Novel compounds as CYP11A1 inhibitors and uses thereof

Abstract

The present invention provides novel compounds of formula (I) as CYP11A1 inhibitors, useful for the treatment of symptoms and diseases affected by steroid hormone receptors, such as symptoms and diseases dependent on androgen receptor (AR), including prostate cancer. The invention also discloses a preparation method, a pharmaceutical composition and application thereof.

Description

Cross-references

[0001] This application claims priority to International Patent Application No. PCT / CN2023 / 093491, filed May 11, 2023; U.S. Patent Application No. 63 / 504,611, filed May 26, 2023; International Patent Application No. PCT / CN2023 / 119980, filed September 20, 2023; U.S. Patent Application No. 63 / 594,170, filed October 30, 2023; U.S. Patent Application No. 63 / 616,921, filed January 2, 2024; and International Patent Application No. PCT / CN2024 / 070542, filed January 4, 2024; the contents of all of the foregoing are incorporated herein by reference in their entirety. Background Technology

[0002] Prostate cancer (PC) is one of the most frequently diagnosed cancers in men and the leading cause of cancer-related death in men worldwide. Advanced prostate cancer has a poor prognosis, with a five-year survival rate of 31-36%. Androgens and their receptors (ARs) are generally considered to play a crucial role in the development and progression of prostate cancer. Therefore, androgen deprivation therapy (ADT), such as surgical or chemical castration, is the primary treatment strategy for castration-sensitive prostate cancer (CSPC). However, despite good early responses to ADT, almost all patients eventually progress from CSPC to a more aggressive phenotype, castration-resistant prostate cancer (CRPC) (Transl Androl Urol. Oct 2021; 10(10):3918–3930).

[0003] Multiple mechanisms contribute to the progression of castration-resistant disease. Existing evidence supports the view that the progression from hormone-naïve to castration-resistant phenotype is associated with the persistent transactivation of the androgen receptor (AR), which remains a key driver in this process. Detailed studies of castration-resistant prostate cancer (CRPC) have shown that despite systemic androgen removal through multiple mechanisms, it still depends on the AR signaling axis (J Carcinog. 2011; 10:20; Transl AndrolUrol. 2015 Jun; 4(3):365–380). These findings have spurred the development of novel agents that inhibit AR signaling, such as enzalutamide (Xtandi), an AR antagonist that prevents nuclear translocation and chromatin binding; and abiraterone acetate (Zytiga), a cytochrome P450 17A1 (CYP17A1) inhibitor that inhibits androgens derived from the adrenal glands, prostate tumors, and the tumor microenvironment. These new treatments offer additional chances of survival; however, the expected resistance to abiraterone or enzalutamide remains a clinical challenge (Oncogene, 2013(32):5501–5511).

[0004] Preclinical studies in castration-resistant prostate cancer (CRPC) have shown that extragonadal steroid hormones other than testosterone may sustain cancer growth by activating mutated or overexpressed androgen receptors (ARs). Mutations in the androgen receptor (AR) ligand-binding domain (LBD) may alter the conformation of the AR, allowing low-affinity steroid hormones to bind to it, thereby promoting cancer growth. Furthermore, low-affinity steroids may be converted to high-affinity AR-binding steroids in cancerous tissue. Therefore, inhibiting the synthesis of most, or even all, steroid hormones may be beneficial for patients with steroid-dependent cancers, such as prostate cancer, even in advanced stages of the disease (Mol Cancer Ther, 2022, 21(12):1765–1776).

[0005] Since all steroid hormones are produced from a single precursor cholesterol through a series of enzymatic reactions, and CYP11A1 is the only enzyme that catalyzes the first step in steroid hormone biosynthesis, it has been hypothesized that inhibiting cytochrome P450 11A1 (CYP11A1) could prevent the synthesis of all steroid hormones. Therefore, compounds with CYP11A1 inhibitory activity could potentially inhibit the synthesis of all steroid hormones, thereby preventing activation of steroid hormone receptors, such as AR. Thus, CYP11A1 inhibitors may have potential applications in the treatment of steroid-dependent cancers such as CRPC (MolCancer Ther, 2022, 21(12):1765–1776). Summary of the Invention

[0006] This invention relates to compounds of formula (I). These compounds are potential CYP11A1 inhibitors and can be used to treat steroid hormone-dependent diseases and symptoms. In particular, the compounds of this invention can be used to treat symptoms and diseases dependent on steroid hormone receptors, including prostate cancer. Pharmaceutical compositions and methods for treating diseases affected by steroid hormone receptors are also provided.

[0007] One aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, deuterated derivative, or stereoisomer thereof. In formula (I), ring A is a monocyclic, bicyclic, or spirocyclic cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group, and optionally surrounded by 1-3 R groups. 1 Substitution; wherein the heterocyclic group contains one or more cyclic heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S) or nitrogen (N), and the cyclic sulfur atom is optionally substituted by two oxo (=O) groups; Ring M is a monocyclic or fused bicyclic ring containing 0-4 independently selected cyclic heteroatoms chosen from oxygen (O), sulfur (S) or nitrogen (N); wherein the cyclic carbon atom is optionally substituted with an oxo (=O) group to form a carbonyl group; Ring B is a 5- or 6-membered aryl or heteroaryl group, and optionally surrounded by 1-3 R groups. 5 replace; X is -CR 6 R 7 -O- or a chemical bond; n is 1 or 2; Z is either C or N; R 1 Each independently represents H and C. 1-7 Alkyl, C 2-7 alkenyl, C 2-7 Alkyne, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkyl, hydroxyalkyl, halogen, haloalkyl, -CN, cyanoalkyl, -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 R12’ cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by 1-3 R groups. 10 replace; R 2 and R 2’ Each of the following can be independently represented as H, halogen, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, -CN, cyanoalkyl, C 1-7 Alkyl, cycloalkyl, or heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R groups. 10 replace; R 3 and R 4 Each is independently H, alkyl, cycloalkyl or heterocyclic, and optionally substituted by one or more substituents, said substituents being independently selected from halogen, haloalkyl, -OH, hydroxyalkyl, alkoxy or -CN; Or, R 3 and R 4 And the atoms they are connected to, optionally forming a 3-7 membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1-3 R atoms. 10 replace; R 5 Each of these groups is independently H, alkyl, halogen, haloalkyl, -OH, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally independently and independently influenced by one or more R groups. 10 replace; R 6 and R 7 Each is independently H, alkyl, cycloalkyl, or heterocyclic, and optionally is influenced by one or more R groups. 10 replace; Or, R 6 and R 7 And the atoms they are connected to, optionally forming 3-7 membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclic groups; wherein the bicyclic or spirocyclic cycloalkyl or heterocyclic group is optionally surrounded by 1-3 R groups. 10 replace; R 10 Each can be independently H, alkyl, halogen, haloalkyl, -OH, hydroxyalkyl, -alkoxy, -alkoxyalkyl, CN, or cyanoalkyl; R 11 R 12 and R 12’ Each is independently H, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic, and each is optionally influenced by one or more R groups. 10replace; Or, R 12 and R 12’ And the atoms they are connected to, optionally forming cycloalkyl or heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1-3 R atoms. 10 replace; All heterocyclic groups not appearing in ring A contain 1-4 cyclic heteroatoms, each of which is independently oxygen (O), sulfur (S) or nitrogen (N); All heterocyclic rings present are single-ring, double-ring, bridging double-ring, fused double-ring, helical, or multi-ring structures; and All the heterocycles mentioned are either unsaturated or partially saturated; All of the aforementioned heteroaryl groups contain 1-4 cyclic heteroatoms, each of which is independently oxygen (O), sulfur (S), or nitrogen (N); Any hydrogen (H) may be optionally replaced by deuterium (D); p or q can be 0, 1, 2 or 3 independently; Or a pharmaceutically acceptable salt, tautomer, or stereoisomer of a compound of formula (I).

[0008] In some embodiments, the compound has the structure of formula (II) or (III): Or it may be a pharmaceutically acceptable salt, tautomer, or stereoisomer. In formula (II) or (III), ring A is a monocyclic, bicyclic, or spirocyclic cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group, and optionally surrounded by 1-3 R groups. 1 Substitution; wherein the heterocyclic group contains one or more cyclic heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S) or nitrogen (N), and the cyclic sulfur atom is optionally substituted by two oxo (=O) groups; Ring M is a monocyclic or fused bicyclic ring containing 0-4 cyclic heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S); wherein the cyclic carbon atom is optionally substituted with an oxo (=O) group to form a carbonyl group; Ring B is a 5- or 6-membered aryl or heteroaryl group, and optionally surrounded by 1-3 R groups. 5 replace.

[0009] In some embodiments, the compound has a structure of formula (IIa) or (IIIa): Or it may be a pharmaceutically acceptable salt, tautomer, or stereoisomer. In formula (IIa) or (IIIa), ring A is a monocyclic, fused bicyclic, or spirocyclic cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group, and optionally surrounded by 1-3 R groups. 1 Substitution; wherein the heterocyclic group contains one or more cyclic heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S) or nitrogen (N), and the cyclic sulfur atom is optionally substituted by two oxo (=O) groups; Ring M is a monocyclic or fused bicyclic ring containing 0-4 independently selected cyclic heteroatoms chosen from nitrogen (N), oxygen (O), or sulfur (S); wherein the cyclic carbon atom is optionally substituted with an oxo (=O) group to form a carbonyl group; and Ring B is a 5- or 6-membered aryl or heteroaryl group, and optionally surrounded by 1-3 R groups. 5 replace.

[0010] In some implementation schemes, for

[0011] In some implementation schemes, for

[0012] In some embodiments, the compound has the structure of formula (IV) or (V): Or it may be a pharmaceutically acceptable salt, tautomer, or stereoisomer. In formula (IV) or (V), ring A is a monocyclic, bicyclic, or spirocyclic cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group, and optionally surrounded by 1-3 R groups. 1 Substitution; wherein the heterocyclic group contains one or more cyclic heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S) or nitrogen (N), and the cyclic sulfur atom is optionally substituted by two oxo (=O) groups; Ring M is a monocyclic or fused bicyclic ring containing 0-4 cyclic heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S); wherein the cyclic carbon atom is optionally substituted with an oxo (=O) group to form a carbonyl group.

[0013] Examples of ring M include, but are not limited to, the following: as well as In these examples, Ring M can be arbitrarily divided by R 2 and / or R 2’ replace; Y1 is NR, O, or -CRR'-; Y2 is N, O, or =CR-; Y3 is O, NR, or -CRR'-; Y4 represents N, O, or CR; W1 and W2 are each independently O, S, NR or -CRR'-; Z1, Z2, Z3, Z4, Z5, and Z6 are each independently N or CR; R or R' is H, alkyl, or cycloalkyl; and The dashed circle inside the ring This indicates that the ring contains 1, 2, or 3 double bonds, as long as the valence electrons are allowed.

[0014] In some implementations, ring M is: And ring M is arbitrarily assigned to R 2 and / or R 2’ replace.

[0015] Examples of ring A include, but are not limited to: as well as And ring A is arbitrarily divided by 1-3 Rs 1 Group substitution.

[0016] In some implementation schemes, R 1 -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’ , where R 11 Each of the following is independently H, cycloalkyl, heterocyclic, haloalkyl, alkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted with one or more alkyl, halogen, or haloalkyl groups; R 12 and R 12’ Each can be independently H, cycloalkyl, haloalkyl, or alkyl.

[0017] In some implementation schemes, R 3 and R 4Each is independently H or alkyl, and any hydrogen is optionally substituted with D; or, R 3 and R 4 Together with the atoms they are connected to, they form a 3-7 membered cycloalkyl group.

[0018] In some implementation schemes, R 6 and R 7 Each is independently H or alkyl.

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

[0020] Exemplary compounds of the present invention include, but are not limited to, the following structures:

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

[0022] Another aspect of the invention includes a pharmaceutical composition comprising: a therapeutically effective dose of the compound, and its pharmaceutically acceptable salt, tautomer, deuterated derivative or stereoisomer, in combination with one or more pharmaceutically acceptable carriers or excipients.

[0023] Such compounds or pharmaceutical compositions according to the present invention are used to treat steroid hormone receptor-dependent symptoms and diseases. In some embodiments, the steroid hormone receptor-dependent symptoms and diseases are cancers, including but 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 pharmaceutical composition may include a second therapeutic agent.

[0025] Another aspect of the 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 dose of the compound or pharmaceutical composition to the subject requiring treatment.

[0026] Another aspect of the invention provides the use of said compounds in the manufacture of medicaments for treating symptoms and diseases affected by steroid hormone receptors. Detailed Implementation

[0027] Preferred embodiments of the present invention will now be described in detail, with further examples thereof. The invention has been described in conjunction with preferred embodiments, but it should be understood that the invention is not limited to these embodiments. Rather, the invention includes alternatives, modifications, and equivalents that may be included within the spirit and scope of the invention as defined in the claims. Furthermore, numerous specific details are provided in the detailed description of the invention to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention can be practiced without relying on these specific details. In other instances, known methods, procedures, components, and other features are not described in detail to avoid unnecessarily obscuring certain aspects of the invention. definition

[0028] Unless the context otherwise requires, references to formula (I) in all parts of this document (including uses, methods and other aspects of the invention) include references to all other formulas, subgroups, preferred embodiments and examples as defined herein.

[0029] Unless otherwise stated, the following terms as used in this specification and claims shall have the following meanings:

[0030] As used in this article, the word "or" refers to either "and" or "or". In other words, the word "or" can also be replaced with "and / or".

[0031] In the various terms used in the definition, for example, “X”, “Y1” and “Z1” are used as general symbols in this document to represent various specific chemical elements.

[0032] Dashed lines represent single or double bonds. Fill in the valence bonds of the atoms that connect these bonds as required.

[0033] As used in this article, the term "unsaturated bond" refers to a double or triple bond.

[0034] As used herein, the term “unsaturated” or “partially unsaturated” refers to a portion containing at least one double or triple bond.

[0035] As used in this article, the term "saturation" refers to a portion that does not contain double or triple bonds, i.e., a portion that contains only single bonds.

[0036] As used herein, the term "alkyl" itself, or as another substituent, refers to a linear (i.e., unbranched or straight-chain) or branched hydrocarbon chain consisting of carbon and hydrogen atoms without unsaturated bonds, having the stated number of carbon atoms (e.g., C1-C1). 10 Or C 1-10 Alkyl groups. Whenever they appear herein, numerical ranges such as “1 to 10” refer to each integer within a given range; for example, “1-10 carbon atoms” means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., and so on, including 10 carbon atoms, although this definition also covers the presence of the term “alkyl” in ranges not specified. Typical saturated linear or straight-chain alkyl groups include, but are not limited to: -methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; while saturated branched alkyl groups include, but are not limited to: -isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is attached to the parent molecule by a single bond. Unless otherwise specified in this specification, the alkyl group may optionally be substituted with one or more substituents.

[0037] When any hydrogen atom in an alkyl group is replaced by deuterium (D), the alkyl group is called a "deuterated alkyl group".

[0038] The term "alkylene" itself, or as part of another molecule, refers to a divalent group derived from an alkane, which can be straight-chain or branched. In this case, the prefix (e.g., C) is used. 1-4 C 1-7 C 1-20 C 2-7 C 3-7 (etc.) indicates the number of carbon atoms or a range of carbon atoms. For example, the term "C" as used in this article 1-4 "Alkylene" refers to an alkylene group having 1-4 carbon atoms. Linear C 1-8 Examples of alkylene groups include, but are not limited to: -(CH2) n -, where n is an integer between 1 and 7, for example -CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-. Branch C 1-7 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] As used herein, the term "alkenyl" itself, or as another substituent, refers to an unsaturated branched or straight chain containing at least one carbon-carbon double bond, obtained by removing a hydrogen atom from a single carbon atom of a parent olefin. This group may have a cis or trans conformation at the double bond. Typical alkenyl groups include, but are not limited to, vinyl, propenyl, etc.

[0040] As used herein, the term "alkynyl" itself, or as another substituent, refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear, branched, or a combination of both. Examples of alkynyl groups include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptyynyl, etc.

[0041] As used herein, the term "cycloalkyl" itself, or as another substituent, refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms. The term "cycloalkyl" includes: monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, fused cycloalkyl, and spirocyclic cycloalkyl. In bridged cycloalkyl, the rings share at least two non-adjacent atoms. In fused bicyclic cycloalkyl, the two rings share a covalent bond. In spirocyclic cycloalkyl, the two distinct rings share a single atom.

[0042] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond (i.e., C=C). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. The term "heterocyclic alkenyl" is a cycloalkenyl group as defined above, in which at least one carbon atom of the ring is substituted by a heteroatom, for example, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocyclic alkenyl groups can be substituted or unsubstituted.

[0043] The term "heterocyclic alkyl" is a cycloalkyl group as defined above and is included in the meaning of the term "cycloalkyl" in which at least one carbon atom in the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocyclic alkyl groups may be substituted or unsubstituted.

[0044] As used herein, the term "heterocyclic" or "heterocyclic group" refers to a group derived from a monocyclic, bridged bicyclic, fused bicyclic, spirocyclic, or polycyclic group, comprising at least one non-aromatic ring containing one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents, as defined). The heterocycle may be unsaturated, saturated, or partially unsaturated. In some embodiments, the heterocycle may comprise 1-4 heteroatoms as ring members. The heterocyclic group of the present invention can be attached to a parent molecule via a carbon atom or heteroatom in the group. Therefore, the term includes, but is not limited to, "heterocyclic alkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle."

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

[0046] As used herein, the term "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0047] The term "haloalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been independently replaced by a halogen selected from fluorine, chlorine, bromine, or iodine. "Fluoroalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been replaced by a fluorine atom. Unless otherwise specified, haloalkyl groups may include as many chemically permissible halogen atoms as substituents on the alkyl group as possible. For example, a fluoroethyl group may be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0048] As used herein, the term "hydrogen" (or H) includes: its isotope deuterium (D or...). 2 H) and tritium ( 3 H), that is, any hydrogen atom in the compound of the present invention can be replaced by deuterium (D or H). 2 H) or tritium ( 3 H) substitution.

[0049] As used herein, the term "alkoxy" refers to a saturated straight-chain or branched hydrocarbon group bonded to an oxygen atom. Typical saturated straight-chain alkoxy groups include: methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, etc.; while saturated branched alkoxy groups include: isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, isopentoxy, etc. Cyclic alkoxy groups are referred to herein as "cycloalkoxy". 1-4An alkoxy group is an alkyl group having 1, 2, 3, or 4 carbon atoms. Alkoxy groups can be attached to a molecule through one or two bonding sites.

[0050] As used herein, the term “haloalkoxy” refers to an alkoxy group that has been substituted with 1 to 6 halogens.

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

[0052] As used herein, the term "aryl" refers to a monocyclic or fused polycyclic group of 6-12 carbon atoms with a fully conjugated π-electron system. Examples of aryl groups, not limited to these, include phenyl, naphthyl, and anthracene. An "aryl" group can be substituted or unsubstituted.

[0053] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring (i.e., a ring sharing an adjacent atom pair) of 5-12 ring atoms, comprising one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and further having a fully conjugated π-electron system. Examples of unsubstituted heteroaryl groups, not limited to these, include: pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetraazole, triazine, carbazolium, benzimidazole, benzoxazole, benzothiazole, indazole, and quinazoline. Heteroaryl groups can be substituted or unsubstituted.

[0054] As used herein, the term "aryl" refers to a bidentate group obtained by removing two hydrogen atoms from two different aromatic ring atoms of an aromatic compound, the group containing 3-20 ring atoms, unless otherwise stated. Preferably, each ring contains 5-7 ring atoms.

[0055] As used in this article, the term "hydroxyl group" refers to -OH.

[0056] The term "hydroxyalkyl" itself, or as another substituent, refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Therefore, the term "hydroxyalkyl" encompasses all types, including monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, etc. In a "hydroxyalkyl" group, the alkyl group can be linear (i.e., straight-chain or unbranched) or branched; thus, "hydroxyalkyl" groups include both straight-chain and branched hydroxyalkyl groups.

[0057] As used herein, the term "cyano" or "-CN" refers to the -CN group. The term "cyanoalkyl" or "-alk-CN" as used herein refers to an alkyl group containing at least one -CN substituent. Generally, if a compound is attached to a "-alk-CN" group, the alkyl portion of the "-alk-CN" group is attached to the compound. In a "cyanoalkyl" group, the alkyl group can be linear (i.e., straight-chain or unbranched) or branched; therefore, "cyanoalkyl" groups include both straight-chain and branched-chain cyanoalkyl groups.

[0058] As used herein, the term "amino" refers to -NH2. The term "alkylamino" refers to a group with the structural formula -NHR, and "dialkylamino" refers to a group with the structural formula -NRR', where R and R' are each independently alkyl.

[0059] As used herein, the term "-SO2-" or "-S(=O)2-" refers to sulfur dioxide, with the structural formula:

[0060] As used herein, the term "carbonyl" or "-C(=O)-" or "-CO-" refers to a structure with the following formula: . group.

[0061] As used herein, the terms "-CO2-" or "-COO-" refer to structures with the following formula: . group.

[0062] The groups defined above may include prefixes and / or suffixes commonly used in this art to construct other recognized substituents. For example, the terms "haloalkoxy" or "(haloalkyl)oxy" refer to a haloalkyl group that is attached to a parent molecule group via an oxygen atom. The term "(haloalkyl)oxyalkyl" refers to an alkyl group that is substituted with one, two, or three (haloalkyl)oxy groups.

[0063] As used in this paper, the term "none" in defining variables, such as "X", means that the defined variable does not exist, and therefore the two groups connected by that variable are directly connected to each other.

[0064] As used herein, the term “oxo” (used alone or in combination with other terms) refers to (=O).

[0065] As used in this article, the term "bond" refers to a covalent connection between two atoms or two groups, and can be a single bond, a double bond, or a triple bond.

[0066] The term "stereoisomer" refers to isomers that have the same composition but differ only in the spatial arrangement of atoms, not in the order of atomic bonding. When a publicly disclosed compound is named or characterized structurally but without indicating stereochemistry, it should be understood that the name or structure includes all possible stereoisomers, including: the main single stereoisomer and combinations thereof. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular variants that are mirror images of each other but cannot be superimposed. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The terms "racemic mixture" or "racemic mixture" refer to a mixture consisting of two enantiomers in equimolar amounts, wherein the mixture is not optically active.

[0067] The term "optical activity" refers to a structural property of a molecule that prevents it from overlapping with its mirror image.

[0068] As used herein, the term "tautomer" refers to two or more isomers of a compound that coexist in equilibrium and are readily interconvertible through the migration of atoms or groups within the molecule. Therefore, this invention aims to cover all possible tautomers, even if a structure exhibits only one of them.

[0069] The term “optional” or “optionally” means that the event or condition described below may occur, but not necessarily, and that the description includes both the possibility that the event or condition occurs and the possibility that it does not. For example, “optionally alkyl-substituted heterocyclic group” means that the alkyl group may or may not be present, and this description includes both the possibility that the heterocyclic group is alkyl-substituted and the possibility that the heterocyclic group is not alkyl-substituted.

[0070] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid, including inorganic or organic bases and acids. These salts, after careful medical evaluation, are suitable for contact with patient tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, possess a reasonable risk-benefit ratio, and are effective for their intended use. Salts derived from inorganic bases include: aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include: primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrogenated amine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, teroneamine, etc.

[0071] When the compounds of the present invention are basic, their salts can be prepared using pharmaceutically acceptable non-toxic acids (including inorganic and organic acids). These acids include: acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrogen bromide, hydrochloric acid, isoethanesulfonic acid, lactic acid, maleic acid, malic acid, fluorenic acid, methanesulfonic acid, mucopolysaccharides, nitric acid, barmonic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Citric acid, hydrogen bromide, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid are particularly preferred.

[0072] It should be understood that, as used herein, references to compounds of structural formula (I) also include pharmaceutically acceptable salts.

[0073] "Pharmaceutical composition" means a mixture of one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, with other chemical components (such as pharmaceutically acceptable excipients). The purpose of a pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0074] "Pharmaceuticalally acceptable excipients" are inert substances added to a pharmaceutical composition to further facilitate the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0075] The term "therapeutic effective dose" refers to the dose of a compound administered that can alleviate one or more symptoms of the disease being treated to some extent. In cancer treatment, a therapeutic effective dose is a dose that can achieve the following therapeutic effects: (1) reducing tumor volume; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and / or (4) alleviating one or more symptoms associated with cancer.

[0076] In this document, the terms “subject” or “patient” are used interchangeably and refer to any animal subject, including but not limited to humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cattle, sheep, goats, pigs, turkeys, and chickens), and pets (e.g., dogs, cats, and rodents).

[0077] As those skilled in the art will understand, the compounds described herein can be administered to patients in various forms depending on the chosen route of administration. The compounds described herein can be administered orally, by injection, sublingually, sublingually, nasally, rectally, via patch, pump, or transdermally, and pharmaceutical compositions can be prepared accordingly. Parenteral administration includes intravenous injection, intraperitoneal injection, subcutaneous injection, intramuscular injection, transepithelial, intranasal, intrapulmonary, intracerebrospinal fluid, rectal, and local administration. Parenteral administration can be performed by continuous injection over a selected time period. Heterogeneous forms

[0078] The present invention provides novel compounds of formula (I), or pharmaceutically acceptable salts thereof, as CYP11A1 inhibitors.

[0079] It should be understood that certain compounds (or salts, prodrugs, or conjugates) of the present invention may exist in isomeric forms and be isolated, including tautomers, geometric isomers (i.e., cis or trans isomers), optical isomers (i.e., enantiomers and diastereomers), racemates, or any mixture of the above isomeric forms. It should be understood that the present invention includes compounds of formula (I) existing in any isomeric form, or as mixtures thereof, for example, chemicals existing as active monoenantiomers, racemates, or any mixtures thereof. The present invention is intended to cover all isomeric forms of compounds of formula (I).

[0080] Furthermore, the compounds of the present invention (or their salts, prodrugs, or conjugates) may exhibit polymorphism or may form solvates with water or organic solvents. The present invention also includes any such polymorphic forms, any solvates, or any 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

[0081] Step 1: Pyridine (2.0 mL, 2.6 eq) and p-CF3PhSO2Cl (2.8 g, 1.2 eq) were added to a DCM (20 mL) solution of compound 1 (2.0 g, 1.0 eq), and the mixture was stirred at 25 °C for 16 hours. The reaction was purified by column chromatography to obtain a colorless oily compound 2 (1.3 g, 60% yield). 1 H NMR (400MHz, CDCl3) δ3.70-3.39(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: Cs₂CO₃ (2.8 g, 2.0 eq) and compound 3 (1.2 g, 2.0 eq) were added to a DMA (10 mL) solution of compound 2 (1.0 g, 1.0 eq), and the mixture was stirred at 70 °C for 16 hours. The reaction was purified by column chromatography to obtain a colorless oily compound 4 (630 mg, yield 43%). MS m / z: 338.1 (M+1) + . 1 H NMR (400MHz, CDCl3) δ7.75-7.51(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: DIEA (160 mg, 3.0 eq) and methyl methanesulfonyl methanesulfonate (143 mg, 2.0 eq) were added to a DCM solution of compound 4 (140 mg, 1.0 eq) in 5 mL. The mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated and dissolved in CH3CN (3 mL). DIEA (72 μL, 1.0 eq) and iodoisoindoline (132 mg, 2.0 eq) were added, and the mixture was stirred at 20 °C for 2 hours. The reaction was purified by column chromatography to obtain compound 5. MS m / z: 439.2 (M+1) + .

[0084] Step 4: Compound 5 (150 mg, 1.0 eq) was dissolved in HCl / MeOH (2 M, 1.7 mL) and stirred at 20 °C for 0.5 h. The reaction mixture was concentrated and dissolved in DCM (5 mL), and DIEA (293 μL, 5.0 eq) and Ms₂O (117 mg, 2.0 eq) were added. The mixture was stirred at 20 °C for 0.5 h. The reaction was purified by column chromatography to give 2-(isoindoline-2-ylmethyl)-5-(((1R,5S,6r)-3-(methanesulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)methoxy)-4H-pyran-4-one. MS m / z: 417.1 (M+1) + . 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),7.43(s,4H),6.74(s,1H),4.82(br s,4H),4.68(s,2H),3.89(d,J=7.2Hz,2H),3.53(d,J=9.2Hz,2H),3.39(d,J=9.2Hz,2H),2.88(s,3H),1.73(br s,2H),1.40-1.36(m,1H).

[0085] The synthesis methods of Examples 2-13 are similar to those of Example 1. Example 13 5-(isoindoline-2-ylmethyl)-2-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)-7H-furan[3,2-b]pyran-7-one

[0086] Step 1: NaOH (34 g, 1.2 eq) and I₂ (214 g, 1.2 eq) were added in portions to a solution of 5-hydroxy-2-(hydroxymethyl)pyran-4-one (100 g, 1.0 eq) in H₂O (1200 mL), and the mixture was stirred at 25 °C for 16 hours in an ice bath. The mixture was filtered, and the filter cake was washed with EtOAc (30 mL x 3). The crude product was ground with EtOAc and concentrated under reduced pressure to give compound 2 as a yellow solid (78 g, yield 42%). MS m / z 269.0 (M+1) + .

[0087] Step 2: Cuprous iodide (1.60 g, 0.2 eq) and Pd(PPh3)2Cl2 (2.95 g, 0.1 eq) were added 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). The mixture was stirred at 30 °C for 16 hours. The reaction was purified by column chromatography to give a yellow solid compound 4 (5 g, yield 34%). MS m / z: 348.2 (M+1) + . 1 H NMR(500MHz, CDCl3)δ6.48(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=2.5Hz,2H),1.85(t,J=3.5Hz,1H),1.45(s,9H).

[0088] Following similar steps to Example 1, 5-(isoindoline-2-ylmethyl)-2-((1R,5S,6r)-3-(methanesulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)-7H-furan[3,2-b]pyran-7-one was obtained. MS m / z: 427.1 (M+1) + . 1 H NMR(400MHz,CD3OD)δ7.43(s,4H),6.75(s,1H),6.73(s,1H),4.83(s,4H),4.74 (s,2H),3.68(d,J=9.6Hz,2H),3.51(d,J=8.8Hz,2H),2.94(s,3H),2.33(s,3H).

[0089] The synthesis methods of Examples 14-54 are similar to those of Example 13. Example 55: 6-(isoindoline-2-ylmethyl)-2-(1-(methanesulfonyl)piperidin-4-yl)quinazolin

[0090] Step 1: 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) were added to a solution of compound 1 (5.0 g, 1.0 eq) in THF (100 mL) and H2O (20 mL). The mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction was purified by column chromatography to obtain a red solid compound 3 (7.7 g, yield 96%). MS m / z: 392.1 (M+1) + . 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.23 ​​(d, J = 2.0Hz, 1H), 7.95-7.86 (m, 1H), 7.82-7.76 (m, 1H), 6.82 (br s,1H),4.23(d,J=1.6Hz,2H),3.70(t,J=5.6Hz,2H),2.83(brs,2H),1.51(s,9H).

[0091] Step 2: Tributyltin methanol (4, 9.5 g, 1.5 eq) and X-Phos Pd G2 (1.6 g, 0.1 eq) were added to a toluene (100 mL) solution of compound 3 (7.7 g, 1.0 eq). The mixture was stirred at 90 °C for 1 hour and purified by column chromatography to obtain red solid compound 5 (4.0 g, yield 59%). 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 THF (20 mL) solution of compound 5 (1.9 g, 1.0 eq), stir at 25 °C for 1 hour, and purify the reaction by column chromatography to obtain a white solid compound 6 (1.9 g, 100% yield). MS m / z: 344.1 (M+1) + .

[0093] Following similar steps to Example 1, the compound of Example 55 can be obtained. MS m / z: 423.0 (M+H) + . 1H NMR(400MHz,CD3OD)δ8.98(s,1H),8.33(br s,1H),8.22(d,J=8.4Hz,1H),8.01(d,J=8.4Hz,1H),7.41(s,4H),4.83-4.73(m,6H),3.92(d,J=11. 6Hz,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

[0094] Step 1: Add TMEDA (3.6 mL, 8.0 eq) to a THF (60 mL) solution of chromium dichloride (2.9 g, 8.0 eq), stir at 20 °C for 15 minutes to obtain a blue mixture, add a THF (20 mL) solution of compound 1 (500 mg, 1.0 eq), then add a THF (30 mL) solution of compound 2 (1.25 g, 2.0 eq) and LiI (1.6 g, 4.0 eq), stir at 20 °C for 16 hours, and purify the reaction by column chromatography to obtain a colorless oily compound 3 (300 mg, yield 33%). 1 H NMR (400MHz, CDCl3) δ3.64-3.49(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, 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-methylbut-2-ol (8 mL). Stir at 90 °C for 1 hour. Purify the reaction by column chromatography to obtain a yellow solid compound 5 (140 mg, yield 45%). MS m / z: 369.2 (M+1) + . 1H NMR (400MHz, CDCl3) δ8.53(d,J=1.2Hz,1H),8.29-8.21(m,1H),8.17-8.07(m,1H),8.04-7.89(m,1H),7.31(d,J=8.4Hz,1H),3 .99(s,3H),3.84(d,J=11.2Hz,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: LiAlH4 (43 mg, 3.0 eq) was added to a THF (6 mL) solution of compound 5 (140 mg, 1.0 eq) at -78 °C. The mixture was stirred at 0 °C for 10 minutes. The reaction was purified by column chromatography to obtain a white solid compound 6 (110 mg, yield 85%). MS m / z: 341.2 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.09-7.89(m,2H),7.75(s,1H),7.66(d,J=8.4Hz,1H),7.22(d,J=8.4Hz,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] Following similar steps to Example 1, 6-(isoindoline-2-ylmethyl)-2-((1R,5S,6r)-3-(methylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-yl)quinoline can be obtained. MS m / z: 420.1 (M+1) + . 1 H NMR(500MHz,CD3OD)δ9.00(d,J=8.5Hz,1H),8.53(s,1H),8.34-8.27(m,2H),7.75(d,J=8.5Hz,1H),7.47-7.40(m ,4H),4.96(s,2H),4.82(s,4H),3.85(d,J=10.0Hz,2H),3.67(d,J=10.0Hz,2H),3.02(s,3H),2.75-2.70(m,3H).

[0098] The synthesis methods of Examples 57-133 are similar to those of Example 55. Example A: Detection of H295R Steroid Biosynthesis Inhibition

[0099] The inhibitory effect of the experimental compounds on steroid biosynthesis in NCI-H295R cells (ATCC) was investigated by measuring the cytogenes of pregnenolone (P) and the downstream steroid testosterone (T) catalyzed by CYP11A1. Cells were cultured in Dulbecco modified two-drop F12 medium (DMEM / F12) (Gibco, Cat. No. 11330032) containing phenol red, supplemented with 2% Ultroser G (Pall, Cat. No. 15950-017, USA), 1% ITS-Premix, and 1% penicillin-streptomycin (Hyclone, Cat. No. SV30010, USA). Cells were thawed and passaged four times before the experiment. The maximum number of passages used in the experiment was 10. In this experiment, phenol red-free DMEM / F12 medium was used, supplemented with 10% activated charcoal-free dehorned fetal bovine serum (VivaCell, Cat. No. C3830-0500, USA). 60,000 cells (90 μL per well) were seeded in each well of a 96-well plate and cultured for 24 hours. The experimental compounds were serially diluted in the experimental medium from 1000 nM to 0.15 nM and then added to the wells. After 48 hours of culture, the solution from each well was collected and transferred to 1.5 mL centrifuge tubes. 5 ng / mL of deuterium-labeled testosterone (D3-testosterone) and 50 ng / mL of deuterium-labeled pregnenolone (D4-pregnenolone) were added to 200 μL of acetonitrile. After thorough mixing for 5 minutes, the mixture was centrifuged at 12,700 rpm for 15 minutes. A 250 μL aliquot of the supernatant was collected and dried under a nitrogen atmosphere. Add 150 μL of methanol:water (1:1, v / v) to the dried product, and inject 50 μL of the sample into the LC-MS / MS system for analysis.

[0100] The half-maximum inhibitory concentration (IC50) for steroid biosynthesis inhibition was determined using GraphPad Prism software and a four-variable inhibitor dose-response equation for curve fitting. 50 ). LC-MS / MS analysis of steroid hormones

[0101] Testosterone and pregnenolone were analyzed using a Shimadzu LC30AD HPLC system (Shimadzu, Kyoto, Japan) combined with an AB SCIEX Qtrap 5500 triple quadrupole mass spectrometer (AB Sciex, Framingham, MA, USA) via an ESI interface in positive ionization mode. The analytes and precipitates 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 was a mixture of 10 mM ammonium acetate aqueous solution containing 0.2% formic acid (A) and methanol containing 0.2% formic acid (B), at a flow rate of 0.6 mL / min. The gradient program was set as follows: from 0 min to 0.5 min, component B was 60%; from 0.5 min to 3.5 min, component B was 90%; from 3.5 min to 4.5 min, component B was 90%; from 4.5 min to 5.0 min, component B was 60%. The injection volume was 50 mL.

[0103] The MS / MS parameters were set as follows: ion spray voltage 5500V; curtain gas 35psi; gas 1 55psi; gas 2 55psi; temperature 55℃. The optimized multiple reaction monitoring (MRM) fragmentation precursor ions and MS parameters for each analyte are summarized in Table 1. Table 1. Mass spectrometry parameters of D3-testosterone and D4-pregnenolone

[0104] The compounds of the present invention were screened in the above experiments, and the IC50 of the compounds was... 50 The values ​​are listed in Table 2 below, where "A" represents IC. 50 ≤40nM, “B” indicates IC 50 Values ​​range from 41 to 100 nM, where "C" indicates IC. 50 ≥101nM. Table 2. Analysis of Steroid Biosynthesis Inhibition

Claims

1. A compound of formula (I), In formula (I), ring A is a monocyclic, bicyclic, or spirocyclic cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group, and optionally surrounded by 1-3 R groups. 1 Replace; among them, The heterocyclic group contains one or more cyclic heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S) or nitrogen (N), and the cyclic sulfur atom is optionally substituted by two oxo (=O) groups; Ring M is a monocyclic or fused bicyclic ring containing 0-4 independently selected cyclic heteroatoms chosen from oxygen (O), sulfur (S) or nitrogen (N); wherein the cyclic carbon atom is optionally substituted with an oxo (=O) group to form a carbonyl group; Ring B is a 5- or 6-membered aryl or heteroaryl group, and optionally surrounded by 1-3 R groups. 5 replace; X is -CR 6 R 7 -O- or a chemical bond; n is 1 or 2; Z is either C or N; R 1 Each independently represents H and C. 1-7 Alkyl, C 2-7 alkenyl, C 2-7 Alkyne, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkyl, hydroxyalkyl, halogen, haloalkyl, -CN, cyanoalkyl, -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’ cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by 1-3 R groups. 10 replace; R 2 and R 2’ Each of the following can be independently represented as H, halogen, haloalkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, -CN, cyanoalkyl, C 1-7 Alkyl, cycloalkyl, or heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R groups. 10 replace; R 3 and R 4 Each is independently H, alkyl, cycloalkyl or heterocyclic, and optionally substituted by one or more substituents, said substituents being independently selected from halogen, haloalkyl, -OH, hydroxyalkyl, alkoxy or -CN; Or, R 3 and R 4 And the atoms they are connected to, optionally forming a 3-7 membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1-3 R atoms. 10 replace; R 5 Each of these groups is independently H, alkyl, halogen, haloalkyl, -OH, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally independently and independently influenced by one or more R groups. 10 replace; R 6 and R 7 Each is independently H, alkyl, cycloalkyl, or heterocyclic, and optionally is influenced by one or more R groups. 10 replace; Or, R 6 and R 7 And the atoms they are connected to, optionally forming 3-7 membered monocyclic, bicyclic, or spirocyclic cycloalkyl or heterocyclic groups; wherein the bicyclic or spirocyclic cycloalkyl or heterocyclic group is optionally surrounded by 1-3 R groups. 10 replace; R 10 Each can be independently H, alkyl, halogen, haloalkyl, -OH, hydroxyalkyl, -alkoxy, -alkoxyalkyl, CN, or cyanoalkyl; R 11 R 12 and R 12’ Each is independently H, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic, and each is optionally influenced by one or more R groups. 10 replace; Or, R 12 and R 12’ And the atoms they are connected to, optionally forming cycloalkyl or heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1-3 R atoms. 10 replace; All heterocyclic groups not appearing in ring A contain 1-4 cyclic heteroatoms, each of which is independently oxygen (O), sulfur (S) or nitrogen (N); All heterocyclic rings that appear are monocyclic, bicyclic, bridging bicyclic, fused bicyclic, helical, or multicyclic structures, and are unsaturated or partially saturated. All of the aforementioned heteroaryl groups contain 1-4 cyclic heteroatoms, each of which is independently oxygen (O), sulfur (S), or nitrogen (N); Any hydrogen (H) may be optionally replaced by deuterium (D); p or q can be 0, 1, 2 or 3 independently; Or a pharmaceutically acceptable salt, tautomer, or stereoisomer of a compound of formula (I).

2. The compound according to claim 1, characterized in that, The compound has the structure of formula (II) or (III). In equation (II) or (III), Ring A is a monocyclic, bicyclic, or spirocyclic cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group, and optionally surrounded by 1-3 R groups. 1 Substitution; wherein the heterocyclic group contains one or more cyclic heteroatoms independently selected from boron (B), silicon (Si), oxygen (O), sulfur (S) or nitrogen (N), and the cyclic sulfur atom is optionally substituted by two oxo (=O) groups; Ring M is a monocyclic or fused bicyclic ring containing 0-4 independently selected cyclic heteroatoms chosen from oxygen (O), sulfur (S) or nitrogen (N); wherein the cyclic carbon atom is optionally substituted with an oxo (=O) group to form a carbonyl group; Ring B is a 5- or 6-membered aryl or heteroaryl group, and optionally surrounded by 1-3 R groups. 5 replace; Or a pharmaceutically acceptable salt, tautomer, or stereoisomer of the compound having a structure of formula (II) or (III).

3. The compound according to claim 1 or 2, characterized in that, for 4. The compound according to claim 3, characterized in that, for 5. The compound according to any one of claims 1-4, characterized in that, The compound has a structure of formula (IV) or (V).

6. The compound according to claim 1, 2 or 5, characterized in that, Ring M is Ring M can be arbitrarily divided by R 2 and R 2’ replace; Y1 is NR, O, or -CRR'-; Y2 is N, O, or =CR-; Y3 is O, NR, or -CRR'-; Y4 represents N, O, or CR; W1 and W2 are each independently O, S, NR or -CRR'-; Z1, Z2, Z3, Z4, Z5, and Z6 are each independently N or CR; R or R' is H, alkyl, or cycloalkyl; and The dashed circle inside the ring This indicates that the ring contains 1, 2, or 3 double bonds, as long as the valence electrons allow it; Or a pharmaceutically acceptable salt, tautomer, or stereoisomer of the compound.

7. The compound according to claim 6, characterized in that, Ring M is Ring M can be arbitrarily divided by R 2 and R 2’ replace.

8. The compound according to claim 1, characterized in that, Halogens are -F or -Cl.

9. The compound according to claim 1, 2 or 5, characterized in that, Ring A is And ring A can be arbitrarily divided by 1-3 Rs 1 Group substitution.

10. The compound according to claim 9, characterized in that, R 1 Each is independently -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’ , where R 11 Each of the following is independently H, cycloalkyl, heterocyclic, haloalkyl, alkyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more alkyl, halogen, or haloalkyl groups; R 12 and R 12’ Each can be independently H, cycloalkyl, haloalkyl, or alkyl.

11. The compound according to claim 1, characterized in that, R 3 and R 4 Each is independently H or alkyl, and any hydrogen is optionally substituted with D; or, R 3 and R 4 Together with the atoms they are connected to, they form a 3-7 membered cycloalkyl group.

12. The compound according to claim 1, characterized in that, R 6 and R 7 Each is independently H or alkyl.

13. The compound according to any one of claims 1-12, characterized in that, The compound is selected from:

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

15. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1-14, and a pharmaceutically acceptable carrier or excipient.

16. A method of treating a subject for symptoms and diseases affected by steroid hormone receptors, comprising administering to the subject a therapeutically effective dose of a compound according to any one of claims 1-14 or a pharmaceutical composition according to claim 15.

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

18. The method according to claim 16, characterized in that, The symptoms and diseases affected by steroid hormone receptors are cancer.

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

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

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

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