, cyanoalkyl group, -OR 11 -SO2R 11 -SO2NR 12 R 12 ’, -NR 12 SO2R 11 -C(=O)-R 11 -COOR 11 -COONR 12 R 12 ’, -C(=O)-NR 12 R 12 ’-P(=O)R 12 R 12 ’ represents a cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group; here, the cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally substituted with 1 to 3 R 10 ; R 2 and R 2 ’ each independently represents H, halogen element, haloalkyl group, alkoxy group, alkoxyalkyl group, hydroxyl group, hydroxyalkyl group, -CN, cyanoalkyl group, C 1-7R represents an alkyl group, cycloalkyl group, or heterocyclyl group; here, R optionally represents one or more cycloalkyl groups or heterocyclyl groups. 10 Replaced by; R 3 and R 4 Each independently represents H, an alkyl group, a cycloalkyl group, or a heterocyclyl group, and is optionally substituted with one or more substituents independently selected from halogen elements, haloalkyl groups, -OH, hydroxyalkyl groups, alkoxy groups, or -CN; Alternatively, R 3 and R 4 It optionally forms a 3- to 7-membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclyl group with atoms chemically bonded to both; here, the cycloalkyl or heterocyclyl group optionally has 1 to 3 R 10 Replaced by; R 5 Each of these independently represents H, alkyl group, halogen element, haloalkyl group, -OH, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, -CN, cyanoalkyl group, amino group, alkylamino group, dialkylamino group, aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group; here, aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group may independently represent one or more R groups. 10 Replaced by; R 6 and R 7 Each independently represents H, alkyl group, cycloalkyl group, or heterocyclyl group, and optionally one or more R groups. 10 Replaced by; Alternatively, R 6 and R 7 It optionally forms a 3- to 7-membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclyl group with atoms chemically bonded to both; here, the bicyclic or spirocyclic cycloalkyl or heterocyclyl group optionally has 1 to 3 R 10 Replaced by; R 10Each of these independently represents H, alkyl group, halogen element, haloalkyl group, -OH, hydroxyalkyl group, -alkoxy group, -alkoxyalkyl group, CN, or cyanoalkyl group; R 11 , R 12 and R 12 Each of the ' represents independently H, alkyl group, haloalkyl group, aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group, and each may contain one or more R 10 Replaced by; Alternatively, R 12 and R 12 ' optionally forms a cycloalkyl group or heterocyclyl group with atoms chemically bonded to both; here optionally 1 to 3 R cycloalkyl or heterocyclyl groups 10 Replaced by; Any heterocyclyl group not present in ring A has 1 to 4 ring-forming heteroatoms, each independently being oxygen (O), sulfur (S), or nitrogen (N); Any heterocyclyl group that appears is a monocyclic, bicyclic, bridging bicyclic, fused bicyclic, spirocyclic, or polycyclic ring; Any heterocyclyl group that appears is either unsaturated or partially saturated; Each of the resulting heterocyclyl groups has 1 to 4 ring-forming heteroatoms, each independently being oxygen (O), sulfur (S), or nitrogen (N); Any H can be optionally replaced with deuterium (D); p or q is independently 0, 1, 2, or 3. Alternatively, the present invention provides pharmaceutically acceptable salts, tautomers, or stereoisomers of the compound of formula (I).

[0008] In some embodiments, the compound has the structure of formula (II) or (III), [ka] Alternatively, it may be a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; In formula (II) or (III), ring A represents a monocyclic, bicyclic, or spirocyclic cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group, or heteroaryl group, and optionally 1 to 3 R 1 Substituted with; here, the heterocyclyl group has one or more ring-forming heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S), or nitrogen (N), and the ring-forming sulfur atom is optionally substituted with two oxo (=O) groups; Ring M represents a monocycle or fused dicycle containing 0 to 4 ring-forming heteroatoms independently selected from oxygen (O), sulfur (S), or nitrogen (N); here, the ring-forming carbon atoms are optionally substituted with oxo (=O) to form a carbonyl group; Ring B represents a 5-membered or 6-membered aryl group or heteroaryl group, and may optionally be substituted with 1 to 3 R5 groups.

[0009] In some embodiments, the compound has the structure of formula (IIa) or (IIIa), [ka] Alternatively, it may be a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; In formula (IIa) or (IIIa), ring A represents a monocyclic, condensed bicyclic, or spirocyclic cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group, or heteroaryl group, and optionally 1 to 3 R 1 Substituted with; here, the heterocyclyl group has one or more ring-forming heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S), or nitrogen (N), and the ring-forming sulfur atom is optionally substituted with two oxo (=O) groups; Ring M represents a monocycle or fused dicycle containing 0 to 4 ring-forming heteroatoms independently selected from oxygen (O), sulfur (S), or nitrogen (N); here, the ring-forming carbon atoms are optionally substituted with oxo (=O) to form a carbonyl group; Ring B represents a 5-membered or 6-membered aryl group or heteroaryl group, and optionally 1 to 3 R 5 It will be replaced with.

[0010] In some embodiments, [ka] teeth [ka] [ka] That is the case.

[0011] In some embodiments, [ka] teeth [ka] That is the case.

[0012] In some embodiments, the compound has the structure of formula (IV) or (V), [ka] Alternatively, it may be a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; In formula (IV) or (V), ring A represents a monocyclic, bicyclic, or spirocyclic cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group, or heteroaryl group, and optionally 1 to 3 R 1 Substituted with; here, the heterocyclyl group has one or more ring-forming heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S), or nitrogen (N), and the ring-forming sulfur atom is optionally substituted with two oxo (=O) groups; Ring M represents a monocycle or fused dicycle containing 0 to 4 ring-forming heteroatoms independently selected from oxygen (O), sulfur (S), or nitrogen (N); here, the ring-forming carbon atoms are optionally substituted with oxo (=O) to form a carbonyl group.

[0013] An example of ring M is, [ka] [ka] This includes, but is not limited to, these. In each of the above examples, The circle M can be optionally R 2 and / or R 2’ Replaced by; Y1 represents NR, O, or -CRR'-; Y2 represents N, O, or =CR-; Y3 represents O, NR, or -CRR'-; Y4 represents N, O, or CR; W 1 and W 2 These each independently represent O, S, NR, or -CRR'-; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 Each of these independently represents either N or CR; R or R' represents H, alkyl group or cycloalkyl group, and The dashed circle inside the ring [ka] This indicates that the ring contains 1 to 3 double bonds, as far as the valence allows.

[0014] In several experimental cases, ring M is [ka] [ka] [ka] Yes; and ring M can optionally be R 2 and / or R 2 It will be replaced with '.

[0015] An example of ring A is, [ka] This includes, but is not limited to, ring A, which optionally contains 1 to 3 R 1 It is replaced by the base.

[0016] In some embodiments, R 1 is -OH, C 1-7 Alkyl, -CN, -SO2R 11 ,-COOR 11 -C(=O)R 11 , -NR 12 SO2R 11 -C(=O)-NR 12 R 12 ', -SO2NR 12 R 12 'or -P(=O)R 12 R 12 ' represents; here, R 11 Each independently represents H, a cycloalkyl group, a heterocycloyl group, a haloalkyl group, an alkyl group, an aryl group, or a heteroaryl group; in the above, the aryl group, heteroaryl group, cycloalkyl group, and heterocycloyl group are each optionally substituted with one or more alkyl groups, halo groups, or haloalkyl groups; R 12 and R 12 Each of the 's independently represents H, a cycloalkyl group, a haloalkyl group, or an alkyl group.

[0017] In some embodiments, R 3 and R 4 Each of these independently represents either H or an alkyl group; any H can be optionally replaced with D; or R 3 and R 4 It forms a 3- to 7-membered cycloalkyl group with atoms that are chemically bonded to both.

[0018] In some embodiments, R 6 and R 7 Each of these independently represents either H or an alkyl group.

[0019] In some embodiments, the halogen element is -F or -Cl.

[0020] Representative compounds of the present invention include, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] This includes, but is not limited to, the following:

[0021] In some embodiments, the compounds of the present invention have CYP11A1 inhibitory activity.

[0022] Another aspect of the present invention provides a drug composition comprising a therapeutically effective amount of the compound, a pharmaceutically acceptable salt, tautomer, deuterated derivative or stereoisomer thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0023] The compounds or drug compositions of the present invention are useful in treating steroid hormone receptor-dependent symptoms and diseases. In some embodiments, steroid hormone receptor-dependent symptoms and diseases include, but are not limited to, prostate cancer and breast cancer. In some embodiments, the steroid hormone receptor is AR, and the AR-dependent disease is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC).

[0024] In some other embodiments, the drug composition may include a second therapeutic agent.

[0025] Another aspect of the present invention provides a method for treating steroid hormone receptor-dependent symptoms and diseases in a subject requiring treatment, the method comprising administering a therapeutically effective amount of a compound or drug composition to the subject requiring treatment.

[0026] Another aspect of the present invention provides the use of the compound in the manufacture of agents for treating steroid hormone receptor-mediated symptoms and diseases. [Modes for carrying out the invention]

[0027] We refer in detail to preferred embodiments of the present invention and further describe examples thereof. While we describe the present invention in conjunction with preferred embodiments, it should be understood that these embodiments do not limit the invention. Conversely, the present invention aims to include alternatives, modifications, and equivalents that may fall within the spirit and scope of the invention as defined by the claims. Furthermore, while the detailed description of the present invention includes many details for a full understanding of the invention, it will be apparent to those skilled in the art that the invention can be implemented without these details. In other examples, known methods, processes, components, and other features are not described in detail so as not to unnecessarily complicate certain aspects of the invention. definition

[0028] Unless otherwise specified in the context, any reference to formula (I) in any part of this specification (including uses, methods, and other aspects of the invention) includes references to all other subformulas, subgroups, preferred forms, experimental forms, and representative examples as defined herein.

[0029] Unless otherwise specified, the following terms used in this specification and its claims have the following meanings:

[0030] To the extent used herein, the term "or" has both the meanings of "and" and "or." In other words, the term "or" can be replaced with "and / or."

[0031] Various descriptive terms, such as "X," "Y1," and "Z1," are used as general symbols to represent various specific chemical elements.

[0032] The dashed lines represent single or double bonds necessary to satisfy the valence of the atoms linked by the chemical bond.

[0033] To the extent used herein, the term "unsaturated bond" refers to a double bond or a triple bond.

[0034] As used herein, the terms “unsaturated” or “partially unsaturated” refer to a group containing at least one double or triple bond.

[0035] To the extent used herein, the term “saturated” means a group that does not contain a double or triple bond; in other words, the group contains only a single bond.

[0036] To the extent used herein, “alkyl group” as used by itself or as part of another substituent means a linear (i.e., unbranched or straight-chain) or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, and that hydrocarbon chain group (e.g., C1-C 10 or C 1-10The (alkyl group) contains no unsaturated bonds and has a predetermined number of carbon atoms. When it appears in this specification, a numerical range such as "1 to 10" refers to each integer within the predetermined range. For example, "1 to 10 carbon atoms" means that the alkyl group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, and at most 10 carbon atoms. That being said, this definition also applies to the use of "alkyl group" without a predetermined numerical range. Representative saturated straight-chain alkyl groups include, but are not limited to, -methyl group, -ethyl group, -n-propyl group, -n-butyl group, -n-pentyl group, and -n-hexyl group. Saturated branched alkyl groups include, but are not limited to, -isopropyl group, -sec-butyl group, -isobutyl group, -tert-butyl group, -isopentyl group, 2-methylbutyl group, 3-methylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, and 2,3-dimethylbutyl group. The alkyl group is bonded to the parent molecule by a single bond. Unless otherwise specified in this specification, the alkyl group is optionally substituted by one or more substituents.

[0037] Any H in the "alkyl group" can be replaced by deuterium (D), and the alkyl group is called a "deuterated alkyl group".

[0038] The term "alkylene group", used by itself or as part of another molecule, means a divalent group that can be linear or branched and is derived from an alkane group. In this specification, prefixes (e.g., C 1-4 or C 1-7 or C 1-20 or C 2-7 or C 3-7 etc.) indicate the number of carbon atoms or the range of the number of carbon atoms. For example, as used in this specification, the term "C 1-4 alkylene group" refers to an alkylene group having 1 to 4 carbon atoms. Representative examples of linear C 1-8 alkylene groups are -(CH2) nThis includes, but is not limited to, -(n being an integer from 1 to 7). For example, -(CH2) n - refers to -CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Branch C 1-7 Typical examples of alkylene groups include, but are not limited to, -CH(CH3)-, -CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2CH2-, -CH(CH2CH3)-, -CH(CH2CH3)CH2-, and -CH2CH(CH2CH3)CH2-.

[0039] To the extent used herein, the term “alkenyl group,” used by itself or as part of another substituent, refers to a branched or linear unsaturated hydrocarbon chain group having at least one carbon-carbon double bond, obtained by removing one hydrogen atom from a single carbon atom of a parent alkene group. The group has a cis or trans conformation at the double bond. Typical alkenyl groups include, but are not limited to, ethene and propenyl groups.

[0040] To the extent used herein, the term “alkynyl group,” used by itself or as part of another substituent, refers to a carbon chain that may be linear, branched, or a combination thereof, containing at least one carbon-carbon triple bond. Typical examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl groups.

[0041] To the extent used herein, the term “cycloalkyl group,” used by itself or as part of another substituent, refers to a non-aromatic carbon ring consisting of at least three carbon atoms. Cycloalkyl groups include monocyclic cycloalkyl groups, bicyclic cycloalkyl groups, polycyclic cycloalkyl groups, cross-linked cycloalkyl groups, condensed cycloalkyl groups, and spirocyclic cycloalkyl groups. In cross-linked cycloalkyl groups, multiple rings share at least two non-adjacent atoms. In condensed bicyclic cycloalkyl groups, two rings share a covalent bond. In spirocyclic cycloalkyl groups, two distinct rings share one atom.

[0042] To the extent used herein, the term "cycloalkenyl group" refers to a non-aromatic carbocyclic ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond (C=C). Representative examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl groups. The term "heterocycloalkenyl group" is a type of cycloalkenyl group as defined above, in which at least one carbon atom in the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups may be substituted or unsubstituted.

[0043] The term "heterocycloalkyl group" is a type of cycloalkyl group as defined above and is included in the meaning of the term "cycloalkyl group." At least one carbon atom in its ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl groups and heterocycloalkyl groups can be substituted or unsubstituted.

[0044] To the extent used herein, the terms “heterocyclic” or “heterocyclic group” refer to a group derived from a monocyclic, bridging bicyclic, condensed bicyclic, spirocyclic, or polycyclic group comprising at least one non-aromatic ring, the non-aromatic ring containing a ring-forming heteroatom independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is H or another substituent). The heterocyclic group may be unsaturated, saturated, or partially unsaturated. In certain embodiments, the heterocyclic group may have 1 to 4 heteroatoms as ring members. The heterocyclic groups of the present invention are bonded to the parent molecule via carbon atoms or heteroatoms in the group. Accordingly, the terms include, but are not limited to, “heterocycloalkyl groups,” “heteroaryl groups,” “bicyclic heterocyclic groups,” and “polycyclic heterocyclic groups.”

[0045] The term "ring" refers to a closed structure formed by covalent bonds. Rings include, for example, carbocyclic rings (e.g., aryl, cycloalkyl), heterocyclic rings (e.g., heteroaryl, non-aromatic heterocyclic rings), aromatic rings (e.g., aryl, heteroaryl), and non-aromatic rings (e.g., cycloalkyl, non-aromatic heterocyclic rings). Rings may be optionally substituted. Rings may be monocyclic or polycyclic.

[0046] To the extent used herein, the terms “halo group” or “halogen element” refer to fluorine (fluoro group, -F), chlorine (chloro group, -Cl), bromine (bromo group, -Br), or iodine (iodine group, -I).

[0047] The term "haloalkyl group" refers to the alkyl group as defined above, in which one or more hydrogen atoms are substituted with halogen elements independently selected from fluorine, chlorine, bromine, and iodine. "Fluoroalkyl group" refers to the alkyl group as defined above, in which one or more hydrogen atoms are substituted with fluorine. Unless otherwise specified by a number, a haloalkyl group can have as many halogen atoms as chemically permissible as substituents on the alkyl group. For example, a fluoroethyl group may be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0048] To the extent used herein, the term "hydrogen" (H) refers to its isotope deuterium (D or 2 H) and tritium ( 3 Contains H). Any hydrogen atom in the compound of the present invention is deuterium (D or 2 H) or tritium ( 3 It may be replaced with H).

[0049] To the extent used herein, the terms "alkoxy group" or "alkoxyl group" refer to saturated linear or branched hydrocarbons bonded to an oxygen atom. Typical saturated linear alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, and n-hexythoxy groups. Saturated branched alkoxys include isopropoxyl, sec-butoxy, isobutoxy, tert-butoxy, and isopentoxy groups. Cyclic alkoxy groups are referred to herein as "cycloalkoxy groups." 1-4 An "alkoxy group" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. An alkoxy group can be bonded to a molecule by 1 or 2 bonding sites.

[0050] To the extent used herein, the term "haloalkoxy group" refers to an alkoxy group substituted with 1 to 6 halogen atoms.

[0051] As used herein, the term "alkoxyalkyl group" refers to an alkyl group substituted with one, two, or three alkoxy groups.

[0052] To the extent used herein, the term "aryl group" refers to a monocyclic or polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group of 6 to 12 carbon atoms having a fully conjugated π-electron system. Representative examples of aromatic groups are not limited to these, but also include phenyl, naphthyl, and anthracene groups. "Aryl groups" may be substituted or unsubstituted.

[0053] To the extent used herein, the term "heteroaryl group" refers to a monocyclic or fused ring (i.e., a ring sharing adjacent pairs of atoms) containing 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and having a fully conjugated π-electron system. Representative examples of unsubstituted heteroaryl groups are not limited to these, but include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzothiazole, indazole, and quinazoline groups. Heteroaryl groups may be substituted or unsubstituted.

[0054] To the extent used herein, the term "alylene group" refers to a bidentate group obtained by removing two hydrogen atoms from two different aromatic ring atoms of an aromatic compound, the bidentate group having 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has 5 to 7 ring atoms.

[0055] To the extent used herein, the term "hydroxyl group" or "hydroxyl group" refers to -OH.

[0056] The term "hydroxyalkyl group," used either by itself or as part of another substituent, refers to an alkyl group in which one or more hydrogen atoms are substituted with a hydroxyl group. Therefore, the term "hydroxyalkyl group" includes monohydroxyalkyl groups, dihydroxyalkyl groups, trihydroxyalkyl groups, and so on. In "hydroxyalkyl group," the alkyl group is linear (i.e., straight-chain or unbranched) or branched alkyl, and accordingly, "hydroxyalkyl group" includes straight-chain hydroxyalkyl groups and branched hydroxyalkyl groups.

[0057] To the extent used herein, the terms “cyano group” or “-CN” refer to a -CΞN group; the terms “cyanoalkyl group” or “-alk-CN” refer to an alkyl group having at least one -CN substituent. Generally, when a compound is bonded to an “-alk-CN”, the alkylene portion of the “-alk-CN” is bonded to the compound. In a “cyanoalkyl group”, the alkyl group can be a linear (i.e., straight-chain or unbranched) alkyl group or a branched alkyl group. Accordingly, “cyanoalkyl groups” include straight-chain cyanoalkyl groups and branched cyanoalkyl groups.

[0058] To the extent used herein, the term "amino group" or "amine group" refers to -NH2. The term "alkylamino group" refers to a group having the formula -NHR, and the term "dialkylamino group" refers to a group having the formula -NRR', where R and R' independently represent an alkyl group.

[0059] To the extent used herein, the terms "-SO2-" or "-S(=O)2-" are: [ka] This refers to sulfur dioxide having the following structure.

[0060] To the extent used herein, the terms "carbonyl group" or "-C(=O)-" or "-CO-" are defined as follows: [ka] This refers to a group having the structure shown.

[0061] To the extent used herein, the terms "-CO2-" or "-COO-" are: [ka] This refers to a group having the structure shown.

[0062] The groups defined above include prefixes and / or suffixes commonly used in this art to create additional well-known substituents. For example, the terms “haloalkoxy group” or “(haloalkyl)oxy group” refer to a haloalkyl group bonded to a parent molecular group via an oxygen atom. The term “(haloalkyl)oxyalkyl group” refers to an alkyl group substituted with one, two, or three (haloalkyl)oxy groups.

[0063] To the extent used herein, the term "nothing" defining a variable such as "X" means that the defined variable does not exist, and therefore two atomic groups connected through that variable are directly connected to each other.

[0064] To the extent used herein, the term "OXO" (used alone or in combination with other terms) means (=O).

[0065] To the extent used herein, the term “bond” refers to a covalent bond between two atoms or two groups, and may mean a single bond, a double bond, or a triple bond.

[0066] The term "stereoisomer" refers to isomers of the same structure that differ only in the spatial arrangement of atoms, not in the order of atomic bonding. When a compound is named or depicted by its structure without showing its stereochemistry, the name or structure is understood to include all possible stereoisomers, including pure stereoisomers, and even combinations thereof. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecules that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to a stereoisomer that is not a mirror image of each other. The term "racemate" or "racemic mixture" refers to a mixture consisting of two enantiomers that are not optically active and are present in equimolar amounts.

[0067] The term "chiral" refers to a structural characteristic of a molecule that prevents it from being superimposed onto its own mirror image.

[0068] To the extent used herein, the term "tautomer" refers to two or more isomers of a compound that coexist in equilibrium and are readily interconverted by the movement of atoms or groups of atoms within the molecule. Accordingly, the present invention aims to include all possible tautomers, even if a given structure exhibits only one of those isomers.

[0069] The term "optional" means that the situation or condition described later may occur, but does not necessarily occur, and that the description includes both cases where the situation or condition occurs and cases where it does not. For example, "the heterocyclyl group is optionally substituted with an alkyl group" means that the alkyl group may be present, but does not necessarily exist, and this description includes both cases where the heterocyclyl group is substituted with an alkyl group and cases where it is not.

[0070] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable, non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids, which, within the scope of careful medical evaluation, do not cause excessive toxicity, irritation, allergic reactions or other problems or complications when in contact with patient tissue, have a reasonable benefit / risk ratio, and are effective for their intended use. Salts obtained from inorganic bases include salts of aluminum, ammonium, calcium, copper, iron trivalent, iron divalent, lithium, magnesium, manganese, divalent manganese, potassium, sodium, and zinc. Particularly preferred salts are those of ammonium, calcium, magnesium, potassium, and sodium. Salts obtained from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines, tertiary amines, substituted amines (naturally occurring substituted amines), cyclic amines, and base ion exchange resins, such as salts of arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and others.

[0071] When the compound of the present invention is basic, the salt may be prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethaneic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred acids are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0072] To the extent used herein, it is understood that this includes pharmaceutically acceptable salts of the compound of formula (I).

[0073] "Drug composition" refers to a mixture of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and other chemical components such as pharmaceutically acceptable excipients. The purpose of a drug composition is to facilitate the administration of the compound to an organism.

[0074] "Pharmacologically acceptable excipients" refer to inert substances added to drug compositions to further facilitate the administration of compounds. Typical examples of excipients, but not limited to these, include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0075] The term "therapeutic dose" refers to the amount of a compound administered to alleviate, to some extent, one or more symptoms of the disease being treated. In the context of cancer treatment, the therapeutic dose refers to the amount that has the effect of (1) reducing the size of the tumor, (2) inhibiting tumor metastasis, (3) inhibiting tumor growth, and / or (4) alleviating one or more symptoms associated with cancer.

[0076] To the extent used herein, the terms “subject” and “patient” are interchangeable and refer to any animal subject, including but not limited to humans, laboratory animals (e.g., primates, rats, mice, etc.), livestock (e.g., cattle, sheep, goats, pigs, turkeys, chickens, etc.), and domestic pets (e.g., dogs, cats, rodents, etc.).

[0077] The compounds described herein can be administered to patients in various forms based on a selective route of administration, as will be understood by those skilled in the art. Compounds based on the teachings of the present invention may be administered, for example, orally, by injection, buccal mucosa, sublingual, nasal, rectal, patch, absorption, or transdermal administration, and pharmaceutical compositions may be prepared thereon. Parenteral administration includes methods of intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration. Parenteral administration is carried out by continuous infusion over a selective period. Structure of isomers

[0078] The present invention provides a novel compound of formula (I) or a pharmaceutically acceptable salt thereof that serves as a CYP11A1 inhibitor. [ka]

[0079] Some compounds (or salts, prodrugs, or complexes) of the present invention can exist and be separated in isomeric structures including tautomers, geometric isomers (i.e., cis or trans isomers), optical isomers (i.e., enantiomers and diastereomers), racemates, or any mixture of these isomeric structures. It should be understood that the present invention includes compounds of formula (I) that exist in any isomeric form or as mixtures thereof, for example, compounds of formula (I) that exist in the form of an active single enantiomer, a racemate, or any mixture thereof. The present invention aims to include any isomeric form of compounds of formula (I).

[0080] Furthermore, the compounds (or salts, prodrugs, or complexes) of the present invention may exhibit polymorphisms or form solvates with water or organic solvents. The present invention also encompasses any of these polymorphisms, solvates, or mixtures thereof. Example 1 2-(isoindoline-2-ylmethyl)-5-(((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)methoxy)-4H-pyran-4-one [ka]

[0081] Step 1: Add pyridine (2.0 mL, 2.6 eq) and p-CF3PhSO2Cl (2.8 g, 1.2 eq) to a solution of compound 1 (2.0 g, 1.0 eq) in DCM (20 mL) and stir at 25°C for 16 hours. Purify the reaction product by column chromatography to obtain a colorless oily compound 2 (1.3 g, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 3.70-3.39 (m, 4H), 3.38-3.27 (m, 2H), 1.59-1.50 (m, 2H), 1.49-1.35 (s, 9H), 1.18-1.04 (m, 1H).

[0082] Step 2: Add Cs2CO3 (2.8 g, 2.0 eq) and compound 3 (1.2 g, 2.0 eq) to a DMA (10 mL) solution of compound 2 (1.0 g, 1.0 eq) and stir at 70°C for 16 hours. Purify the reaction mixture by column chromatography to obtain a colorless oily compound 4 (630 mg, 43% yield). MS m / z: 338.1 (M+1) + . 1 H NMR (400 MHz, CDCl3) δ 7.75-7.51 (m, 1H), 6.74-6.28 (m, 1H), 4.57-4.40 (m, 2H), 4.00-3.86 (m, 1H), 3.85-3.73 (m, 1H), 3.69-3.55 (m, 2H), 3.43-3.30 (m, 2H), 3.00 (br s, 1H), 1.61-1.50 (m, 2H), 1.50-1.37 (m, 9H), 1.19-0.98 (m, 1H).

[0083] Step 3: Add DIEA (160 mg, 3.0 eq) and methylsulfonylmethanesulfonate (143 mg, 2.0 eq) to a solution of compound 4 (140 mg, 1.0 eq) in DCM (5 mL), stir at 20°C for 0.5 hours to concentrate the reaction, and dissolve in CH3CN (3 mL). Then add DIEA (72 μL, 1.0 eq) and ioisoindoline (132 mg, 2.0 eq), and stir at 20°C for 2 hours. Purify the reaction by column chromatography to obtain compound 5.

[0084] Step 4: Dissolve compound 5 (150 mg, 1.0 eq) in HCl / MeOH (2 M, 1.7 mL), stir at 20°C for 0.5 hours to concentrate the reaction, and dissolve in DCM (5 mL). Add DIEA (293 μL, 5.0 eq) and Ms2O (117 mg, 2.0 eq) and stir at 20°C for 0.5 hours. Purify the reaction by column chromatography to obtain 2-(isoindolin-2-ylmethyl)-5-(((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)methoxy)-4H-pyran-4-one. MS m / z: 417.1 (M+1) + . 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.43 (s, 4H), 6.74 (s, 1H), 4.82 (br s, 4H), 4.68 (s, 2H), 3.89 (d, J=7.2 Hz, 2H), 3.53 (d, J=9.2 Hz, 2H), 3.39 (d, J=9.2 Hz, 2H), 2.88 (s, 3H), 1.73 (br s, 2H), 1.40-1.36 (m, 1H).

[0085] The synthesis method for Example 2-13 is similar to that of Example 1. JPEG2026517927000031.jpg250170JPEG2026517927000032.jpg255167JPEG2026517927000033.jpg250170JPEG2026517927000034.jpg150170JPEG2026517927000035.jpg170170JPEG2026517927000036.jpg130170JPEG2026517927000037.jpg160170JPEG2026517927000038.jpg150170 Example 13 5-(isoindoline-2-ylmethyl)-2-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)-7H-fluoro[3,2-b]pyran-7-one [ka]

[0086] Step 1: Add NaOH (34 g, 1.2 eq) and I2 (214 g, 1.2 eq) to a solution of 5-hydroxy-2-(hydroxymethyl)pyran-4-one (100 g, 1.0 eq) in H2O (1200 mL), gradually adding in an ice bath and stirring at 25°C for 16 hours. Filter the mixture and wash the filter cake with SiO2 (30 mL x 3). Grind the crude product with SiO2 and concentrate under reduced pressure to obtain yellow solid compound 2 (78 g, 42% yield). MS m / z 269.0 (M+1) + .

[0087] Step 2: Add copper(I) iodide (1.60 g, 0.2 eq) and Pd(PPh3)2Cl2 (2.95 g, 0.1 eq) to a toluene solution (200 mL) of compound 3 (8.7 g, 1.0 eq) (Bioorg. & Med. Chem., 2021, 30, 115964), compound 2 (11.25 g, 41.97 mmol, 1 eq), and triethylamine (116.8 mL, 20.0 eq). Stir at 30°C for 16 hours, and purify the reaction by column chromatography to obtain yellow solid compound 4 (5 g, yield 34%). MS m / z: 348.2 (M+1) + . 1 H NMR (500 MHz, CDCl3) δ 6.48 (s, 1H), 6.30 (s, 1H), 4.56 (s, 2H), 3.77-3.65 (m, 2H), 3.55-3.42 (m, 2H), 2.18 (t, J=2.5 Hz, 2H), 1.85 (t, J=3.5 Hz, 1H), 1.45 (s, 9H).

[0088] 5-(isoindolin-2-ylmethyl)-2-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)-7H-fluoro[3,2-b]pyran-7-one can be obtained by following steps similar to those in Example 1. MS m / z: 427.1 (M+1) + . 1 H NMR (400 MHz, CD3OD) δ 7.43 (s, 4H), 6.75 (s, 1H), 6.73 (s, 1H), 4.83 (s, 4H), 4.74 (s, 2H), 3.68 (d, J=9.6 Hz, 2H), 3.51 (d, J=8.8 Hz, 2H), 2.94 (s, 3H), 2.33 (s, 3H).

[0089] The synthesis methods for Examples 14-54 are similar to those for Example 13. JPEG2026517927000040.jpg190170JPEG2026517927000041.jpg240170JPEG20265179270 00042.jpg230170JPEG2026517927000043.jpg230170JPEG2026517927000044.jpg210170J PEG2026517927000045.jpg220170JPEG2026517927000046.jpg170170JPEG202651792700 0047.jpg200170JPEG2026517927000048.jpg250170JPEG2026517927000049.jpg220170JP EG2026517927000050.jpg180170JPEG2026517927000051.jpg190170JPEG2026517927000 052.jpg200170JPEG2026517927000053.jpg210170JPEG2026517927000054.jpg200170JPE G2026517927000055.jpg220170JPEG2026517927000056.jpg210170JPEG2026517927000057.jpg255167JPEG2026517927000058.jpg170170JPEG2026517927000059.jpg250170Example 55 6-(isoindoline-2-ylmethyl)-2-(1-(methylsulfonyl)piperidine-4-yl)quinoxaline [ka]

[0090] Step 1: Add compound 2 (7.6 g, 1.2 eq), Cs2CO3 (20.1 g, 3.0 eq), and Pd(PPh3)4 (2.37 g, 0.1 eq) to a solution of compound 1 (5.0 g, 1.0 eq) in THF (100 mL) and H2O (20 mL), and stir at 80°C for 1 hour under a nitrogen atmosphere. Then, purify the reaction product by column chromatography to obtain red solid compound 3 (7.7 g, 96% yield). MS m / z: 392.1 (M+1) + . 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.23 ​​(d, J=2.0 Hz, 1H), 7.95-7.86 (m, 1H), 7.82-7.76 (m, 1H), 6.82 (br s, 1H), 4.23 (d, J=1.6 Hz, 2H), 3.70 (t, J=5.6 Hz, 2H), 2.83 (br s, 2H), 1.51 (s, 9H).

[0091] Step 2: Add tributyltin methanol (4, 9.5 g, 1.5 eq) and X-Phos Pd G2 (1.6 g, 0.1 eq) to a solution of compound 3 (7.7 g, 1.0 eq) in toluene (100 mL), stir at 90°C for 1 hour, then purify the reaction by column chromatography to obtain red solid compound 5 (4 g, 59% yield). MS m / z: 342.0 (M+1) + .

[0092] Step 3: Add TEA (1.5 mL, 3.0 eq), Et3SiH (1.7 mL, 3.0 eq), and PdCl2 (63 mg, 0.1 eq) to a solution of compound 5 (1.9 g, 1.0 eq) in THF (20 mL) and stir at 25°C for 1 hour. After the reaction, purify the reaction product by column chromatography to obtain white solid compound 6 (1.9 g, 100% yield). MS m / z: 344.1 (M+1) + .

[0093] The compound of Example 55 can be obtained by following the same steps as in Example 1. MS m / z: 423.0 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 8.33 (br s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.41 (s, 4H), 4.83-4.73 (m, 6H), 3.92 (d, J=11.6 Hz, 2H), 3.28-3.19 (m, 1H), 3.04-2.96 (m, 2H), 2.91 (s, 3H), 2.22-2.14 (m, 2H), 2.11-1.93 (m, 2H). Example 56 6-(isoindoline-2-ylmethyl)-2-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)quinoline [ka]

[0094] Step 1: Add TMEDA (3.6 mL, 8.0 eq) to a solution of chromium(II) chloride (2.9 g, 8.0 eq) in THF (60 mL) and stir at 20°C for 15 minutes to obtain a blue mixture. Add the resulting mixture to a solution of compound 1 (500 mg, 1.0 eq) in THF (20 mL). Then add compound 2 (1.25 g, 2.0 eq) and a solution of LiI (1.6 g, 4.0 eq) in THF (30 mL) and stir at 20°C for 16 hours. After the reaction, purify the reactants by column chromatography to obtain a colorless oily compound 3 (300 mg, yield 33%). 1 H NMR (400 MHz, CDCl3) δ 3.64-3.49 (m, 2H), 3.39-3.25 (m, 2H), 1.68-1.60 (m, 2H), 1.45-1.39 (m, 9H), 1.22 (s, 12H), 0.15-0.31 (m, 1H).

[0095] Step 2: Add cataCXium A Pd G3 (61 mg, 0.1 eq) and Cs2CO3 (821 mg, 3.0 eq) to a solution of compound 3 (260 mg, 1.0 eq) and compound 4 (223 mg, 1.2 eq) in H2O (2 mL) and 2-methylbutyl-2-ol (8 mL), stir at 90°C for 1 hour, and after the reaction, purify the reaction product by column chromatography to obtain yellow solid compound 5 (140 mg, yield 45%). MS m / z: 369.2 (M+1) + . 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J=1.2 Hz, 1H), 8.29-8.21 (m, 1H), 8.17-8.07 (m, 1H), 8.04-7.89 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.99 (s, 3H), 3.84 (d, J=11.2 Hz, 1H), 3.78-3.73 (m, 1H), 3.61-3.51 (m, 2H), 2.39-2.26 (m, 2H), 2.12-2.03 (m, 1H), 1.49 (s, 9H).

[0096] Step 3: Add LiAlH4 (43 mg, 3.0 eq) to a solution of compound 5 (140 mg, 1.0 eq) in THF (6 mL) at -78 °C, stir at 0 °C for 10 minutes, and after the reaction, purify the reactants by column chromatography to obtain a white solid compound 6 (110 mg, 85% yield). MS m / z: 341.2 (M+1) + . 1 H NMR (400 MHz, CDCl3) δ 8.09-7.89 (m, 2H), 7.75 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.91-4.83 (m, 2H), 3.86-3.72 (m, 2H), 3.60-3.50 (m, 2H), 2.34-2.23 (m, 2H), 1.93-1.83 (m, 1H), 1.49 (s, 9H).

[0097] 6-(isoindoline-2-ylmethyl)-2-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)quinoline can be obtained by following the same steps as in Example 1. MS m / z: 420.1 (M+1) + . 1 H NMR (500 MHz, CD3OD) δ 9.00 (d, J=8.5 Hz, 1H), 8.53 (s, 1H), 8.34-8.27 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.47-7.40 (m, 4H), 4.96 (s, 2H), 4.82 (s, 4H), 3.85 (d, J=10.0 Hz, 2H), 3.67 (d, J=10.0 Hz, 2H), 3.02 (s, 3H), 2.75-2.70 (m, 3H).

[0098] The synthesis method for Example 57-133 is similar to that of Examples 55 and 56. JPEG2026517927000062.jpg250170JPEG2026517927000063.jpg250170JPEG2026517927000064.jpg230170JPEG2026517927000065.jpg255167JPEG2026517927000066.jpg240170JPEG2026517927000067.jpg131170JPEG2026517927000068.jpg140170JPEG2026517927000069.jpg250170JPEG2026517927000070.jpg140170JPEG2026517927000071.jpg150170JPEG2026517927000072.jpg150170JPEG2026517927000073.jpg230170JPEG2026517927000074.jpg180170JPEG2026517927000075.jpg240170JPEG2026517927000076.jpg250170JPEG2026517927000077.jpg210170JPEG2026517927000078.jpg255167JPEG2026517927000079.jpg230170JPEG2026517927000080.jpg150170JPEG2026517927000081.jpg140170JPEG2026517927000082.jpg140170JPEG2026517927000083.jpg255167JPEG2026517927000084.jpg140170JPEG2026517927000085.jpg150170JPEG2026517927000086.jpg120170JPEG2026517927000087.jpg160170JPEG2026517927000088.jpg255167JPEG2026517927000089.jpg150170JPEG2026517927000090.jpg150170JPEG2026517927000091.jpg255167JPEG2026517927000092.jpg160170JPEG2026517927000093.jpg250170JPEG2026517927000094.jpg140170JPEG2026517927000095.jpg250170JPEG2026517927000096.jpg255167JPEG2026517927000097.jpg120170JPEG2026517927000098.jpg 150170JPEG2026517927000099.jpg255167JPEG2026517927000100.jpg255167JPEG2026517927000101.jpg140170JPEG2026517927000102.jpg1401 70JPEG2026517927000103.jpg 140170JPEG2026517927000104.jpg 250170JPEG2026517927000105.jpg 255167JPEG2026517927000106.jpg 255167JPEG2026517927000107.jpg 160170JPEG2026517927000108.jpg 240170JPEG2026517927000109.jpg 230170JPEG2026517927000110.jpg 240170 Example A. H295R steroid biosynthesis inhibition test

[0099] The inhibitory effects of experimental compounds on steroid biosynthesis in NCI-H295R cells (ATCC) were investigated by measuring the cellular production of progenenolon (P) and the downstream steroid testosterone (T) catalyzed by CYP11A1. Cells were cultured in Dulbecco's modified Eagle medium F12 (DMEM / F12) (Gibco, Cat. No. 11330032) containing phenol red, supplemented with 2% UltroserG (Pall, Cat. No. 15950-017, USA), 1% ITS-Premix, and 1% penicillin-streptomycin (Hyclone, Cat. No. SV30010, USA). Before the study, cells were thawed and passaged four times. The maximum number of passages for this study was set at 10. In this study, DMEM / F12 supplemented with phenol red-free, 10% charcoal-treated fetal bovine serum (VivaCell, Cat. No. C3830-0500, USA) was used. 60,000 cells (90 μL / well) were seeded per well in a 96-well plate and cultured for 24 hours. Experimental compounds were diluted in the test medium using a serial dilution method from 1000 nM to 0.15 nM and added to the well plate. After 48 hours of culture, the solutions were collected from each well and transferred to individual 1.5 mL centrifuge tubes. Then, 5 ng / mL of deuterated testosterone (D3-testosterone) and 50 ng / mL of deuterated pregnenolone (D4-pregnenolone) were added to 200 μL of acetonitrile. After vigorous mixing for 5 minutes, the mixtures were centrifuged at 12,700 rpm for 15 minutes. The supernatant was collected in 250 μL portions and dried under a nitrogen gas stream. 150 μL of methanol:water (1:1, v / v) was added to the dried product, and 50 μL of the sample was taken and injected into an LC-MS / MS system for analysis.

[0100] Using GraphPad Prism software, the semi-maximal inhibitory concentration (IC) for steroid biosynthesis inhibition was determined by curve fitting using a four-variable inhibitory reaction equation. 50 ) was confirmed. LC-MS / MS analysis of steroid hormones

[0101] Testosterone and progesterone were analyzed via a positive ionization mode ESI interface using a Shimadzu LC30AD HPLC system (Shimadzu, Kyoto, Japan) in combination with an AB Sciex Qtrap 5500 triple quadrupole mass spectrometer (AB Sciex, Framingham, MA, USA). Analytes and IS were separated from the sample matrix using an ACQUITY UPLC BEH Shield RP18 column (1.7 μm, 2.1 × 50 mm, Milford, MA, USA) maintained at 40°C.

[0102] The mobile phase is a mixture of a 10 mM aqueous solution of ammonium acetate containing 0.2% formic acid (A) and methanol containing 0.2% formic acid (B), with a flow rate of 0.6 mL / min. The gradient program was set as follows: 60% solvent B from 0 to 0.5 min; 90% solvent B from 0.5 to 3.5 min; 90% solvent B from 3.5 to 4.5 min; and 60% solvent B from 4.51 to 5.0 min. The injection volume is 50 mL.

[0103] The MS / MS parameters were set as follows: ion spray voltage 5500 V, curtain gas 35 psi, gas 1 55 psi, gas 2 55 psi, and temperature 55 °C. The fragmentation transitions and MS parameters for multiple reaction monitoring (MRM) optimization of each analyte are summarized in Table 1. JPEG2026517927000111.jpg113170

[0104] The compounds of the present invention were selected in the above tests, and the IC of the compounds 50 The values ​​are shown in Table 2 below. Here, "A" is IC. 50 ≤ 40 nM, where "B" is 41 ≤ IC 50 ≤100 nM, where "C" is IC. 50 This represents ≥10¹ nM. Table 2. Analysis of the effect on the suppression of steroid biosynthesis JPEG2026517927000112.jpg255160JPEG2026517927000113.jpg255159JPEG2026517927000114.jpg168170

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. 【Chemistry 1】 (In formula (I), ring A represents a monocyclic, bicyclic, or spirocyclic cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group, or heteroaryl group, and optionally 1 to 3 R １ Substituted with; here, the heterocyclyl group has one or more ring-forming heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S), or nitrogen (N), and the ring-forming sulfur atom is optionally substituted with two oxo (=O) groups; Ring M represents a monocycle or fused dicycle containing 0 to 4 ring-forming heteroatoms independently selected from oxygen (O), sulfur (S), or nitrogen (N); here, the ring-forming carbon atoms are optionally substituted with oxo (=O) to form a carbonyl group; Ring B represents a 5-membered or 6-membered aryl group or heteroaryl group, and optionally 1 to 3 R ５ Replaced by; X is -CR ６ R ７ -O- represents a chemical bond; n represents either 1 or 2; Z represents C or N; R １ is, independently of each other, H, C １－７ alkyl group, C ２－７ alkenyl group, C ２－７ alkynyl group, amino group, alkylamino group, dialkylamino group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, halogen element, haloalkyl group, -CN, cyanoalkyl group, -OR １１ , -SO ２ R １１ , -SO ２ NR １２ R １２ ’, -NR １２ SO ２ R １１ , -C(=O)-R １１ , -COOR １１ , -COONR １２ R １２ ’, -C(=O)-NR １２ R １２ ’, -P(=O)R １２ R １２ ’ represents a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group; here, the cycloalkyl group, the heterocyclyl group, the aryl group or the heteroaryl group is optionally substituted with 1 to 3 R １０ ; R ２ and R ２ ' are, independently, H, halogen element, haloalkyl group, alkoxy group, alkoxyalkyl group, hydroxyl group, hydroxyalkyl group, -CN, cyanoalkyl group, C １－７ R represents an alkyl group, a cycloalkyl group, or a heterocyclyl group; here, R represents one or more cycloalkyl groups as optional. １０ Replaced by; R ３ and R ４ Each independently represents H, an alkyl group, a cycloalkyl group, or a heterocyclyl group, and is optionally substituted with one or more substituents independently selected from halogen elements, haloalkyl groups, -OH, hydroxyalkyl groups, alkoxy groups, or -CN; Or, R ３ and R ４ It optionally forms a 3- to 7-membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclyl group with atoms chemically bonded to both; here, the cycloalkyl or heterocyclyl group optionally has 1 to 3 R １０ Replaced by; R ５ Each of these independently represents H, alkyl group, halogen element, haloalkyl group, -OH, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkoxyalkyl group, -CN, cyanoalkyl group, amino group, alkylamino group, dialkylamino group, aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group; here, aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group may independently contain one or more R groups. １０ Replaced by; R ６ and R ７ Each independently represents H, alkyl, cycloalkyl, or heterocyclyl group, and optionally one or more R １０ Replaced by; Or, R ６ and R ７ Together with atoms chemically bonded to both, it optionally forms a 3- to 7-membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclyl group; here, the bicyclic or spirocyclic cycloalkyl or heterocyclyl group optionally has 1 to 3 R １０ Replaced by; R １０ Each of these independently represents H, alkyl group, halogen element, haloalkyl group, -OH, hydroxyalkyl group, -alkoxy group, -alkoxyalkyl group, CN, or cyanoalkyl group; R １１ , R １２ and R １２ Each of the ' represents independently H, alkyl group, haloalkyl group, aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group, and each may contain one or more R １０ Replaced by; Or, R １２ and R １２ ' optionally forms a cycloalkyl group or heterocyclyl group with atoms chemically bonded to both; here optionally 1 to 3 R cycloalkyl groups or heterocyclyl groups １０ Replaced by; Any heterocyclyl group not appearing in ring A has 1 to 4 ring-forming heteroatoms, each independently being oxygen (O), sulfur (S), or nitrogen (N); Any heterocyclyl group that appears is a monocyclic, bicyclic, bridging bicyclic, condensed bicyclic, spirocyclic, or polycyclic ring, and is unsaturated or partially saturated; Each of the resulting heterocyclyl groups has 1 to 4 ring-forming heteroatoms, each independently being oxygen (O), sulfur (S), or nitrogen (N); Any H can be optionally replaced with deuterium (D); p or q is independently 0, 1, 2, or 3.

2. The compound according to claim 1, characterized by having the structure of formula (II) or (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. 【Chemistry 2】 (In formula (II) or (III), ring A represents a monocyclic, bicyclic, or spirocyclic cycloalkyl group, cycloalkenyl group, or heterocyclyl group, and optionally 1 to 3 R １ Substituted with; here, the heterocyclyl group has one or more ring-forming heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S), or nitrogen (N), and the ring-forming sulfur atom is optionally substituted with two oxo (=O) groups; Ring M represents a monocycle or fused dicycle containing 0 to 4 ring-forming heteroatoms independently selected from oxygen (O), sulfur (S), or nitrogen (N); here, the ring-forming carbon atoms are optionally substituted with oxo (=O) to form a carbonyl group; Ring B represents a 5-membered or 6-membered aryl group or heteroaryl group, and optionally 1 to 3 R ５ (It will be replaced by...) 【Request Item 3】 【Chemistry 3】 【Chemistry 4】 The compound according to claim 1 or 2, characterized in that it is the compound described above. [Request Item 4] [Chemistry 5] but 【Transformation 6】 The compound according to claim 3, characterized in that it is the compound described above.

5. A compound according to any one of claims 1-4, characterized by having the structure of formula (IV) or (V). 【Transformation 7】

6. The circle M is 【Chemistry 9】 【Chemistry 10】 And ring M can optionally be R ２ and R ２ The compound according to claim 1, 2, or 5, characterized by being substituted with ', or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. (In the above formula, Y １ represents NR, O, or -CRR'-; Y ２ represents N, O, or =CR-; Y ３ represents O, NR, or -CRR'-; Y ４ represents N, O, or CR; W １ and W ２ Each of these independently represents O, S, NR, or -CRR'-; Z １ Z ２ Z ３ Z ４ Z ５ and Z ６ Each independently represents N or CR; R or R' represents H, an alkyl group, or a cycloalkyl group; the dashed circle within the ring. 【Chemistry 11】 This indicates that the ring contains 1 to 3 double bonds, as far as the valence allows.

7. The circle M is 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 Yes, and the ring M can optionally be R ２ and R ２ The compound according to claim 6, characterized by being substituted with '.

8. The compound according to claim 1, characterized in that the halogen element is -F or -Cl.

9. Ring A is 【Chemistry 15】 【Chemistry 16】 Furthermore, ring A may have 1 to 3 R １ The compound according to claim 1, 2, or 5, characterized by being substituted with a group.

10. R １ -OH, C １－７ Alkyl, -CN, -SO ２ R １１ , -COOR １１ , -C(=O)R １１ , -NR １２ SO ２ R １１ , -C(=O)-NR １２ R １２ ', -SO ２ NR １２ R １２ 'or -P(=O)R １２ R １２ ' represents; R １１ Each independently represents H, a cycloalkyl group, a heterocycloyl group, a haloalkyl group, an alkyl group, an aryl group, or a heteroaryl group; the aryl group, heteroaryl group, cycloalkyl group, and heterocycloyl group are each optionally substituted with one or more alkyl groups, halo groups, or haloalkyl groups; R １２ and R １２ Each of the 's independently represents H, a cycloalkyl group, a haloalkyl group, or an alkyl group. The compound according to feature 9.

11. R ３ and R ４ each independently represent H or an alkyl group; any H is optionally replaced by D; or, R ３ and R ４ together with the atoms to which both are chemically bonded form a 3- to 7-membered cycloalkyl group The compound according to feature 1.

12. R ６ and R ７ The compound according to claim 1, characterized in that each of them independently represents H or an alkyl group. 【Request Item 13】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 Having a structure selected from The compound according to any one of claims 1 to 12.

14. A compound according to any one of claims 1 to 13, characterized in that it is a cytochrome P450 11A1 (CYP11A1) inhibitor.

15. A drug composition comprising a compound according to any one of claims 1 to 14 in a therapeutically effective amount, and a pharmaceutically acceptable carrier or excipient.

16. A method for treating steroid hormone receptor-mediated symptoms and diseases, characterized by administering to a subject in need of treatment a therapeutically effective amount of the compound according to any one of claims 1-14 or the drug composition according to claim 15.

17. The method according to 16, characterized in that the steroid hormone receptor is an androgen receptor (AR).

18. The method according to 16, characterized in that the symptoms and disease mediated by steroid hormone receptors are cancer.

19. The method according to 18, characterized in that the cancer is prostate cancer or breast cancer.

20. The method according to 19, characterized in that the prostate cancer is castration-resistant prostate cancer (CRPC).

21. Uses of the compound according to any one of claims 1-14 in the manufacture of a drug for treating symptoms and diseases mediated by steroid hormone receptors.

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