Inhibitors of the Menin-MLL Interaction

Abstract

This invention provides compounds and pharmaceutical compositions that inhibit / block menin-MLL interactions, as well as methods for treating diseases or disorders related to menin-MLL interactions. [Solution] The following compounds are provided. JPEG2026143650001059.jpg55170

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and interest to U.S. Provisional Patent Application No. 63 / 287,716, entitled “Inhibitors of Menin-MLL Interaction,” filed 9 December 2021, U.S. Provisional Patent Application No. 63 / 306,399, entitled “Inhibitors of Menin-MLL Interaction,” filed 3 February 2022, and U.S. Provisional Patent Application No. 63 / 397,322, entitled “Inhibitors of Menin-MLL Interaction,” filed 11 August 2022, the disclosures thereof being incorporated herein by reference in their entirety for all purposes.

[0002] (Area of ​​disclosure) This disclosure relates to inhibitors of the interaction between menin and MLL. The inhibitors described herein may be useful in treating diseases or disorders associated with menin-MLL interaction, such as cancer. In particular, this disclosure relates to compounds and pharmaceutical compositions that inhibit / block menin-MLL interaction, methods for treating diseases or disorders associated with menin-MLL interaction, and methods for synthesizing these compounds. [Background technology]

[0003] (background) MLL (mixed-lineage leukemia) gene translocations frequently occur in invasive human acute myeloid and lymphocytic leukemia in both children and adults. When MLL fuses with one of more than 60 different genes, a chimeric MLL fusion protein is produced that promotes proliferation and inhibits hematopoietic differentiation, ultimately leading to acute leukemia. The prognosis for leukemia patients with MLL translocations is extremely poor, and they rarely respond to currently available treatments. The risk of relapse is very high with conventional chemotherapy and stem cell transplantation, and the overall 5-year survival rate is only about 35% of patients.

[0004] Menin is an essential cofactor of oncogenic MLL fusion proteins, and the menin-MLL interaction is crucial for the development of acute leukemia in vivo. Targeting the menin-MLL interaction with small molecules is an attractive strategy for developing novel anticancer drugs. Recent developments, including the determination of the menin crystal structure and the development of potent small molecule and peptide-mimicking inhibitors, demonstrate the feasibility of targeting the menin-MLL interaction. On the other hand, biochemical and structural studies have revealed that MLL binds to menin in a complex bivalent mode involving two MLL motifs, and therefore inhibiting this protein-protein interaction presents a challenge.

[0005] Chromosomal rearrangements of the MLL gene located in chromosome band 11q23 are observed in patients with de novo acute myeloid (AML) and acute lymphoblastic (ALL) leukemia, as well as in treatment-associated leukemia or myelodysplastic syndromes (MDS). As a result of chromosomal translocation, the MLL gene fuses with one of over 60 different protein partners, including the most frequent AF4, AF9, ENL, AF6, ELL, and AF10. Disruption of MLL due to gene fusion upregulates the expression of HOXA9 and MEIS1 genes, which are crucial for leukemia development. The role of HOXA genes in leukemia transformation has been validated in both in vitro and in vivo models, showing that the upregulation of HOXA9 and MEIS1 genes mediated by the MLL fusion protein leads to enhanced proliferation and blockade of hematopoietic differentiation, ultimately resulting in acute leukemia. The prognosis for leukemia patients with MLL translocations is extremely poor (3-year event-free survival rate is 20%), and the response to available treatments is poor, making it clear that new treatment options are needed.

[0006] The oncogenic function of MLL fusion proteins is critically dependent on direct interaction with menin. Menin is a 67kDa protein encoded by the MEN1 (Multiple Endocrine Neoplasia I) gene, localized on chromosome 11q13. Menin is a universally expressed protein, primarily localized in the nucleus. Menin directly binds to the N-terminus of MLL, which is retained in all MLL fusion proteins, and plays a crucial role in the recruitment of MLL and MLL fusions to target genes, including HOXA9. Loss of menin binding by MLL fusion proteins eliminates their oncogenic properties in vitro and in vivo. Mutations in the N-terminus of MLL-ENL oncoproteins result in the protein being unable to bind to menin, losing its ability to upregulate Hox gene expression and inducing leukemia in mice. Expression of dominant-negative inhibitors composed of an amino-terminal MLL sequence inhibits the proliferation of MLL-AF9 transformed myeloid cells and blocks leukemic transformation.

[0007] Inhibition of the interaction between histone methyltransferase MLL1 (KMT2A) and menin has recently emerged as a novel therapeutic strategy. Beneficial therapeutic effects are hypothesized in leukemia, prostate, breast, liver, and synovial sarcoma models. In these indications, menin-mediated MLL1 recruitment has been described as decisively regulating the expression of disease-related genes.

[0008] Blocking the menin-MLL interaction is a viable approach to reverse the oncogenic activity of MLL fusion proteins in leukemia and could lead to new therapies. [Overview of the project]

[0009] (overview) A first aspect of this disclosure relates to a compound of formula (I): [ka] or relating to its pharmaceutically acceptable salts, prodrugs, stereoisomers, solvates, or tautomers [in the formula] X 1 , X2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from CH or N; X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 at least one of which is N; W is -CN; Alternatively, W and ring B, together with the atoms to which they are bonded and any intervening atoms, form a 5- to 10-membered heterocyclic ring; each R 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, NH2, NHCH3, and N(CH3)2, wherein said alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; each R 2 is independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 9 R 10 , C3-C 10 cycloalkyl, aryl, heterocyclyl, and heteroaryl; L is selected from (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q C(O); R 3 These are hydrogen, deuterium, C1-C6 alkyl, and C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 Selected from; L 4 teeth, [ka] and; L 5 (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q Selected from C(O); Ring B is C3-C 14 Selected from cycloalkyl, 3- to 10-membered heterocyclic, aryl, and heteroaryl groups, where cycloalkyl, heterocyclic, aryl, or heteroaryl groups are halogens, CN, NO2, oxo, OH, and NR. 9 R 10 , optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 Selected from heterocyclyl, aryl, or heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, C1-C6 alkyl, and C1-C6 alkoxy; Each R 5 H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10Selected independently from cycloalkyl groups; R 6 H, C1-C6 alkyl, -C(O)R 7 ,-NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)2NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 Selected from cycloalkyl, C1-C6 alkanediyl heterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediyl heteroaryl, the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 7 R 8 , OR 8 , NR 9 R 10 Selected from, R 8 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected from cycloalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH, CN, NO2, NR 9 R 10 Optionally substituted with one or more substituents independently selected from; Each R 9 and R 10 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic ring is optionally substituted with one or more substituents independently selected from halogens, OH, NH2, C1-C6 alkyl, and C1-C6 alkoxy rings; Alternatively, R 9 and R 10 Together with the atoms to which they are bonded and any intervening atoms, they form a 3-14 membered heterocycle; R 11 C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from; m and n are integers independently selected from 1, 2, and 3, respectively; p is an integer selected from 0, 1, and 2; r is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, 3, and 4; s is an integer selected from 0, 1, and 2; Cycloalkyls are monocyclic or polycyclic saturated carbon rings containing 3–18 carbon atoms; Aryls are cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings; A heterocyclyl is a saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridging, or spirocyclic) or 11-14 member tricyclic system (fused, bridging, or spirocyclic) having one or more heteroatoms selected from O, N, S, P, Se, or B; A heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

[0010] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include excipients, diluents, or surfactants.

[0011] Another aspect of the present disclosure relates to a method for treating a disease or disorder related to the interaction of menin and MLL. The method comprises administering to a patient in need of treatment for a disease or disorder related to the interaction of menin and MLL an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0012] Another aspect of this disclosure relates to a method for inhibiting the interaction between menine and MLL. The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0013] Another aspect of the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of a pharmacopoeia for inhibiting the interaction between menine and MLL.

[0014] Another aspect of this disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with the inhibition of the interaction between menin and MLL.

[0015] Another aspect of this disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0016] Another aspect of this disclosure relates to a method for treating or preventing a disease or disorder disclosed herein in a subject that requires treatment or prevention of such disease or disorder. The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient requiring treatment.

[0017] Another aspect of this disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0018] The disclosure further provides a method for treating a disease or disorder related to the interaction of menin and MLL, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] This disclosure provides inhibitors of the interaction between menin and MLL, which are therapeutic agents in the treatment of diseases and disorders.

[0020] This disclosure further provides compounds and compositions having improved efficacy and safety profiles compared to known inhibitors of menin-MLL interaction. This disclosure also provides agents having novel mechanisms of action against menin-MLL interaction in the treatment of various types of diseases.

[0021] The disclosure further provides a method for treating a disease or disorder related to the interaction of menin and MLL, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0022] This disclosure provides inhibitors of the interaction between menin and MLL, which are therapeutic agents in the treatment of diseases and disorders.

[0023] The disclosure further provides a method for treating a disease, disorder, or condition selected from cancer, acute myeloid leukemia (AML), and acute lymphoblastic (ALL), leukemia, or myelodysplastic syndrome (MDS), comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] In some embodiments, the present disclosure provides compounds that can be obtained by or obtained by methods for preparing the compounds described herein (for example, methods comprising one or more steps described in general procedure A or B).

[0025] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (for example, the intermediates are selected from the intermediates described in the preparation examples described below herein).

[0026] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0027] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure, comprising one or more steps described herein.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure, but suitable methods and materials are described below. Furthermore, materials, methods, and examples are illustrative and not intended to be limiting. In the event of any inconsistency between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0029] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0030] (Detailed explanation) This disclosure provides a method for treating, preventing, or improving a disease or disorder related to the inhibition of the interaction between menin and MLL1 by administering a therapeutically effective amount of one of the compounds disclosed herein to a subject in need.

[0031] Details of this disclosure are described in the attached description below. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure, but only illustrative methods and materials are described here. Other features, purposes and advantages of this disclosure will become apparent from this specification and the claims. In this specification and the attached claims, singular forms include plural forms unless the context makes it clear otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0032] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "element" means one or more elements.

[0033] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise specified.

[0034] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group could be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group could have one or more substituents other than hydrogen. For example, at any point along the chain, it could be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups. Preferred substituents used for any substitution of the listed groups are, but are not limited to, halogens, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O This includes (OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is set out below.

[0035] As used herein, the term “substituted” means that a particular group or site has one or more suitable substituents, and the substituents may be linked to the particular group or site at one or more positions. For example, aryl substituted with cycloalkyl indicates that the cycloalkyl is linked to one atom of the aryl by bonding or by condensation with the aryl to share two or more common atoms.

[0036] In this specification, the term "unsubstituted" means that a particular group does not have substituents.

[0037] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If it contains two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be bonded at one point (e.g., biphenyl) or condensed (e.g., naphthyl). The aryl group can be optionally substituted at any bonding point with one or more substituents, e.g., one to five substituents. Examples of substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. Substituents can be optionally substituted themselves. Furthermore, if the aryl group contains two fused rings, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused with a fully unsaturated aromatic ring. Examples of these aryl ring systems include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannerenyl.

[0038] Unless otherwise defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, comprising one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. A polycyclic aromatic radical may comprise two or more fused rings, and may further comprise two or more spiro-fused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, “condensed” means two rings sharing two ring atoms. Unless otherwise specified, “spiro-condensed” means two rings sharing one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tetracyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical may be independently substituted with one or more substituents as described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranil, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrro [3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,[3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyridinyl, tetrahydropy Roro[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyrimidinyl, flo[2,3-c]pyrimidinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzoisoxazolyl, flo[2,3-b]pyrimidinyl Lidinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazole-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,This includes, but is not limited to, [3-b]pyrrolyl, 3H-indolyl, and their derivatives. Furthermore, if it contains two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused with the saturated or partially unsaturated rings described herein. Furthermore, if it contains three or more fused rings, the heteroaryl group as defined herein may spirocondense one or more saturated or partially unsaturated rings. Any saturated or partially unsaturated ring described herein may be optionally substituted with one or more oxos. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridine-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, and 1,5,6,7-tetrahydrocyclopenta[b]pyrrolidinyl. Contains zolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidine-7(4H)-onlyl, 3,4-dihydropyrazino[1,2-a]indole-1(2H)-onyl, or benzo[c][1,2]oxabolol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrolo[1,2-d][1,4]oxazine-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrolo[1,2-d][1,4]oxazine]-9'-onyl.

[0039] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0040] Alkyl refers to a linear or branched saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0041] "Alkoxy" refers to a linear or branched saturated hydrocarbon containing 1 to 12 carbon atoms, including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0042] An "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in its chain. The double bond of the alkenyl group may be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted. Alkenyls as defined herein may be straight-chain or branched.

[0043] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0044] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the monovalent alkyl groups described above may be alkylenes obtained by the extraction of a second hydrogen atom from the alkyl. As defined herein, alkylenes may be C1-C6 alkylenes. Alkylenes may further be C1-C4 alkylenes. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0045] "Cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3–18 carbon atoms. Polycyclic cycloalkyls may be condensed bicyclic cycloalkyls, cross-linked bicyclic cycloalkyls, or spiro-condensed bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0046] A "heterocyclyl," "heterocyclic," or "heterocycloalkyl" containing 3 to 24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, is monocyclic or polycyclic, where the rings are non-aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. A polycyclic heterocycloalkyl contains at least one non-aromatic ring. Polycyclic heterocyclic compounds can be crosslinked, condensed, or spirocondensed. Substituents can be optionally substituted themselves. Examples of heterocyclyl rings include, but are not limited to, oxetanil, azetidinil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, oxazolinil, oxazolidinil, thiazolinil, thiazolidinil, pyranil, thiopyranil, tetrahydropyranil, dioxalinil, piperidinil, morpholinil, thiomorpholinil, thiomorpholinil S-oxide, thiomorpholinil S-dioxide, piperazinil, azepinil, oxepinil, diazepinil, tropanil, oxazolidinonil, homotropanil, 2-oxa-5-azabicyclo[2.2.2]octane, and 2,6-diazaspiro[3.3]heptanil.

[0047] The term "aromatic" refers to a planar ring having 4n+2 electrons in a conjugated system. In this specification, "conjugated system" means a system in which p orbitals having delocalized electrons are linked, and this system may contain lone pairs of electrons.

[0048] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, which is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0049] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein, which is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and others.

[0050] As used herein, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0051] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-source bicyclic system in which both rings are linked by a single atom. The rings may differ in size and properties, or they may be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be substituted with heteroatoms (e.g., O, N, S, or P). (C3-C 12 Spirocycloalkyls are spiro rings containing 3 to 12 carbon atoms. One or more carbon atoms may be substituted with heteroatoms.

[0052] The terms “spiroheterocycloalkyl,” “spiroheterocycle,” or “spiroheterocyclyl” are understood to mean a spirocycle in which at least one of the rings is heterocycle (for example, at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0053] The term "solvate" refers to various stoichiometric complexes formed by a solute and a solvent. Such solvents for the purposes of this disclosure are not those that can impede the biological activity of the solute. Suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are usually called hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0054] As used herein, the term “alkyl-aryl” (and its variations, e.g., C1-C6 alkyl-aryl) refers to a chemical moiety containing an alkyl group covalently bonded to an aryl group, where the bond to the rest of the molecule rests on the first group described, i.e., the alkyl group. Similarly, alkyl-alkoxy refers to a chemical moiety containing an alkyl group covalently bonded to an alkoxy group, where the bond to the rest of the molecule rests on the alkyl group. This nomenclature can also be used, for example, for alkenyl-aryl, alkenyl-heteroaryl, alkynyl-aryl, and alkynyl-heteroaryl.

[0055] As a non-limiting example, C1 alkylphenyls are, [ka] This refers to; C2 alkenyl-furanyl is, [ka] This refers to; C1 alkyl-C2 alkoxy, [ka] This refers to, for example.

[0056] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences can be in their composition (geometric isomers) or their ability to rotate the plane of polarization (stereoisomers). Regarding stereoisomers, the compound of formula (I) may have one or more chiral carbon atoms and can arise as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0057] This disclosure also relates to isotope-labeled compounds of formula I (e.g., 2 H and 14 The intention is to deuterate (i.e., labeled with C). 2 H or D) isotopes and carbon-14 (i.e., 14C) Isotopes are particularly preferred in terms of ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and may therefore be preferred in some situations. Isotope-labeled compounds of formula I can generally be prepared by replacing unisotopically labeled reagents with appropriate isotope-labeled reagents, following procedures similar to those disclosed in the following schemes and / or examples.

[0058] This disclosure also includes pharmaceutical compositions comprising therapeutically effective amounts of the disclosed compounds and pharmaceutically acceptable carriers. Typical “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, and hydrochloride. This includes hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picric acid, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

[0059] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0060] "Effective dose" is the amount that, when used in conjunction with the compound, is effective in treating or preventing a disease in the subject described herein.

[0061] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in the transport or delivery of a pharmaceutical product from one organ or part of the body to another.

[0062] The term “to treat” in relation to an object refers to improving at least one symptom of the disorder in that object. Treating includes curing, improving, or at least partially improving the disorder.

[0063] In this disclosure, unless otherwise specified, the term “disability” is used to mean the term “disease,” “condition,” or “illness,” and is used interchangeably with the term “disease,” “condition,” or “illness.”

[0064] As used in this disclosure, the terms “administer,” “give administration,” or “give administration” refer to either directly administering the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or administering a prodrug derivative or analogue of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject so that an equivalent amount of the active compound can be formed in the subject’s body.

[0065] As used in this disclosure, the term “prodrug” means a compound that can be converted in vivo into the disclosed compound by metabolic means (e.g., hydrolysis).

[0066] The term "salt" refers to a pharmaceutically acceptable salt.

[0067] The term “pharmaceutically acceptable salt” also refers to a salt of a composition of this disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0068] As used herein, "menine / MLL interaction inhibitor" refers to a compound of formula I and / or a composition comprising a compound of formula I that inhibits the interaction between menine and MLL.

[0069] The amount of compounds in the compositions described herein required to achieve a therapeutic effect can be determined empirically by conventional procedures for a particular purpose. Generally, when a therapeutic agent (e.g., a compound or composition of Formula I described herein (and / or additional agents)) is administered for therapeutic purposes, the therapeutic agent is given in a pharmacologically effective dose. "Pharmacologically effective amount," "pharmacologically effective dose," "therapeutably effective amount," or "effective amount" means an amount sufficient to produce a desired physiological effect or to achieve a desired outcome, particularly for treating a disorder or disease. As used herein, an effective amount includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of disease symptoms), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse the symptoms of a disorder or disease. For example, administering a therapeutic agent to a patient with cancer provides a therapeutic benefit not only when the underlying condition is eradicated or improved, but also when the patient reports a reduction in the severity or duration of disease-related symptoms, such as a decrease in tumor burden, a decrease in circulating tumor cells, or an increase in progression-free survival. Therapeutic benefits also include stopping or slowing the progression of the underlying disease or disability, regardless of whether improvement is achieved. Compounds of the Disclosure

[0070] In various embodiments, the inhibitor of the menin-MML interaction is a compound having a structure represented by formula (I): [Chemical] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein in the formula X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from CH or N; X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 at least one of which is N; W is -CN; alternatively, W and ring B, together with the atoms to which they are bonded and any intervening atoms, form a 5- to 10-membered heterocyclic ring; each R 1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic ring, aryl, heteroaryl, OH, NH2, NHCH3, and N(CH3)2, and said alkyl, alkoxy, alkenyl, alkynyl, heterocyclic ring, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic ring, aryl, and heteroaryl; each R 2 is independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 9 R 10 , C3-C 10 cycloalkyl, aryl, heterocyclyl, and heteroaryl; L is (CR 5 2) q, (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q Selected from C(O); R 3 These are hydrogen, deuterium, C1-C6 alkyl, and C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 Selected from; L 4 teeth, [ka] and; L 5 (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q Selected from C(O); Ring B is C3-C 14 Selected from cycloalkyl, 3- to 10-membered heterocyclic, aryl, and heteroaryl groups, where cycloalkyl, heterocyclic, aryl, or heteroaryl groups are halogens, CN, NO2, oxo, OH, and NR. 9 R 10 , optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 Selected from heterocyclyl, aryl, or heteroaryl, Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are optionally substituted with one or more substituents independently selected from halogens, OH, NH2, C1-C6 alkyl, and C1-C6 alkoxy compounds; Each R 5 H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected independently from cycloalkyl groups; R 6 H, C1-C6 alkyl, -C(O)R 7 ,-NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)2NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 Selected from cycloalkyl, C1-C6 alkanediyl heterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediyl heteroaryl, the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 7 R 8 , OR 8 , NR 9 R 10 Selected from, R 8 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected from cycloalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH, CN, NO2, NR9 R 10 Optionally substituted with one or more substituents independently selected from; Each R 9 and R 10 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10 The molecule is cycloalkyl, aryl, heteroaryl, or heterocyclic, and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one or more substituents independently selected from halogens, OH, NH2, C1-C6 alkyl, and C1-C6 alkoxy; Alternatively, R 9 and R 10 Together with the atoms to which they are bonded and any intervening atoms, they form a 3-14 membered heterocycle; R 11 C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from; m and n are integers independently selected from 1, 2, and 3, respectively; p is an integer selected from 0, 1, and 2; r is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, 3, and 4; s is an integer selected from 0, 1, and 2.

[0071] For inhibitors having the structure represented by formula (I), cycloalkyl is a monocyclic or polycyclic saturated carbocyclic ring containing 3-18 carbon atoms; aryl is a cyclic aromatic hydrocarbon group having 1-3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridging, or spiro-ring), or 11-14 member tricyclic (fused, bridging, or spiro-ring) system having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5-24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

[0072] In one embodiment, the present disclosure provides compounds of formula (I) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 1’ , X 2 , X 3 , X 4 , X 5 , X 6 Y, L, m, n, p, and r are as described herein.

[0073] For the compound of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 L, L 4 , L 5 B, W, X 1 , X 2 , X 3 , X 4, X 5 , X 6 m, n, p, r, q, and s may each be selected from the groups described herein, where applicable. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 L, L 4 , L 5 B, W, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 It is understood that any of the bases described herein for m, n, p, r, q, and s may be combined, where applicable. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7, R8, R9, R10, R11, L, L 4 , L 5 B, W, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 It is understood that m, n, p, r, q, and the remaining one or more s can be combined with any of the groups described herein.

[0074] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 Each is independently selected from CH or N; X 1 , X 2 , X 3 , X 4 , X 5, and X 6 At least one of them is N; W is -CN; Alternatively, W and ring B, together with the atoms to which they are bonded and any intervening atoms, form a 5-10 membered heterocycle; Each R 1 These include halogens, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 A cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, OH, NH2, NHCH3, and N(CH3)2 is independently selected from alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl, halogen, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; Each R 2 These are halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and NR. 9 R 10 , C3-C 10 Independently selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; L is (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q Selected from C(O); R 3 These are hydrogen, deuterium, C1-C6 alkyl, and C3-C 10Cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 Selected from; L 4 teeth, [ka] and; L 5 (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q Selected from C(O); Ring B is C3-C 14 Selected from cycloalkyl, 3- to 10-membered heterocyclic, aryl, and heteroaryl groups, where cycloalkyl, heterocyclic, aryl, or heteroaryl groups are halogens, CN, NO2, oxo, OH, and NR. 9 R 10 , optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 4 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 Selected from heterocyclyl, aryl, or heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, C1-C6 alkyl, and C1-C6 alkoxy; Each R 5 H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected independently from cycloalkyl groups; R 6H, C1-C6 alkyl, -C(O)R 7 ,-NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)2NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 Selected from cycloalkyl, C1-C6 alkanediyl heterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediyl heteroaryl, the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, NO2, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 7 R 8 , OR 8 , NR 9 R 10 Selected from, R 8 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected from cycloalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH, CN, NO2, NR 9 R 10 Optionally substituted with one or more substituents independently selected from; Each R 9 and R 10 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C 10The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic ring is optionally substituted with one or more substituents independently selected from halogens, OH, NH2, C1-C6 alkyl, and C1-C6 alkoxy rings; Alternatively, R 9 and R 10 Together with the atoms to which they are bonded and any intervening atoms, they form a 3-14 membered heterocycle; R 11 C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from; m and n are integers independently selected from 1, 2, and 3, respectively; p is an integer selected from 0, 1, and 2; r is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, 3, and 4; s is an integer selected from 0, 1, and 2.

[0075] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 Each of these is independently selected from CH or N; X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least one of them is N.

[0076] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 Each of these is independently selected from CH or N; X 1, X 2 , X 3 , X 4 , X 5 , and X 6 At least two of them are N.

[0077] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 Each of these is independently selected from CH or N; X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least three of them are N.

[0078] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 Each of these is independently selected from CH or N; X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least four of them are N.

[0079] In some embodiments, X 1 It is either CH or N.

[0080] In some embodiments, X 1 CH is and H is R 1 It is optionally replaced.

[0081] In some embodiments, X 1 It is CH.

[0082] In some embodiments, X 1 CR 1 That is the case.

[0083] In some embodiments, X 1 It is N.

[0084] In some embodiments, X 2 It is either CH or N.

[0085] In some embodiments, X 2 CH is and H is R 1 It is optionally replaced.

[0086] In some embodiments, X 2 It is CH.

[0087] In some embodiments, X 2 CR 1 That is the case.

[0088] In some embodiments, X 2 It is N.

[0089] In some embodiments, X 3 It is either CH or N.

[0090] In some embodiments, X 3 CH is and H is R 1 It is optionally replaced.

[0091] In some embodiments, X 3 It is CH.

[0092] In some embodiments, X 3 CR 1 That is the case.

[0093] In some embodiments, X 3 It is N.

[0094] In some embodiments, X 4 It is either CH or N.

[0095] In some embodiments, X 4 CH is and H is R 1 It is optionally replaced.

[0096] In some embodiments, X 4 It is CH.

[0097] In some embodiments, X 4 CR 1 That is the case.

[0098] In some embodiments, X 4 It is N.

[0099] In some embodiments, X 5 It is either CH or N.

[0100] In some embodiments, X 5 CH is and H is R 1 It is optionally replaced.

[0101] In some embodiments, X 5 CR 1 That is the case.

[0102] In some embodiments, X 5 It is N.

[0103] In some embodiments, X 6 It is either CH or N.

[0104] In some embodiments, X 6 CH is and H is R 1 It is optionally replaced.

[0105] In some embodiments, X 6 It is CH.

[0106] In some embodiments, X 6 CR 1 That is the case.

[0107] In some embodiments, X 6 It is N.

[0108] In some embodiments, X 1 and X 6 Each of these is N.

[0109] In some embodiments, X 1 and X 6 Each of these is N, and X 2 , X 3 , X 4 and X 5 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0110] In some embodiments, X 1 and X 6 Each of these is N, and X 2 , X 3 , X 4 and X 5 Each of them is CH.

[0111] In some embodiments, X 1 and X 6 Each of these is N, and X 2 , X 4 , and X 5 Each of them is CH, and X 3 CR 1 That is the case.

[0112] In some embodiments, X 1 and X 6 Each of these is N, and X 2 , X 4 , and X 5 Each of them is CH, and X 3 This is CF.

[0113] In some embodiments, X 1 and X 6 Each of these is N, and X 2 , X 3 , and X 5Each of them is CH, and X 4 CR 1 That is the case.

[0114] In some embodiments, X 1 and X 6 Each of these is N, and X 2 , X 3 , and X 5 Each of them is CH, and X 4 This is CF.

[0115] In some embodiments, X 5 and X 6 Each of these is N.

[0116] In some embodiments, X 5 and X 6 Each of these is N, and X 1 , X 2 , X 3 and X 4 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0117] In some embodiments, X 5 and X 6 Each of these is N, and X 1 , X 2 , X 3 and X 4 Each of them is CH.

[0118] In some embodiments, X 1 and X 5 Each of these is N.

[0119] In some embodiments, X 1 and X 5 Each of these is N, and X 2 , X 3 , X 4 and X 6 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0120] In some embodiments, X 1 and X 5 Each of these is N, and X 2 , X 3 , X 4 and X 6 Each of them is CH.

[0121] In some embodiments, X 1 , X 4 and X 6 Each of these is N.

[0122] In some embodiments, X 1 , X 4 and X 6 Each of these is N, and X 2 , X 3 , and X 5 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0123] In some embodiments, X 1 , X 4 and X 6 Each of these is N, and X 2 , X 3 , and X 5 Each of them is CH.

[0124] In some embodiments, X 1 , X 3 and X 6 Each of these is N.

[0125] In some embodiments, X 1 , X 3 and X 6 Each of these is N, and X 2 , X 4 , and X 5 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0126] In some embodiments, X 1 , X 3 and X6 Each of these is N, and X 2 , X 4 , and X 5 Each of them is CH.

[0127] In some embodiments, X 1 , X 2 and X 6 Each of these is N.

[0128] In some embodiments, X 1 , X 2 and X 6 Each of these is N, and X 3 , X 4 , and X 5 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0129] In some embodiments, X 1 , X 2 and X 6 Each of these is N, and X 3 , X 4 , and X 5 Each of them is CH.

[0130] In some embodiments, X 1 , X 2 , X 4 and X 6 Each of these is N.

[0131] In some embodiments, X 1 , X 2 , X 4 and X 6 Each of these is N, and X 3 and X 5 Each of them is CH, and each H is optionally R 1 It will be replaced by this.

[0132] In some embodiments, X 1 , X 2 , X 4 and X 6 Each of these is N, and X3 and X 5 Each of them is CH.

[0133] Several embodiments, each R 1 These include halogens, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, and NR 9 R 10 Independently selected from alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl, halogen, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups;

[0134] In some embodiments, R 1 It is a halogen.

[0135] In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 It is I.

[0136] In some embodiments, R 1 It is F.

[0137] Several embodiments, each R 1 C3-C 10A cycloalkyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, and C2-C6 alkynyl-heteroaryl is independently selected. In some embodiments, each R 1 C3-C 10 A molecule is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0138] Several embodiments, each R 1 R is independently selected from C1-C6 alkyl and C1-C6 alkoxy. In some embodiments, each R 1 C3-C 10 Selected independently from cycloalkyl and aryl. In some embodiments, each R 1 The heterocyclic and heteroaryl compounds are selected independently.

[0139] In some embodiments, R 1 It is a C1-C6 alkyl group.

[0140] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is n-propyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is n-butyl. In some embodiments, R 1 is iso-butyl. In some embodiments, R 1 is sec-butyl. In some embodiments, R 1 is tert-butyl. In some embodiments, R 1 is pentill. In some embodiments, R1 It is hexyl.

[0141] In some embodiments, R 1 It is a C1-C6 alkoxy.

[0142] In some embodiments, R 1 is methoxy. In some embodiments, R 1 is ethoxy. In some embodiments, R 1 is a propoxy. In some embodiments, R 1 is butoxy. In some embodiments, R 1 It is pentoxy. In some embodiments, one R 1 It is hexoxy.

[0143] In some embodiments, R 1 teeth, [ka] That is the case.

[0144] In some embodiments, p is 1, and R 1 teeth, [ka] That is the case.

[0145] In some embodiments, R 1 C3-C 10 It is a cycloalkyl group.

[0146] In some embodiments, R 1 This is a single-ring C3-C 10 It is cycloalkyl. In some embodiments, R 1 This is a polycyclic C3-C 10 It is a cycloalkyl group.

[0147] In some embodiments, R 1 It is a C5-C6 cycloalkyl group.

[0148] In some embodiments, R 1 R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is cyclohexyl. In some embodiments, R 1 is cycloheptyl. In some embodiments, R 1 is cyclooctyl. In some embodiments, R 1 is cyclononyl. In some embodiments, R 1 It is cyclodecyl.

[0149] In some embodiments, R 1 This is a condensed polycyclic C3-C 10 It is cycloalkyl. In some embodiments, R 1 This is a cross-linked polycyclic C3-C 10 It is cycloalkyl. In some embodiments, R 1 C3-C 10 It is a spirocycloalkyl.

[0150] In some embodiments, R 1 It is a C2-C6 alkenyl.

[0151] In some embodiments, R 1 is a C2 alkenyl. In some embodiments, R 1 is a C3 alkenyl. In some embodiments, R 1 is a C4 alkenyl. In some embodiments, R 1 is a C5 alkenyl. In some embodiments, R 1 This is a C6 alkenyl.

[0152] In some embodiments, R 1 This is a C2-C6 alkynyl compound.

[0153] In some embodiments, R 1 is C2 alkynyl. In some embodiments, R 1 is C3 alkynyl. In some embodiments, R 1 is C4 alkynyl. In some embodiments, R 1 is C5 alkynyl. In some embodiments, R 1 This is C6 alkynyl.

[0154] In some embodiments, R 1 is a complex algebra. In some embodiments, R 1 is a 3-10 member complex ring. In some embodiments, R 1 R is a heterocycle containing one, two, or three heteroatoms. In some embodiments, R 1 A heterocycle is a 3-10 membered ring containing one, two, or three heteroatoms.

[0155] In some embodiments, R 1 It is a monoring heteroring. In some embodiments, R 1 It is a polycyclic heteroalgebra.

[0156] In some embodiments, R 1 is a 3-membered complex ring. In some embodiments, R 1 is a 4-membered complex ring. In some embodiments, R 1 is a 5-membered complex ring. In some embodiments, R 1 is a 6-membered complex ring. In some embodiments, R 1 is a 7-membered complex ring. In some embodiments, R 1 is an 8-membered complex ring. In some embodiments, R 1 is a 9-membered complex ring. In some embodiments, R 1 This is a 10-membered complex ring.

[0157] In some embodiments, R 1 This is a 5- to 6-member complex ring.

[0158] In some embodiments, R 1 That is Ariel.

[0159] In some embodiments, R 1 It is a C6 aryl compound (e.g., phenyl).

[0160] In some embodiments, R 1 is a heteroaryl compound. In some embodiments, R 1 It is a 5- to 6-membered heteroaryl compound.

[0161] In some embodiments, R 1 It is a C1-C6 alkyl-aryl compound.

[0162] In some embodiments, R 1 is a methylaryl compound. In some embodiments, R 1 is ethyl-aryl. In some embodiments, R 1 R is a propyl-aryl compound. In some embodiments, R 1 is n-propylaryl. In some embodiments, R 1 is iso-propyl-aryl. In some embodiments, R 1 is butyl-aryl. In some embodiments, R 1 is n-butyl-aryl. In some embodiments, R 1 isobutylaryl. In some embodiments, R 1 is sec-butyl-aryl. In some embodiments, R 1 is tert-butyl-aryl. In some embodiments, R 1 is pentyl-aryl. In some embodiments, R 1 It is a hexyl-aryl compound.

[0163] In some embodiments, R 1 It is a C1-C6 alkyl-heteroaryl compound.

[0164] In some embodiments, R 1 is a methyl heteroaryl compound. In some embodiments, R 1 is an ethyl heteroaryl compound. In some embodiments, R 1 is a propyl heteroaryl compound. In some embodiments, R 1 is an n-propyl heteroaryl compound. In some embodiments, R 1 is an isopropyl heteroaryl. In some embodiments, R 1 is a butyl heteroaryl. In some embodiments, R 1 is an n-butyl heteroaryl. In some embodiments, R 1 is an iso-butyl heteroaryl. In some embodiments, R 1 is sec-butyl-heteroaryl. In some embodiments, R 1 is a tert-butyl heteroaryl. In some embodiments, R 1 is a pentyl heteroaryl. In some embodiments, R 1 It is a hexyl heteroaryl compound.

[0165] In some embodiments, R 1 It is a C2-C6 alkenyl-aryl compound.

[0166] In some embodiments, R 1 is a C2 alkenyl-aryl. In some embodiments, R 1 is a C3 alkenyl-aryl. In some embodiments, R 1 is a C4 alkenyl-aryl. In some embodiments, R 1 is a C5 alkenyl-aryl. In some embodiments, R 1は、 It is a C6 alkenyl-aryl compound.

[0167] In some embodiments, R 1 It is a C2-C6 alkenyl heteroaryl compound.

[0168] In some embodiments, R 1 is a C2 alkenyl heteroaryl. In some embodiments, R 1 is a C3 alkenyl heteroaryl. In some embodiments, R 1 is a C4 alkenyl heteroaryl. In some embodiments, R 1 is a C5 alkenyl heteroaryl. In some embodiments, R 1 It is a C6 alkenyl heteroaryl compound.

[0169] In some embodiments, R 1 It is a C2-C6 alkynyl-aryl compound.

[0170] In some embodiments, R 1 is a C2 alkynyl-aryl compound. In some embodiments, R 1 is a C3 alkynyl-aryl compound. In some embodiments, R 1 is a C4 alkynyl-aryl compound. In some embodiments, R 1 is a C5 alkynyl-aryl compound. In some embodiments, R 1 It is a C6 alkynyl-aryl compound.

[0171] In some embodiments, R 1 It is a C2-C6 alkynyl heteroaryl compound.

[0172] In some embodiments, R 1 is a C2 alkynyl heteroaryl. In some embodiments, R 1 is a C3 alkynyl heteroaryl. In some embodiments, R 1 is a C4 alkynyl heteroaryl. In some embodiments, R 1is a C5 alkynyl heteroaryl. In some embodiments, R 1 It is a C6 alkynyl heteroaryl compound.

[0173] In some embodiments, R 1 , NR 9 R 10 In some embodiments, R 1 NHR 10 In some embodiments, R 1 It is NHCH3.

[0174] In some embodiments, p is 2, and one R 1 , NR 9 R 10 And the other R 1 C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, and NR 9 R 10. Selected from alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl, halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 9 R 10 , C3-C 10 It is optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups.

[0175] In some embodiments, p is 2, and one R 1 NHCH3 is the other R 1 is a C1-C6 alkyl group that is optionally substituted with one or more halogens. In some embodiments, p is 2, and one R 1NHCH3 is the other R 1 is a C1-C6 alkyl group that is optionally substituted with one or more fluoropolymers. In some embodiments, one of the R 1 NHCH3 is the other R 1 It is CH2CF3.

[0176] In some embodiments, R 1 is a C1-C6 alkyl substituted with one or more halogens. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more F groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more Cl atoms. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more Br groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more I groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more OH groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more NH2 groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more C1-C6 alkyl groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R 1 is one or more NR 9 R 10 It is a C1-C6 alkyl substituted with R. In some embodiments, 1 is one or more C3-C 10 It is a C1-C6 alkyl group substituted with a cycloalkyl group. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more C2-C6 alkenyl groups. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more C2-C6 alkynyl groups. In some embodiments, R 1is a C1-C6 alkyl substituted with one or more heterocycles. In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more aryl groups. In some embodiments, R 1 This is a C1-C6 alkyl group substituted with one or more heteroaryl groups.

[0177] In some embodiments, R 1 is a C1-C6 alkyl group substituted with one or more fluorine atoms. In some embodiments, R 1 is a methyl group substituted with one or more F groups. In some embodiments, R 1 is ethyl substituted with one or more F. In some embodiments, R 1 is a propyl substituted with one or more F. In some embodiments, R 1 is an n-propyl substituted with one or more F. In some embodiments, R 1 is an isopropyl substituted with one or more F. In some embodiments, R 1 is butyl substituted with one or more F. In some embodiments, R 1 is n-butyl substituted with one or more F. In some embodiments, R 1 is iso-butyl substituted with one or more F. In some embodiments, R 1 is sec-butyl substituted with one or more F. In some embodiments, R 1 is tert-butyl substituted with one or more F. In some embodiments, R 1 is a pentyl substituted with one or more Fs. In some embodiments, R 1 This is a hexyl molecule substituted with one or more F atoms.

[0178] In some embodiments, R 1 (CH2) 0-5 It is CF3. In some embodiments, R 1 is CF3. In some embodiments, R 1It is CH2CF3.

[0179] In some embodiments, R 1 is -CH2CF3. In some embodiments, R 1 It is -CF2CF3.

[0180] In some embodiments, p is 1, and R 1 (CH2) 0-5 It is CF3. In some embodiments, p is 1 and R 1 is CF3. In some embodiments, p is 1 and R 1 This is CH2CF.

[0181] In some embodiments, p is 2 and at least one R 1 (CH2) 0-5 It is CF3. In some embodiments, p is 2 and at least one R 1 is CF3. In some embodiments, p is 2 and at least one R 1 It is CH2CF3.

[0182] In some embodiments, R 1 teeth, [ka] That is the case.

[0183] In some embodiments, R 1 teeth, [ka] That is the case.

[0184] In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more halogens. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more F. In some embodiments, R 1is a C1-C6 alkoxy substituted with one or more Cl atoms. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more Br. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more I. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more OH groups. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more NH2 groups. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more C1-C6 alkyl groups. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more C1-C6 alkoxys. In some embodiments, R 1 is one or more NR 12 R 13 It is a C1-C6 alkoxy substituted with R. In some embodiments, R 1 is one or more C3-C 10 It is a C1-C6 alkoxy substituted with a cycloalkyl group. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more C2-C6 alkenyls. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more C2-C6 alkynyl groups. In some embodiments, R 1 is a C1-C6 alkoxy substituted with one or more heterocycles. In some embodiments, R 1 is an aryl-substituted C1-C6 alkoxy. In some embodiments, R 1 This is a C1-C6 alkoxy substituted with one or more heteroaryl groups.

[0185] In some embodiments, R 1 C3-C is a C3-C substituted with one or more halogens. 10 It is cycloalkyl. In some embodiments, R 1 C3-C is a C3-C substituted with one or more Fs. 10It is cycloalkyl. In some embodiments, R 1 This is a C3-C substituted with one or more Cl atoms. 10 It is cycloalkyl. In some embodiments, R 1 This is a C3-C substituted with one or more Br atoms. 10 It is cycloalkyl. In some embodiments, R 1 C3-C is a C3-C that is substituted with one or more I. 10 Cycloalkyl. In some embodiments, R 1 This is a C3-C molecule substituted with one or more OH groups. 10 It is cycloalkyl. In some embodiments, R 1 This is a C3-C molecule substituted with one or more NH2 groups. 10 It is cycloalkyl. In some embodiments, R 1 C3-C substituted with one or more C1-C6 alkyl groups 10 It is cycloalkyl. In some embodiments, R 1 C3-C substituted with one or more C1-C6 alkoxy groups 10 It is cycloalkyl. In some embodiments, R 1 is one or more NR 12 R 13 C3-C replaced by 10 It is cycloalkyl. In some embodiments, R 1 is one or more C3-C 10 Cycloalkyl-substituted C3-C 10 It is cycloalkyl. In some embodiments, R 1 This is a C3-C substituted with one or more C2-C6 alkenyls. 10 It is cycloalkyl. In some embodiments, R 1 This is a C3-C substituted with one or more C2-C6 alkynyl groups. 10 It is cycloalkyl. In some embodiments, R 1 This is a C3-C substituted with one or more heteroalgebras. 10 It is cycloalkyl. In some embodiments, R 1 C3-C is a C3-C molecule substituted with one or more aryl groups. 10It is cycloalkyl. In some embodiments, R 1 C3-C substituted with one or more heteroaryls 10 It is a cycloalkyl group.

[0186] In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more halogens. In some embodiments, R 1 is a C2-C6 alkenyl substituted with F. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more Cl atoms. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more Br. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more I. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more OH groups. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more NH2 groups. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more C1-C6 alkyl groups. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more C1-C6 alkoxys. In some embodiments, R 1 is one or more NR 12 R 13 It is a C2-C6 alkenyl substituted with R. In some embodiments, R 1 is one or more C3-C 10 It is a C2-C6 alkenyl substituted with a cycloalkyl group. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more C2-C6 alkenyls. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more C2-C6 alkynyls. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more heterocycles. In some embodiments, R 1is a C2-C6 alkenyl substituted with one or more aryls. In some embodiments, R 1 This is a C2-C6 alkenyl substituted with one or more heteroaryl groups.

[0187] In some embodiments, R 1 is a C2-C6 alkynyl substituted with one or more halogens. In some embodiments, R 1 This is a C2-C6 alkynyl substituted with one or more heteroaryl groups.

[0188] In some embodiments, R 1 is a heterocycle substituted with one or more halogens. In some embodiments, R 1 It is a heterocycle substituted with one or more heteroaryl groups.

[0189] In some embodiments, R 1 is an aryl substituted with one or more halogens. In some embodiments, R 1 This is an aryl compound that is substituted with one or more heteroaryl compounds.

[0190] In some embodiments, R 1 is a heteroaryl substituted with one or more halogens. In some embodiments, R 1 This is a heteroaryl compound that is substituted with one or more heteroaryl compounds.

[0191] In some embodiments, R 1 is a C1-C6 alkyl-aryl substituted with one or more halogens. In some embodiments, R 1 This is a C1-C6 alkyl-aryl substituted with one or more heteroaryls.

[0192] In some embodiments, R 1 teeth, [ka] That is the case.

[0193] In some embodiments, p is 1, and R 1 teeth, [ka] That is the case.

[0194] In some embodiments, R 1 is a C1-C6 alkyl-heteroaryl substituted with one or more halogens. In some embodiments, R 1 This is a C1-C6 alkyl-heteroaryl substituted with one or more heteroaryls.

[0195] In some embodiments, R 1 teeth, [ka] That is the case.

[0196] In some embodiments, p is 1, and R 1 teeth, [ka] That is the case.

[0197] In some embodiments, R 1 teeth, [ka] That is the case.

[0198] In some embodiments, p is 1, and R 1 teeth, [ka] That is the case.

[0199] In some embodiments, R 1 teeth, [ka] That is the case.

[0200] In some embodiments, p is 1, and R 1 teeth, [ka] That is the case.

[0201] In some embodiments, R 1 is a C2-C6 alkenyl-aryl substituted with one or more halogens. In some embodiments, R 1 It is a C2-C6 alkenyl-aryl substituted with one or more heteroaryls.

[0202] In some embodiments, R 1 is a C2-C6 alkenyl heteroaryl substituted with one or more halogens. In some embodiments, R 1 It is a C2-C6 alkenyl heteroaryl substituted with one or more heteroaryls.

[0203] In some embodiments, R 1 is a C2-C6 alkynyl-aryl substituted with one or more halogens. In some embodiments, R 1 It is a C2-C6 alkynyl-aryl compound substituted with one or more heteroaryls.

[0204] In some embodiments, R 1 teeth, [ka] That is the case.

[0205] In some embodiments, p is 1, and R 1 teeth, [ka] That is the case.

[0206] In some embodiments, R1 is a C2-C6 alkynyl heteroaryl substituted with one or more halogens. In some embodiments, R 1 It is a C2-C6 alkynyl heteroaryl substituted with one or more heteroaryls.

[0207] In some embodiments, R 1 R is an unsubstituted C1-C6 alkyl group. In some embodiments, R 1 is an unsubstituted C1-C6 alkoxy. In some embodiments, R 1 is unsubstituted C3-C 10 It is cycloalkyl. In some embodiments, R 1 R is an unsubstituted C2-C6 alkenyl. In some embodiments, R 1 is an unsubstituted C2-C6 alkynyl. In some embodiments, R 1 is a non-substituted heteroalgebra. In some embodiments, R 1 is an unsubstituted aryl. In some embodiments, R 1 R is an unsubstituted heteroaryl. In some embodiments, R 1 R is an unsubstituted C1-C6 alkyl-aryl. In some embodiments, R 1 R is an unsubstituted C1-C6 alkyl-heteroaryl. In some embodiments, R 1 R is an unsubstituted C2-C6 alkenyl-aryl. In some embodiments, R 1 R is an unsubstituted C2-C6 alkenyl heteroaryl. In some embodiments, R 1 R is an unsubstituted C2-C6 alkynyl-aryl. In some embodiments, R 1 It is an unsubstituted C2-C6 alkynyl heteroaryl compound.

[0208] In some embodiments, R 1 It is -OH.

[0209] In some embodiments, R 1 It is -NH2.

[0210] In some embodiments, R 1 It is -NHCH3.

[0211] In some embodiments, R 1 This is -N(CH3)2.

[0212] In some embodiments, L is (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q It is selected from C(O).

[0213] In some embodiments, L is (CR 5 2) q That is the case.

[0214] In some embodiments, L is (CR 5 2) q It is O.

[0215] In some embodiments, L is (CR 5 2) q S(O) s That is the case.

[0216] In some embodiments, s is an integer selected from 0, 1, and 2.

[0217] In some embodiments, s is 0.

[0218] In some embodiments, s is 1.

[0219] In some embodiments, s is 2.

[0220] In some embodiments, s is 0 and L is (CR 5 2) q It is S.

[0221] In some embodiments, s is 1 and L is (CR 5 2) q S(O).

[0222] In some embodiments, s is 2 and L is (CR 5 2) q S(O)2.

[0223] In some embodiments, L is (CR 5 2) q C(O).

[0224] In some embodiments, L is (CR 5 2) q and the compound is of Formula I-1:

化

[0225] In some embodiments, L is (CR 5 2) q O, and the compound is of Formula I-2:

化

[0226] In some embodiments, L is (CR 5 2) q S(O) s and the compound is of Formula I-3:

化

[0227] In some embodiments, L is (CR 5 2) q S(O)2, and the compound is of Formula I-3’:

化

[0228] In some embodiments, L is (CR 5 2) q The compound is C(O) and is of formula I-4: [ka] .

[0229] In some embodiments, L is (CR 5 2) q The compound is C(O) and is of formula I-4': [ka] .

[0230] In some embodiments, q is an integer selected from 0, 0, 1, 2, 3, and 4.

[0231] In some embodiments, q is 0.

[0232] In some embodiments, q is 1.

[0233] In some embodiments, q is 2.

[0234] In some embodiments, q is 3.

[0235] In some embodiments, q is 4.

[0236] In some embodiments, q is 0 and L is a combination.

[0237] In some embodiments, q is 0 and L is S(O)².

[0238] In some embodiments, q is 0 and L is C(O).

[0239] Several embodiments, each R 5 H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 It is selected independently of cycloalkyl groups.

[0240] In some embodiments, R 5 H is H.

[0241] In some embodiments, R 5 It is a C1-C6 alkyl group.

[0242] In some embodiments, R 5 It is methyl.

[0243] In some embodiments, q is 1 and L is C(R 5 )2.

[0244] In some embodiments, q is 1 and L is CH2.

[0245] In some embodiments, q is 1 and L is C(R 5 ) 2O.

[0246] In some embodiments, q is 1 and L is CH2O.

[0247] In some embodiments, q is 1 and L is C(R 5 ) It is 2S.

[0248] In some embodiments, q is 1 and L is CH2S.

[0249] In some embodiments, q is 1 and L is C(R 5 ) 2S(O).

[0250] In some embodiments, q is 1 and L is CH2S(O).

[0251] In some embodiments, q is 1 and L is C(R 5 It is 2S(O)2.

[0252] In some embodiments, q is 1 and L is CH2S(O)2.

[0253] In some embodiments, q is 1 and L is C(R 5 )2C(O).

[0254] In some embodiments, q is 1 and L is CH2C(O).

[0255] In some embodiments, q is 1 and L is C(R 5 )2C(R 5 )2.

[0256] In some embodiments, q is 1 and L is CH2CH2.

[0257] In some embodiments, q is 1 and L is C(R 5 )2C(R 5 ) 2O.

[0258] In some embodiments, q is 1 and L is CH2CH2O.

[0259] In some embodiments, q is 1 and L is C(R 5 )2C(R 5 ) It is 2S.

[0260] In some embodiments, q is 1 and L is CH2CH2S.

[0261] In some embodiments, q is 1 and L is C(R 5 )2C(R 5 ) 2S(O).

[0262] In some embodiments, q is 1 and L is CH2CH2S(O).

[0263] In some embodiments, q is 1 and L is C(R 5 )2C(R 5 It is 2S(O)2.

[0264] In some embodiments, q is 1 and L is CH2CH2S(O)2.

[0265] In some embodiments, q is 1 and L is C(R 5 )2C(R 5 )2C(O).

[0266] In some embodiments, q is 1 and L is CH2CH2C(O).

[0267] In some embodiments, q is 1 and L is (C(R 5 )2)3.

[0268] In some embodiments, q is 1 and L is CH2CH2CH2.

[0269] In some embodiments, q is 1 and L is (C(R 5 )2)3O.

[0270] In some embodiments, q is 1 and L is CH2CH2CH2O.

[0271] In some embodiments, q is 1 and L is (C(R 5 )2)3S.

[0272] In some embodiments, q is 1 and L is CH2CH2CH2S.

[0273] In some embodiments, q is 1 and L is (C(R 5 )2)3S(O).

[0274] In some embodiments, q is 1 and L is CH2CH2CH2S(O).

[0275] In some embodiments, q is 1 and L is (C(R 5 )2)3S(O)2.

[0276] In some embodiments, q is 1 and L is CH2CH2CH2S(O)2.

[0277] In some embodiments, q is 1 and L is (C(R 5 )2)3C(O).

[0278] In some embodiments, q is 1 and L is CH2CH2CH2C(O).

[0279] In some embodiments, q is 1 and L is (C(R 5 )2)4.

[0280] In some embodiments, q is 1 and L is CH2CH2CH2CH2.

[0281] In some embodiments, q is 1 and L is (C(R 5 )2)4O.

[0282] In some embodiments, q is 1 and L is CH2CH2CH2CH2O.

[0283] In some embodiments, q is 1 and L is (C(R 5 )2)4S.

[0284] In some embodiments, q is 1 and L is CH2CH2CH2CH2S.

[0285] In some embodiments, q is 1 and L is (C(R 5 )2)4S(O).

[0286] In some embodiments, q is 1 and L is CH2CH2CH2CH2S(O).

[0287] In some embodiments, q is 1 and L is (C(R 5 )2)4S(O)2.

[0288] In some embodiments, q is 1 and L is CH2CH2CH2CH2S(O)2.

[0289] In some embodiments, q is 1 and L is (C(R 5 )2)4C(O).

[0290] In some embodiments, q is 1 and L is CH2CH2CH2CH2C(O).

[0291] In some embodiments, L is CH2.

[0292] In some embodiments, L is CH2CH2.

[0293] In some embodiments, L is C(O).

[0294] In some embodiments, L is CH2CH2O.

[0295] Several embodiments, each R 2 These are halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, and NR. 9 R 10 , C3-C 10 It is independently selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl groups.

[0296] In some embodiments, R 2 It is a halogen.

[0297] In some embodiments, R2 is F.

[0298] In some embodiments, R 2 is Cl.

[0299] In some embodiments, R 2 is Br.

[0300] In some embodiments, R 2 is I.

[0301] In some embodiments, R 2 is OH.

[0302] In some embodiments, R 2 is CN.

[0303] In some embodiments, R 2 is C1-C6 alkyl.

[0304] In some embodiments, R 2 is methyl.

[0305] In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is iso-propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is iso-butyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R2 It is hexyl.

[0306] In some embodiments, R 2 It is a C1-C6 alkoxy.

[0307] In some embodiments, R 2 It is methoxy.

[0308] In some embodiments, R 2 It is ethoxy.

[0309] In some embodiments, R 2 It is a propoxy.

[0310] In some embodiments, R 2 teeth, [ka] That is the case.

[0311] In some embodiments, R 2 teeth, [ka] That is the case.

[0312] In some embodiments, R 2 It is Butokishi.

[0313] In some embodiments, R 2 teeth, [ka] That is the case.

[0314] In some embodiments, R 2 teeth, [ka] That is the case.

[0315] In some embodiments, R 2 teeth, [ka] That is the case.

[0316] In some embodiments, R 2 It is pentoxy.

[0317] In some embodiments, R 2 It is hexoxy.

[0318] In some embodiments, R 2 , NR 9 R 10 That is the case.

[0319] In some embodiments, R 2 It is NH2.

[0320] In some embodiments, R 2 It is NHCH3.

[0321] In some embodiments, R 2 This is N(CH3)2.

[0322] In some embodiments, R 2 C3-C 10 It is a cycloalkyl group.

[0323] In some embodiments, R 2 It is cyclopropyl.

[0324] In some embodiments, R 2 It is cyclobutyl.

[0325] In some embodiments, R 2 It is cyclopentyl.

[0326] In some embodiments, R 2 That is Ariel.

[0327] In some embodiments, R 2 It is phenyl.

[0328] In some embodiments, R 3 These are hydrogen, deuterium, C1-C6 alkyl, and C3-C 10 Cycloalkyl, and L 4 Selected from.

[0329] In some embodiments, R 3 H is H.

[0330] In some embodiments, R 3 It is a C1-C6 alkyl group.

[0331] In some embodiments, R 3 It is methyl.

[0332] In some embodiments, R 3 C3-C 10 It is a cycloalkyl group.

[0333] In some embodiments, R 3 It is cyclopropyl.

[0334] In some embodiments, R 3 L 4 That is the case.

[0335] In some embodiments, L 4 teeth, [ka] That is the case.

[0336] In some embodiments, L 5 (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) sand (CR 5 2) q It is selected from C(O).

[0337] In some embodiments, L 5 (CR 5 2) q That is the case.

[0338] In some embodiments, L 5 (CR 5 2) q It is O.

[0339] In some embodiments, L 5 (CR 5 2) q S(O) s That is the case.

[0340] In some embodiments, s is an integer selected from 0, 1, and 2.

[0341] In some embodiments, s is 0.

[0342] In some embodiments, s is 1.

[0343] In some embodiments, s is 2.

[0344] In some embodiments, s is 0 and L is (CR 5 2) q It is S.

[0345] In some embodiments, s is 1 and L is (CR 5 2) q S(O) is the case.

[0346] In some embodiments, s is 2 and L is (CR 5 2) q It is S(O)2.

[0347] In some embodiments, L 5 (CR5 2) q It is C(O).

[0348] In some embodiments, L 5 (CR 5 2) q The compound is of formula I-11: [ka] .

[0349] In some embodiments, L 5は、 (CR 5 2) q The compound is O, and the compound is of formula I-12: [ka] .

[0350] In some embodiments, L 5 (CR 5 2) q The compound is S(O)2, and the compound is of formula I-13: [ka] .

[0351] In some embodiments, L 5 (CR 5 2) q The compound is S(O)2, and its formula is that of formula I-14: [ka] .

[0352] In some embodiments, q is an integer selected from 0, 1, 2, 3, and 4.

[0353] In some embodiments, q is 0.

[0354] In some embodiments, q is 1.

[0355] In some embodiments, q is 2.

[0356] In some embodiments, q is 3.

[0357] In some embodiments, q is 4.

[0358] In some embodiments, q is 0 and L 5 It is a combination.

[0359] In some embodiments, q is 0 and L 5 This is S(O)2.

[0360] In some embodiments, q is 0 and L 5 It is C(O).

[0361] Several embodiments, each R 5 H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 It is selected independently of cycloalkyl groups.

[0362] In some embodiments, R 5 H is H.

[0363] In some embodiments, R 5 It is a C1-C6 alkyl group.

[0364] In some embodiments, R 5 It is methyl.

[0365] In some embodiments, q is 1 and L 5 C(R 5 )2.

[0366] In some embodiments, q is 1 and L 5 This is CH2.

[0367] In some embodiments, q is 1 and L 5 C(R 5 ) 2O.

[0368] In some embodiments, q is 1 and L 5 It is CH2O.

[0369] In some embodiments, q is 1 and L 5 C(R 5 ) It is 2S.

[0370] In some embodiments, q is 1 and L 5 It is CH2S.

[0371] In some embodiments, q is 1 and L 5 C(R 5 ) 2S(O).

[0372] In some embodiments, q is 1 and L 5 It is CH2S(O).

[0373] In some embodiments, q is 1 and L 5 C(R 5 It is 2S(O)2.

[0374] In some embodiments, q is 1 and L 5 It is CH2S(O)2.

[0375] In some embodiments, q is 1 and L 5 C(R 5 )2C(O).

[0376] In some embodiments, q is 1 and L 5 It is CH2C(O).

[0377] In some embodiments, q is 1 and L 5 C(R 5 )2C(R5 )2.

[0378] In some embodiments, q is 1 and L 5 It is CH2CH2.

[0379] In some embodiments, q is 1 and L 5 C(R 5 )2C(R 5 ) 2O.

[0380] In some embodiments, q is 1 and L 5 It is CH2CH2O.

[0381] In some embodiments, q is 1 and L 5 C(R 5 )2C(R 5 ) It is 2S.

[0382] In some embodiments, q is 1 and L 5 This is CH2CH2S.

[0383] In some embodiments, q is 1 and L 5 C(R 5 )2C(R 5 ) 2S(O).

[0384] In some embodiments, q is 1 and L 5 It is CH2CH2S(O).

[0385] In some embodiments, q is 1 and L 5 C(R 5 )2C(R 5 It is 2S(O)2.

[0386] In some embodiments, q is 1 and L 5 It is CH2CH2S(O)2.

[0387] In some embodiments, q is 1 and L 5C(R 5 )2C(R 5 )2C(O).

[0388] In some embodiments, q is 1 and L 5 It is CH2CH2C(O).

[0389] In some embodiments, q is 1 and L 5 (C(R 5 )2)3.

[0390] In some embodiments, q is 1 and L 5 This is CH2CH2CH2.

[0391] In some embodiments, q is 1 and L 5 (C(R 5 )2)3O.

[0392] In some embodiments, q is 1 and L 5 It is CH2CH2CH2O.

[0393] In some embodiments, q is 1 and L 5 (C(R 5 )2)3S.

[0394] In some embodiments, q is 1 and L 5 This is CH2CH2CH2S.

[0395] In some embodiments, q is 1 and L 5 (C(R 5 )2)3S(O).

[0396] In some embodiments, q is 1 and L 5 This is CH2CH2CH2S(O).

[0397] In some embodiments, q is 1 and L 5 (C(R 5)2)3S(O)2.

[0398] In some embodiments, q is 1 and L 5 This is CH2CH2CH2S(O)2.

[0399] In some embodiments, q is 1 and L 5 (C(R 5 )2)3C(O).

[0400] In some embodiments, q is 1 and L 5 It is CH2CH2CH2C(O).

[0401] In some embodiments, q is 1 and L 5 (C(R 5 )2)4.

[0402] In some embodiments, q is 1 and L 5 This is CH2CH2CH2CH2.

[0403] In some embodiments, q is 1 and L 5 (C(R 5 )2)4O.

[0404] In some embodiments, q is 1 and L 5 It is CH2CH2CH2CH2O.

[0405] In some embodiments, q is 1 and L 5 (C(R 5 )2)4S.

[0406] In some embodiments, q is 1 and L 5 This is CH2CH2CH2CH2S.

[0407] In some embodiments, q is 1 and L 5 (C(R 5 )2)4S(O).

[0408] In some embodiments, q is 1 and L 5 This is CH2CH2CH2CH2S(O).

[0409] In some embodiments, q is 1 and L 5 (C(R 5 )2)4S(O)2.

[0410] In some embodiments, q is 1 and L 5 This is CH2CH2CH2CH2S(O)2.

[0411] In some embodiments, q is 1 and L 5 (C(R 5 )2)4C(O).

[0412] In some embodiments, q is 1 and L 5 This is CH2CH2CH2CH2C(O).

[0413] In some embodiments, L 5 It is -CH2-.

[0414] In some embodiments, L 5 teeth, [ka] That is the case.

[0415] In some embodiments, L 5 teeth, [ka] That is the case.

[0416] In some embodiments, L 5 teeth, [ka] The compound is of formula I-21: [ka] .

[0417] In some embodiments, L 5 teeth, [ka] That is the case.

[0418] In some embodiments, L 5 teeth, [ka] The compound is of formula I-22: [ka] .

[0419] In some embodiments, L 5 teeth, [ka] That is the case.

[0420] In some embodiments, L 5 teeth, [ka] That is the case.

[0421] In some embodiments, L 5 teeth, [ka] The compound is of formula I-23: [ka] .

[0422] In some embodiments, L 5 teeth, [ka] That is the case.

[0423] In some embodiments, L 5 teeth, [ka] The compound is of formula I-24: [ka] .

[0424] In some embodiments, L 5 teeth, [ka] That is the case.

[0425] In some embodiments, ring B is an aryl, heteroaryl, 3-~8-membered heterocycle, or C3-C 14 Cycloalkyl, aryl, heteroaryl, heterocyclic or cycloalkyl, halogen, CN, NO2, oxo, OH, NR 9 R 10、 It is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0426] In some embodiments, ring B is an aryl, and the aryl is a halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0427] In some embodiments, ring B is phenyl, and phenyl is a halogen, CN, NO2, oxo, OH, NR 9 R10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0428] In some embodiments, ring B is benzenediyl, and benzenediyl is halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0429] In some embodiments, ring B is benzenediyl-1,4, and benzenediyl-1,4 is halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0430] In some embodiments, ring B is benzenediyl-1,3, and benzenediyl-1,3 is halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0431] In some embodiments, ring B is benzenediyl-1,2, and benzenediyl-1,2 is halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0432] In some embodiments, ring B is phenyl.

[0433] In some embodiments, ring B is benzenediyl.

[0434] In some embodiments, ring B is benzenediyl-1,4.

[0435] In some embodiments, ring B is benzenediyl-1,3.

[0436] In some embodiments, ring B is benzenediyl-1,2.

[0437] In some embodiments, ring B is a heteroaryl, and the heteroaryl is a halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0438] In some embodiments, ring B is a heteroaryl ring.

[0439] In some embodiments, ring B is a monocyclic 5-membered heteroaryl.

[0440] In some embodiments, ring B is a monocyclic 5-membered heteroaryl containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0441] In some embodiments, ring B is a monocyclic 5-membered heteroaryl containing two N ring heteroatoms, with the remaining ring atom being C.

[0442] In some embodiments, ring B is a monocyclic 5-membered heteroaryl containing one N and one O as ring heteroatoms, with the remaining ring atom being C.

[0443] In some embodiments, ring B is a monocyclic 5-membered heteroaryl containing one oxygen atom as a ring heteroatom, with the remaining ring atoms being carbon.

[0444] In some embodiments, ring B is a monocyclic 5-membered heteroaryl containing one sulfurous (S) ring heteroatom, with the remaining ring atoms being carbon (C).

[0445] In some embodiments, ring B is a monocyclic 6-membered heteroaryl.

[0446] In some embodiments, ring B is a monocyclic 6-membered heteroaryl containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0447] In some embodiments, ring B is a monocyclic 6-membered heteroaryl containing two N as ring heteroatoms, and the remaining ring atom is C.

[0448] In some embodiments, ring B is a monocyclic 6-membered heteroaryl containing three N as ring heteroatoms, with the remaining ring atom being C.

[0449] In some embodiments, ring B is a bicyclic 9-membered heteroaryl.

[0450] In some embodiments, ring B is a bicyclic 9-membered heteroaryl containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0451] In some embodiments, ring B is a bicyclic 9-membered heteroaryl containing two N ring heteroatoms, with the remaining ring atom being C.

[0452] In some embodiments, ring B is a bicyclic 9-membered heteroaryl containing three N ring heteroatoms, with the remaining ring atom being C.

[0453] In some embodiments, ring B is a bicyclic 9-membered heteroaryl containing one oxygen atom as a ring heteroatom, with the remaining ring atoms being carbon.

[0454] In some embodiments, ring B is a bicyclic 9-membered heteroaryl containing one sulfurous (S) ring heteroatom, with the remaining ring atoms being carbon (C).

[0455] In some embodiments, ring B is a bicyclic 10-membered heteroaryl.

[0456] In some embodiments, ring B is a bicyclic 10-membered heteroaryl containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0457] In some embodiments, ring B is a bicyclic 10-membered heteroaryl containing two N atoms as ring heteroatoms, with the remaining ring atom being C.

[0458] In some embodiments, ring B is a bicyclic 10-membered heteroaryl containing three N ring heteroatoms, with the remaining ring atom being C.

[0459] In some embodiments, ring B is a 3- to 8-membered heterocycle, and the heterocycle consists of halogen, CN, NO2, oxo, OH, and NR. 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0460] In some embodiments, ring B is a 3- to 8-membered heterocyclic ring.

[0461] In some embodiments, ring B is a 3-membered heterocyclic ring.

[0462] In some embodiments, ring B is a 3-membered heteroring containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0463] In some embodiments, ring B is a 4-membered heterocyclic ring.

[0464] In some embodiments, ring B is a 4-membered heteroring containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0465] In some embodiments, ring B is a 5-membered heterocyclic ring.

[0466] In some embodiments, ring B is a 5-membered heteroring containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0467] In some embodiments, ring B is [ka] That is the case.

[0468] In some embodiments, ring B is [ka] That is the case.

[0469] In some embodiments, ring B is a 5-membered heteroring containing two N ring heteroatoms, with the remaining ring atoms being C.

[0470] In some embodiments, ring B is [ka] That is the case.

[0471] In some embodiments, ring B is a 5-membered heteroring containing one O as a ring heteroatom, and the remaining ring atoms are C.

[0472] In some embodiments, ring B is a 5-membered heteroring containing one sulfurous sulfurous ring heteroatom, with the remaining ring atoms being carbon.

[0473] In some embodiments, ring B is a 6-membered heterocyclic ring.

[0474] In some embodiments, ring B is a 6-membered heteroring containing one N as a ring heteroatom, and the remaining ring atoms are C.

[0475] In some embodiments, ring B is [ka] That is the case.

[0476] In some embodiments, ring B is a 6-membered heteroring containing one N as a ring heteroatom, and the remaining ring atoms are aryl-substituted C.

[0477] In some embodiments, ring B is [ka] That is the case.

[0478] In some embodiments, ring B is [ka] That is the case.

[0479] In some embodiments, ring B is a 6-membered heteroring containing two N as ring heteroatoms, and the remaining ring atoms are C.

[0480] In some embodiments, ring B is [ka] That is the case.

[0481] In some embodiments, ring B is [ka] That is the case.

[0482] In some embodiments, ring B is [ka] That is the case.

[0483] In some embodiments, ring B is [ka] That is the case.

[0484] In some embodiments, ring B is a 6-membered heteroring containing one N and one O as ring heteroatoms, with the remaining ring atoms being C.

[0485] In some embodiments, ring B is [ka] That is the case.

[0486] In some embodiments, ring B is [ka] That is the case.

[0487] In some embodiments, ring B is [ka] That is the case.

[0488] In some embodiments, ring B is [ka] That is the case.

[0489] In some embodiments, ring B is [ka] That is the case.

[0490] In some embodiments, ring B is a 6-membered heteroring containing one N, one S, and one O as ring heteroatoms, with the remaining ring atoms being C.

[0491] In some embodiments, ring B is [ka] That is the case.

[0492] In some embodiments, ring B is a 7-membered heterocyclic ring.

[0493] In some embodiments, ring B is a monocyclic 7-membered heterocyclic ring.

[0494] In some embodiments, ring B is a monocyclic 7-membered heteroring containing one N as a ring heteroatom, with the remaining ring atoms being C.

[0495] In some embodiments, ring B is [ka] That is the case.

[0496] In some embodiments, ring B is a monocyclic 7-membered heteroring containing two N ring heteroatoms, with the remaining ring atom being C.

[0497] In some embodiments, ring B is [ka] That is the case.

[0498] In some embodiments, ring B is a monocyclic 7-membered heteroring containing one N and one O as ring heteroatoms, with the remaining ring atoms being C.

[0499] In some embodiments, ring B is [ka] That is the case.

[0500] In some embodiments, ring B is [ka] That is the case.

[0501] In some embodiments, ring B is a biring 7-membered complex ring.

[0502] In some embodiments, ring B is a bicyclic 7-membered heteroring containing two N ring heteroatoms, with the remaining ring atom being C.

[0503] In some embodiments, ring B is [ka] That is the case.

[0504] In some embodiments, ring B is C3-C 14 It is a cycloalkyl, and cycloalkyl is a halogen, CN, NO2, oxo, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups.

[0505] In some embodiments, ring B is a monocyclic cycloalkyl group.

[0506] In some embodiments, ring B is a condensed bicyclic cycloalkyl group.

[0507] In some embodiments, ring B is a crosslinked bicyclic cycloalkyl group.

[0508] In some embodiments, ring B is a spironicyclic cycloalkyl group.

[0509] In some embodiments, ring B is a 3-membered cycloalkyl group.

[0510] In some embodiments, ring B is a 4-membered cycloalkyl group.

[0511] In some embodiments, ring B is a 5-membered cycloalkyl group.

[0512] In some embodiments, ring B is a monocyclic 5-membered cycloalkyl group.

[0513] In some embodiments, ring B is a crosslinked bicyclic 5-membered cycloalkyl group.

[0514] In some embodiments, ring B is [ka] That is the case.

[0515] In some embodiments, ring B is [ka] That is the case.

[0516] In some embodiments, ring B is a 6-membered cycloalkyl group.

[0517] In some embodiments, ring B is a monocyclic 6-membered cycloalkyl group.

[0518] In some embodiments, ring B is [ka] That is the case.

[0519] In some embodiments, ring B is a 7-membered cycloalkyl group.

[0520] In some embodiments, ring B is a monocyclic 7-membered cycloalkyl group.

[0521] In some embodiments, ring B is [ka] That is the case.

[0522] In some embodiments, R 6 H, C1-C6 alkyl, -C(O)R 7 ,-NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)2NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 Selected from cycloalkyl, C1-C6 alkanediyl heterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediyl heteroaryl, where alkyl, cycloalkyl, aryl, or heteroaryl are halogens, CN, NO2, oxo, OH, NR 9 R 10 , C 1 It is optionally substituted with one or more substituents independently selected from C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0523] In some embodiments, R 6 H is H.

[0524] In some embodiments, R 6 These are C1-C6 alkyl groups, where alkyl is a halogen, OH, CN, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0525] In some embodiments, R 6 It is a C1-C6 alkyl group.

[0526] In some embodiments, R 6 It is CH3.

[0527] In some embodiments, R 6 These are halogen, CN, NO2, oxo, OH, NR 9 R 1 These are C1-C6 alkanediylaryl compounds optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0528] In some embodiments, R 6 This is a C1-C6 alkanediylaryl compound that is optionally substituted with one C1-C6 alkoxy.

[0529] In some embodiments, R 6 teeth, [ka] That is the case.

[0530] In some embodiments, R 6 It is C2H5.

[0531] In some embodiments, R 6 It is propyl.

[0532] In some embodiments, R 6 It is n-propyl.

[0533] In some embodiments, R 6 It is i-propyl.

[0534] In some embodiments, R 6 It is butyl.

[0535] In some embodiments, R 6 It is n-butyl.

[0536] In some embodiments, R 6 It is i-butyl.

[0537] In some embodiments, R 6 teeth, [ka] That is the case.

[0538] In some embodiments, R 6 It is tert-butyl.

[0539] In some embodiments, R 6 It is pentyl.

[0540] In some embodiments, R 6 It is hexyl.

[0541] In some embodiments, R 6 is -C(O)R 7 That is the case.

[0542] In some embodiments, R 7 R 8 , OR 8 , NR 9 R 10 Selected from.

[0543] In some embodiments, R 7 R 8 That is the case.

[0544] In some embodiments, R 7 is OR 8 That is the case.

[0545] In some embodiments, R 7 , NR 9 R 10 That is the case.

[0546] In some embodiments, R 8 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected from cycloalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0547] In some embodiments, R 8 H is H.

[0548] In some embodiments, R 8 These are C1-C6 alkyl groups, where alkyl is a halogen, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0549] In some embodiments, R 8 It is a C4-C6 alkyl group.

[0550] In some embodiments, R 8 is -CH3. In some embodiments, R 8 is -C2H5. In some embodiments, R 8 is -CH2CH2CH3. In some embodiments, R 8 is -CH(CH3)2. In some embodiments, R 8 is -CH2CH2CH2CH3. In some embodiments, R 8 is -CH2CH(CH3)2. In some embodiments, R 8 is pentill. In some embodiments, R 8 It is hexyl.

[0551] In some embodiments, R 8These are C2-C6 alkenyls, and alkenyls are halogens, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0552] In some embodiments, R 8 It is a C2-C6 alkenyl.

[0553] In some embodiments, R 8 -CH=CH2.

[0554] In some embodiments, R 8 The equation is -CH=CH-CH3.

[0555] In some embodiments, R 8 -CH=CH-CH2-NR 9 R 10 That is the case.

[0556] In some embodiments, R 8 teeth, [ka] That is the case.

[0557] In some embodiments, R 8 teeth, [ka] That is the case.

[0558] In some embodiments, R 8 It is a C2-C6 alkynyl, and alkynyl is a halogen, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0559] In some embodiments, R 8 C3-C 10It is a cycloalkyl, and cycloalkyls are halogens, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0560] In some embodiments, R 6 is -NHC(O)R 7 That is the case.

[0561] In some embodiments, R 7 R 8 , OR 8 , NR 9 R 10 Selected from.

[0562] In some embodiments, R 7 , NR 9 R 10 That is the case.

[0563] In some embodiments, R 7 It is NH2.

[0564] In some embodiments, R 7 It is NHCH3.

[0565] In some embodiments, R 7 R 8 That is the case.

[0566] In some embodiments, R 8 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected from cycloalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0567] In some embodiments, R 8 H is H.

[0568] In some embodiments, R 8 These are C1-C6 alkyl groups, where alkyl is a halogen, OH, CN, NO2, NR 9 R 10 It is optionally substituted with one or more substituents selected independently of it.

[0569] In some embodiments, R 8 It is a C1-C6 alkyl group.

[0570] In some embodiments, R 8 Methyl.

[0571] In some embodiments, R 6 is S(O) s R 11 That is the case.

[0572] In some embodiments, s is an integer selected from 0, 1, and 2.

[0573] In some embodiments, s is 0.

[0574] In some embodiments, s is 1.

[0575] In some embodiments, s is 2.

[0576] In some embodiments, R 6 -SR 11 That is the case.

[0577] In some embodiments, R 6 is -S(O)R 11 That is the case.

[0578] In some embodiments, R 6 is -S(O)2R 11 That is the case.

[0579] In some embodiments, R 11 C1-C6 alkyl, C3-C 10Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from.

[0580] In some embodiments, R 11 It is a C1-C6 alkyl group.

[0581] In some embodiments, R 11 It is methyl.

[0582] In some embodiments, R 11 It is ethyl.

[0583] In some embodiments, R 11 It is propyl.

[0584] In some embodiments, R 11 It is n-propyl.

[0585] In some embodiments, R 11 It is i-propyl.

[0586] In some embodiments, R 11 It is butyl.

[0587] In some embodiments, R 11 It is n-butyl.

[0588] In some embodiments, R 11 It is i-butyl.

[0589] In some embodiments, R 11 It is tert-butyl.

[0590] In some embodiments, R 11 is pentill. In some embodiments, R 11 It is hexyl.

[0591] In some embodiments, R 11 C3-C10 It is a cycloalkyl group.

[0592] In some embodiments, R 11 This is a single-ring C3-C 10 Cycloalkyl.

[0593] In some embodiments, R 11 It is cyclopropyl.

[0594] In some embodiments, R 11 It is cyclobutyl.

[0595] In some embodiments, R 11 It is cyclopentyl.

[0596] In some embodiments, R 11 It is cyclohexyl.

[0597] In some embodiments, R 11 It is cycloheptyl.

[0598] In some embodiments, R 11 This is a double-ring type C5-C 10 It is a cycloalkyl group.

[0599] In some embodiments, R 11 This is a bicyclic condensation C5-C 10 It is a cycloalkyl group.

[0600] In some embodiments, R 11 This is a double-ring bridge C5-C 10 It is a cycloalkyl group.

[0601] In some embodiments, R 11 This is a biring spiro C5-C 10 It is a cycloalkyl group.

[0602] In some embodiments, R 11 It is a C1-C6 alkoxy.

[0603] In some embodiments, R 11 , NR 9 R 10 That is the case.

[0604] In some embodiments, R 6 It is -S(O)2-C1-C6-alkyl.

[0605] In some embodiments, R 6 This is -S(O)2CH3.

[0606] In some embodiments, R 6 This is -S(O)2CH2CH3.

[0607] In some embodiments, R 6 It is -S(O)2(CH2)2CH3.

[0608] In some embodiments, R 6 It is -S(O)2(CH2)3CH3.

[0609] In some embodiments, R 6 This is -S(O)2CH(CH3)2.

[0610] In some embodiments, R 6 teeth, [ka] That is the case.

[0611] In some embodiments, R 6 is -NHS(O)2R 11 That is the case.

[0612] In some embodiments, R 6 It is -NHS(O)2CH3.

[0613] In some embodiments, R 6 It is -NHS(O)2CH2CH3.

[0614] In some embodiments, R 6 is -NHS(O)2NR 9 R 10 That is the case.

[0615] In some embodiments, R 6 It is -NHS(O)2NH2.

[0616] In some embodiments, R 6 teeth, [ka] That is the case.

[0617] In some embodiments, R 6 teeth, [ka] That is the case.

[0618] In some embodiments, L 4 The selection is made from Table 1. JPEG2026143650000091.jpg200150JPEG2026143650000092.jpg223150JPEG2026143650000093.jpg66150

[0619] In some embodiments, R 4 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 Selected from aryl, heteroaryl, or heterocyclic, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic are halogens, OH, NR 9 R 10 The molecule is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 alkoxy groups.

[0620] In some embodiments, R 4 H is H.

[0621] In some embodiments, R 4 It is a C1-C6 alkyl group.

[0622] In some embodiments, R 4 It is methyl.

[0623] In some embodiments, W is -CN.

[0624] In some embodiments, W and ring B, together with the atoms to which they are bonded and any intervening atoms, form a 5-10 membered heterocycle.

[0625] In some embodiments, the compound is of formula I-31: [ka]

[0626] In some embodiments, the compound is of formula I-32: [ka]

[0627] In some embodiments, the compound is of formula I-33: [ka] , R B These are halogen, CN, NO2, oxo, OH, NR 9 R 10 , is selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic; b is an integer selected from 0, 1, 2, 3, and 4; and all other variables are as defined herein.

[0628] In some embodiments, m and n are integers independently selected from 1, 2, and 3, respectively.

[0629] In some embodiments, each m is 1.

[0630] In some embodiments, each m is 2.

[0631] In some embodiments, each m is 3.

[0632] In some embodiments, each n is 1.

[0633] In some embodiments, each n is 2.

[0634] In some embodiments, each n is 3.

[0635] In some embodiments, the values ​​of m and n are selected from Table 2. JPEG2026143650000097.jpg84150

[0636] In some embodiments, p is an integer selected from 0, 1, and 2.

[0637] In some embodiments, p is 0.

[0638] In some embodiments, p is 1.

[0639] In some embodiments, p is 2.

[0640] In some embodiments, r is an integer selected from 0, 1, 2, and 3.

[0641] In some embodiments, r is 0.

[0642] In some embodiments, r is 1.

[0643] In some embodiments, r is 2.

[0644] In some embodiments, r is 3.

[0645] In some embodiments, the compound is of formula (IA): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0646] In some embodiments, the compound is of formula (I-A'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0647] In some embodiments, the compound is of formula (IB): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0648] In some embodiments, the compound is of formula (I-B'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0649] In some embodiments, the compound is of formula (IC): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0650] In some embodiments, the compound is of formula (I-C'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0651] In some embodiments, the compound is of formula (ID): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0652] In some embodiments, the compound is of formula (I-D'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0653] In some embodiments, the compound is of formula (II): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0654] In some embodiments, the compound is of formula (I-I'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0655] In some embodiments, the compound is of formula (I-II): JPEG2026143650000108.jpg65170, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0656] In some embodiments, the compound is of formula (I-II'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0657] In some embodiments, the compound is of formula (I-III): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0658] In some embodiments, the compound is of formula (I-III'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0659] In some embodiments, the compound is of formula (I-IV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0660] In some embodiments, the compound is of formula (I-IV'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0661] In some embodiments, the compound is of formula (IV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0662] In some embodiments, the compound is of formula (I-V'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0663] In some embodiments, the compound is of formula (I-VI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0664] In some embodiments, the compound is of formula (I-VI'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0665] In some embodiments, the compound is of formula (I-VII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0666] In some embodiments, the compound is of formula (I-VII'): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0667] In some embodiments, the compound is of formula (Ia): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0668] In some embodiments, the compound is of formula (Ib): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0669] In some embodiments, the compound is of formula (Ic): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0670] In some embodiments, the compound is of formula (Id): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0671] In some embodiments, the compound is of formula (Ie): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0672] In some embodiments, the compound is of formula (If): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0673] In some embodiments, the compound is of formula (Ig): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0674] In some embodiments, the compound is of formula (Ih): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0675] In some embodiments, the compound is of formula (Ii): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (all variables as defined herein).

[0676] In some embodiments, the compound is selected from Table 3, or from its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers (all variables are as defined herein). JPEG2026143650000129.jpg184150JPEG2026143650000130.jpg218150JPEG2026143650000131.jpg217150JPEG2026143650000132.jpg211150JPEG2026143650000133.jpg218150JPEG2026143650000134.jpg218150JPEG2026143650000135.jpg218150JPEG2026143650000136.jpg218150JPEG2026143650000137.jpg218150JPEG2026143650000138.jpg218150JPEG2026143650000139.jpg218150JPEG2026143650000140.jpg218150JPEG2026143650000141.jpg200150JPEG2026143650000142.jpg221150JPEG2026143650000143.jpg212150JPEG2026143650000144.jpg221150JPEG2026143650000145.jpg221150JPEG2026143650000146.jpg212150JPEG2026143650000147.jpg221150JPEG2026143650000148.jpg221150JPEG2026143650000149.jpg212150JPEG2026143650000150.jpg221150JPEG2026143650000151.jpg221150JPEG2026143650000152.jpg187150JPEG2026143650000153.jpg198150JPEG2026143650000154.jpg198150JPEG2026143650000155.jpg198150JPEG2026143650000156.jpg198150JPEG2026143650000157.jpg198150JPEG2026143650000158.jpg198150JPEG2026143650000159.jpg198150JPEG2026143650000160.jpg198150JPEG2026143650000161.jpg198150JPEG2026143650000162.jpg198150JPEG2026143650000163.jpg198150JPEG2026143650 000164.jpg198150JPEG2026143650000165.jpg198150JPEG2026143650000166.jpg198150JPEG2026 143650000167.jpg198150JPEG2026143650000168.jpg216150JPEG2026143650000169.jpg216150JP EG2026143650000170.jpg216150JPEG2026143650000171.jpg216150JPEG2026143650000172.jpg21 6150JPEG2026143650000173.jpg216150JPEG2026143650000174.jpg216150JPEG202614365000017 5.jpg216150JPEG2026143650000176.jpg216150JPEG2026143650000177.jpg216150JPEG202614365 0000178.jpg216150JPEG2026143650000179.jpg216150JPEG2026143650000180.jpg216150JPEG202 6143650000181.jpg216150JPEG2026143650000182.jpg216150JPEG2026143650000183.jpg164150.

[0677] In some embodiments, the compound is selected from Table 4, or from its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers (all variables are as defined herein). JPEG2026143650000184.jpg186150JPEG2026143650000185.jpg220150JPEG2026143650000186.jpg183150JPEG2026143650000187.jpg183150JPEG2026143650000188.jpg220150JPEG2026143650000189.jpg220150JPEG2026143650000190.jpg220150JPEG2026143650000191.jpg220150JPEG2026143650000192.jpg220150JPEG2026143650000193.jpg220150JPEG2026143650000194.jpg220150JPEG2026143650000195.jpg220150JPEG2026143650000196.jpg220150JPEG2026143650000197.jpg218150JPEG2026143650000198.jpg221150JPEG2026143650000199.jpg221150JPEG2026143650000200.jpg212150JPEG2026143650000201.jpg221150JPEG2026143650000202.jpg221150JPEG2026143650000203.jpg212150JPEG2026143650000204.jpg221150JPEG2026143650000205.jpg222150JPEG2026143650000206.jpg210150JPEG2026143650000207.jpg200150JPEG2026143650000208.jpg189150JPEG2026143650000209.jpg198150JPEG2026143650000210.jpg198150JPEG2026143650000211.jpg193150JPEG2026143650000212.jpg193150JPEG2026143650000213.jpg198150JPEG2026143650000214.jpg198150JPEG2026143650000215.jpg198150JPEG2026143650000216.jpg198150JPEG2026143650000217.jpg198150JPEG2026143650000218.jpg198150JPEG20261436500002 19.jpg198150JPEG2026143650000220.jpg198150JPEG2026143650000221.jpg198150JPEG20261436500 00222.jpg198150JPEG2026143650000223.jpg207150JPEG2026143650000224.jpg216150JPEG20261436 50000225.jpg216150JPEG2026143650000226.jpg219150JPEG2026143650000227.jpg216150JPEG202614 3650000228.jpg216150JPEG2026143650000229.jpg216150JPEG2026143650000230.jpg216150JPEG202 6143650000231.jpg216150JPEG2026143650000232.jpg216150JPEG2026143650000233.jpg216150JPEG2 026143650000234.jpg216150JPEG2026143650000235.jpg216150JPEG2026143650000236.jpg216150JP EG2026143650000237.jpg216150JPEG2026143650000238.jpg216150JPEG2026143650000239.jpg62150.

[0678] In some embodiments, the compound is of formula (IAIdI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0679] In some embodiments, the compound is of formula (IAIdI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0680] In some embodiments, the compound is of the formula (IAIdI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0681] In some embodiments, the compound is of the formula (IAIdI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0682] In some embodiments, the compound is of the formula (IAIdI-1-AH-1): [ka] (IAIdI-1-AH-1) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0683] In some embodiments, the compound is of formula (IBIdI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0684] In some embodiments, the compound is of formula (IBIdI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0685] In some embodiments, the compound is of the formula (IBIdI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0686] In some embodiments, the compound is of the formula (IBIdI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0687] In some embodiments, the compound is of the formula (IBIdI-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0688] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0689] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0690] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BG): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0691] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0692] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0693] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0694] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0695] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-II): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0696] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-II-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0697] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-III): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0698] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-III-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0699] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0700] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IV-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0701] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0702] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BVa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0703] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BVa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0704] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BVa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0705] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0706] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VI-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0707] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VI-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0708] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VI-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0709] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0710] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0711] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VIII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0712] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VIII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0713] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VIII-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0714] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-VIII-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0715] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0716] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IX-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0717] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IX-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0718] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IX-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0719] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B (The C1-C6 alkyl group is C1-C6 alkyl, and all other variables are as defined herein.)

[0720] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BXa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0721] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BXa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0722] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BXa**): [ka] (IBIdI-1-AH-1-BXa**) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0723] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BXa***): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0724] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-BXa****): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0725] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0726] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XI-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0727] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XI-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0728] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XI-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0729] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0730] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0731] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-IX-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0732] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XII-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0733] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XIII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0734] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XIII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0735] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XIV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0736] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XIV-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0737] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0738] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XV-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0739] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0740] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVI-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0741] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVI-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0742] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVI-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0743] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0744] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0745] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVII-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0746] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVII-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0747] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-GG): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R GG (The elements are selected from H, C1-C6 alkyl, aryl, and heteroaryl, and all other variables are as defined herein.)

[0748] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVIII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0749] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVIII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0750] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVIII-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0751] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVIII-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0752] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVIII-a***): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0753] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XVIII-a****): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0754] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XIX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0755] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XIX-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0756] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0757] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XX-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0758] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0759] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXI-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0760] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0761] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0762] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXIII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0763] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXIII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0764] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXIV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0765] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXIV-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0766] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXV): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0767] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXV-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0768] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-GT): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R T H, C1-C6 alkyl, C3-C 10 (Independently selected from cycloalkyl, aryl, and heteroaryl groups).

[0769] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXVI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0770] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXVI-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0771] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXVII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0772] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXVII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0773] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-GGG): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (G is selected from CH2, O, S, NH, and all other variables are as defined herein).

[0774] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXVIII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0775] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXVIII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0776] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXIX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0777] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXIX-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0778] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXX): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0779] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXX-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0780] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXXI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0781] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXXI-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0782] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXXII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0783] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXXII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0784] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXXIII): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0785] In some embodiments, the compound is of the formula (IBIdI-1-AH-1-B-XXXIII-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0786] In some embodiments, the compound is of the formula (IBIdI-1-AH-2): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0787] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0788] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0789] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-BG): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0790] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0791] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0792] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0793] In some embodiments, the compound is of the formula (IBIdI-1-AH-2-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0794] In some embodiments, the compound is of the formula (IBIdI-1-AH-3): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0795] In some embodiments, the compound is of the formula (IBIdI-1-AH-3-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0796] In some embodiments, the compound is of the formula (IBIdI-1-AH-3-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0797] In some embodiments, the compound is of the formula (IBIdI-1-AH-3-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0798] In some embodiments, the compound is of the formula (IBIdI-1-AH-3-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0799] In some embodiments, the compound is of the formula (IBIdI-1-AH-3-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0800] In some embodiments, the compound is of the formula (IBIdI-1-AH-3-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0801] In some embodiments, the compound is of the formula (IBIdI-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0802] In some embodiments, the compound is of the formula (IBIdI-1-BH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0803] In some embodiments, the compound is of the formula (IBIdI-1-BH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0804] In some embodiments, the compound is of the formula (IBIdI-1-BH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0805] In some embodiments, the compound is of the formula (IBIdI-1-BH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0806] In some embodiments, the compound is of the formula (IBIdI-1-BH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0807] In some embodiments, the compound is of the formula (IBIdI-1-C): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0808] In some embodiments, the compound is of the formula (IBIdI-1-CH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0809] In some embodiments, the compound is of the formula (IBIdI-1-CH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0810] In some embodiments, the compound is of the formula (IBIdI-1-CH-1-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0811] In some embodiments, the compound is of the formula (IBIdI-1-CH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0812] In some embodiments, the compound is of the formula (IBIdI-1-CH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0813] In some embodiments, the compound is of the formula (IBIdI-1-CH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0814] In some embodiments, the compound is of the formula (IBIdI-1-CH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0815] In some embodiments, the compound is of the formula (IBIdI-1-CH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0816] In some embodiments, the compound is of the formula (IBIdI-1-D): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0817] In some embodiments, the compound is of the formula (IBIdI-1-DH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0818] In some embodiments, the compound is of the formula (IBIdI-1-DH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0819] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0820] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0821] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-BG): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0822] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0823] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0824] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0825] In some embodiments, the compound is of the formula (IBIdI-1-DH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0826] In some embodiments, the compound is of the formula (IBIdI-1-E): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0827] In some embodiments, the compound is of the formula (IBIdI-1-EH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0828] In some embodiments, the compound is of the formula (IBIdI-1-EH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0829] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0830] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0831] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-BG): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0832] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0833] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0834] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0835] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0836] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-B-II): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0837] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-B-II-a): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0838] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-B-II-a*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0839] In some embodiments, the compound is of the formula (IBIdI-1-EH-1-B-II-a**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0840] In some embodiments, the compound is of formula (IBIdI-2): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0841] In some embodiments, the compound is of the formula (IBIdI-2-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0842] In some embodiments, the compound is of the formula (IBIdI-2-AH): [ka] (IBIdI-2-AH) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0843] In some embodiments, the compound is of the formula (IBIdI-2-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0844] In some embodiments, the compound is of the formula (IBIdI-2-AH-1-h): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0845] In some embodiments, the compound is of the formula (IBIdI-2-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0846] In some embodiments, the compound is of the formula (IBIdI-2-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0847] In some embodiments, the compound is of the formula (IBIdI-2-AH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0848] In some embodiments, the compound is of the formula (IBIdI-2-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0849] In some embodiments, the compound is of the formula (IBIdI-2-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0850] In some embodiments, the compound is of the formula (IB-II-dI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0851] In some embodiments, the compound is of the formula (IB-II-dI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0852] In some embodiments, the compound is of the formula (IB-II-dI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0853] In some embodiments, the compound is of the formula (IB-II-dI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0854] In some embodiments, the compound is of the formula (IB-II-dI-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0855] In some embodiments, the compound is of the formula (IB-II-dI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0856] In some embodiments, the compound is of the formula (IB-II-dI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0857] In some embodiments, the compound is of the formula (IB-II-dI-1-AH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0858] In some embodiments, the compound is of the formula (IB-II-dI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0859] In some embodiments, the compound is of the formula (IB-II-dI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0860] In some embodiments, the compound is of the formula (IB-III-dI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0861] In some embodiments, the compound is of the formula (IB-III-dI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0862] In some embodiments, the compound is of the formula (IB-III-dI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0863] In some embodiments, the compound is of the formula (IB-III-dI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0864] In some embodiments, the compound is of the formula (IB-III-dI-1-AH-1): [ka] (IB-III-dI-1-AH-1) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0865] In some embodiments, the compound is of the formula (IB-III-dI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0866] In some embodiments, the compound is of the formula (IB-III-dI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0867] In some embodiments, the compound is of the formula (IB-III-dI-1-AH-1-BIa): [ka] (IB-III-dI-1-AH-1-BIa) , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0868] In some embodiments, the compound is of the formula (IB-III-dI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0869] In some embodiments, the compound is of the formula (IB-III-dI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0870] In some embodiments, the compound is of the formula (IB-IV-dI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0871] In some embodiments, the compound is of the formula (IB-IV-dI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0872] In some embodiments, the compound is of the formula (IB-IV-dI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0873] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0874] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0875] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0876] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0877] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0878] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0879] In some embodiments, the compound is of the formula (IB-IV-dI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0880] In some embodiments, the compound is of formula (IBVdI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0881] In some embodiments, the compound is of formula (IBVdI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0882] In some embodiments, the compound is of the formula (IBVdI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0883] In some embodiments, the compound is of the formula (IBVdI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0884] In some embodiments, the compound is of the formula (IBVdI-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0885] In some embodiments, the compound is of the formula (IBVdI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0886] In some embodiments, the compound is of the formula (IBVdI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0887] In some embodiments, the compound is of the formula (IBVdI-1-AH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0888] In some embodiments, the compound is of the formula (IBVdI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0889] In some embodiments, the compound is of the formula (IBVdI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0890] In some embodiments, the compound is of the formula (IB-VI-dI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0891] In some embodiments, the compound is of the formula (IB-VI-dI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0892] In some embodiments, the compound is of the formula (IB-VI-dI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0893] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0894] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0895] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0896] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0897] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0898] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0899] In some embodiments, the compound is of the formula (IB-VI-dI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0900] In some embodiments, the compound is of the formula (IB-VII-dI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0901] In some embodiments, the compound is of formula (IB-VII-dI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0902] In some embodiments, the compound is of the formula (IB-VII-dI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0903] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0904] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH-1): [ka] (IB-VII-dI-1-AH-1) , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0905] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0906] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0907] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH-1-BIa): [ka] (IB-VII-dI-1-AH-1-BIa) , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0908] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0909] In some embodiments, the compound is of the formula (IB-VII-dI-1-AH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0910] In some embodiments, the compound is of formula (ICIdI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0911] In some embodiments, the compound is of formula (ICIdI-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0912] In some embodiments, the compound is of the formula (ICIdI-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0913] In some embodiments, the compound is of the formula (ICIdI-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0914] In some embodiments, the compound is of the formula (ICIdI-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0915] In some embodiments, the compound is of the formula (ICIdI-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0916] In some embodiments, the compound is of the formula (ICIdI-1-BH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0917] In some embodiments, the compound is of the formula (ICIdI-1-BH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0918] In some embodiments, the compound is of the formula (ICIdI-1-BH-1-B): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0919] In some embodiments, the compound is of the formula (ICIdI-1-BH-1-BI): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0920] In some embodiments, the compound is of the formula (ICIdI-1-BH-1-BIa): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0921] In some embodiments, the compound is of the formula (ICIdI-1-BH-1-BIa*): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0922] In some embodiments, the compound is of the formula (ICIdI-1-BH-1-BIa**): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0923] In some embodiments, the compound is of formula (II): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0924] In some embodiments, the compound is of formula (IBIdI-II): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0925] In some embodiments, the compound is of formula (IBIdI-II-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0926] In some embodiments, the compound is of the formula (IBIdI-II-1-A): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0927] In some embodiments, the compound is of the formula (IBIdI-II-1-AH): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0928] In some embodiments, the compound is of the formula (IBIdI-II-1-AH-1): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0929] In some embodiments, the compound is of formula (Ia): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0930] In some embodiments, the compound is of formula I': [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0931] In some embodiments, the compound is of formula (Ib): [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0932] In some embodiments, the compound is of formula (Ic): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0933] In some embodiments, the compound is of formula (Id): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0934] In some embodiments, the compound is of formula (Ie): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0935] In some embodiments, the compound is of formula (If): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0936] In some embodiments, the compound is of formula (Ig): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0937] In some embodiments, the compound is of formula (Ih): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0938] In some embodiments, the compound is of formula (Ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0939] In some embodiments, the compound is of formula (Ij): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0940] In some embodiments, the compound is of formula (Ik): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B H, C1-C6 alkyl, C3-C 10 Selected from cycloalkyl, aryl, and heteroaryl (all other variables are as defined herein).

[0941] In some embodiments, the compound is of formula (Il): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof (wherein the formula, index u is an integer selected from 1, 2, and 3, index w is an integer selected from 1, 2, and 3, and all other variables are as defined herein).

[0942] In some embodiments, the compound is of formula (Im): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B The form is independently selected from the oxo, M is selected from CH2, O, and NH, and all other variables are as defined herein.

[0943] In some embodiments, the compound is of formula (In): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B (The elements are selected from H, C1-C6 alkyl, and aryl, and all other variables are as defined herein.)

[0944] In some embodiments, the compound is of formula (Io): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0945] In some embodiments, the compound is of formula (Ip): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is H, C1-C6 alkyl, or two R B (Selected independently from the form oxo, and all other variables are as defined herein).

[0946] In some embodiments, the compound is of formula (Ir): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0947] In some embodiments, the compound is of formula (Is): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0948] In some embodiments, the compound is of formula (It): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0949] In some embodiments, the compound is of formula I'-a: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0950] In some embodiments, the compound is of formula I'-b: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0951] In some embodiments, the compound is of formula I'-c: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0952] In some embodiments, the compound is of formula I'-d: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0953] In some embodiments, the compound is of formula I'-e: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0954] In some embodiments, the compound is of formula I'-f: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0955] In some embodiments, the compound is of formula I'-g: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0956] In some embodiments, the compound is of formula I'-h: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0957] In some embodiments, the compound is of formula I'-i: [ka] , or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0958] In some embodiments, the compound is selected from the compounds listed in Table 5, and their pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers.

[0959] In some embodiments, the compound is selected from the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0960] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0961] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 5 and their pharmaceutically acceptable salts.

[0962] In some embodiments, the compound is selected from the compounds listed in Table 5.

[0963] JPEG2026143650000520.jpg219156JPEG2026143650000521.jpg211156JPEG2026143650000522.jpg218156JPEG2026143650000523.jpg21115 6JPEG2026143650000524.jpg204156JPEG2026143650000525.jpg211156JPEG2026143650000526.jpg182156JPEG2026143650000527.jpg18915 6JPEG2026143650000528.jpg211159JPEG2026143650000529.jpg211159JPEG2026143650000530.jpg211159JPEG2026143650000531.jpg21115 9JPEG2026143650000532.jpg211159JPEG2026143650000533.jpg211159JPEG2026143650000534.jpg175159JPEG2026143650000535.jpg89159

[0964] In some embodiments, the compound is a neutral form (i.e., not a salt) of any one of the compounds listed in Table 5.

[0965] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 5.

[0966] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds listed in Table 5.

[0967] In some embodiments, the compound is a sodium or potassium salt of any one of the compounds listed in Table 5.

[0968] In some embodiments, the compound is a sodium salt of any one of the compounds listed in Table 5.

[0969] In some embodiments, the compound is a potassium salt of any one of the compounds listed in Table 5.

[0970] In some embodiments, the present disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0971] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5, as well as its prodrug and pharmaceutically acceptable salt.

[0972] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5 and a pharmaceutically acceptable salt thereof.

[0973] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 5 and a pharmaceutically acceptable salt thereof.

[0974] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5.

[0975] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using isotopic labeling reagents instead of non-isotopic labeling reagents.

[0976] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0977] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0978] The term “isotope derivative,” as used herein, refers to a derivative of a compound in which one or more atoms are isotope-enriched or labeled. For example, an isotope derivative of a compound of formula (I) is isotope-enriched with respect to one or more isotopes or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, the isotope derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 The isotope derivative is enriched or labeled with respect to one or more atoms selected from S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., with respect to one or more atoms thereof). 2 (It is concentrated with H.)

[0979] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 5, as well as its prodrug and pharmaceutically acceptable salt.

[0980] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 5 and a pharmaceutically acceptable salt thereof.

[0981] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds listed in Table 5 and a pharmaceutically acceptable salt thereof.

[0982] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 5.

[0983] It is understood that deuterium-labeled compounds contain deuterium atoms with a deuterium abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0984] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium uptake in each deuterium atom), at least 4000 (60% deuterium uptake), at least 4500 (67.5% deuterium uptake), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium uptake), at least 6000 (90% deuterium uptake), at least 6333.3 (95% deuterium uptake), at least 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium uptake), or at least 6633.3 (99.5% deuterium uptake) for each deuterium atom. As used herein, the term “deuterium enrichment factor” means the ratio of the deuterium abundance to the natural abundance of deuterium.

[0985] It is understood that deuterium-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using a deuterium-labeled reagent instead of a non-deuterium-labeled reagent.

[0986] Compounds of the present disclosure containing the above-mentioned deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. Furthermore, deuterium (i.e., 2 Substitution with H) can provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement.

[0987] In some embodiments, the compound is 18 It is an F-labeled compound.

[0988] In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135It is an I-labeled compound, or any combination thereof.

[0989] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 It is an S-labeled compound, or any combination thereof.

[0990] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It is understood that S-labeled compounds can be prepared using any of the various techniques recognized in this art. For example, deuterium-labeled compounds can generally be prepared using non-isotope labeling reagents instead. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 It can be prepared by using an S-labeled reagent and performing the procedures disclosed in the scheme and / or examples described herein.

[0991] the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, containing one or more S atoms, are within the scope of the present disclosure. Furthermore, isotopes (e.g., 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Substitution with S) can provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement.

[0992] To avoid any doubt, in this specification, where a group is limited by "as described herein," it should be understood that such group encompasses the broadest definition that first appears, as well as each and all of the specific definitions relating to that group.

[0993] The various functional groups and substituents constituting the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More commonly, the molecular weight of the compound is less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600, for example 550 daltons or less.

[0994] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonic citrate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are salts with alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that give a pharmaceutically acceptable cation, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0995] It will be understood that any one compound of any of the formulas disclosed herein and any pharmaceutically acceptable salt thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the said compound.

[0996] As used herein, the term "isomerism" means compounds that have the same molecular formula but differ in the order of their atomic bonding or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that cannot be superimposed on each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a "racemic mixture."

[0997] As used herein, the term “chiral center” refers to a carbon atom bonded to four different substituents.

[0998] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds with multiple chiral centers may exist as individual diastereomers or as a mixture of diastereomers called a “diastereomer mixture.” When a single chiral center is present, the stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center were ranked according to the Cahn, Ingold, and Prelog ordering rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0999] As used herein, the term “geometric isomer” means a diastereomer that exists due to interfering rotations around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, and, according to the Cahn-Ingold-Prelog rule, indicate that the group is on the same side or opposite side of the double bond within the molecule.

[1000] It should be understood that the compounds disclosed herein may be represented as different chiral or geometric isomers. Furthermore, if a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude all isomeric forms, nor should all isomers necessarily possess the same level of activity.

[1001] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropic isomers. It should also be understood that not all atropic isomers have the same level of activity.

[1002] In this specification, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are spatially distinct. Atropic isomers exist because the rotation of a large group around a central bond is hindered and restricted. While such atropic isomers typically exist as a mixture, recent advances in chromatography techniques have made it possible to separate a mixture of two atropic isomers, if selected.

[1003] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal transfer of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomers. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring chain tautomerism occurs as a result of an aldehyde group (-CHO) of a sugar chain molecule reacting with one of the hydroxyl groups (-OH) of the same molecule to give it a cyclic (ring-shaped) form, as seen in glucose.

[1004] It should be understood that the compounds disclosed herein may be represented as different tautomers. Where a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any tautomers. It should be understood that certain tautomers may have higher levels of activity than others.

[1005] Any compound of any of the formulas disclosed herein may exist in many different tautomer forms, and a reference to a compound of formula (I) includes all such forms. To avoid ambiguity, if a compound may exist in one of several tautomer forms and only one is specifically described or illustrated, nevertheless all others are encompassed by formula (I) or (II). Examples of tautomer forms include, for example, the following tautomer pairs: keto-, enol-, and enolate- forms, such as keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acid-nitro. [ka]

[1006] As a non-limiting example of the tautomerism of the compound of formula (I), the substituent R represented by OH is 1 Examples of compounds having the following characteristics can be given: [ka]

[1007] Compounds with the same molecular formula but different bonding properties or order of their atoms, or different arrangements of their atoms in space, are called "isomers." Isomers with different arrangements of atoms in space are called "stereoisomers." Stereoiomers that are not mirror images of each other are called diastereomers, and stereoisomers that cannot be superimposed as mirror images of each other are called enantiomers. If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers are characterized by the absolute configuration of their chiral center, described by Cahn and Prelog's R- and S-sequence rules, or by the way the molecule rotates its plane of polarization, and are called dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[1008] The compounds of this disclosure may have one or more chiral centers; such compounds may be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the descriptions or nomenclature of specific compounds in this specification and claims are intended to include both individual enantiomers and mixtures thereof, racemates, or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of this disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that have inflammasome inhibitory activity.

[1009] This disclosure also includes compounds of the disclosure as defined herein that involve one or more isotopic substitutions.

[1010] It should be understood that any compound of any of the formulas described herein includes, where applicable, the compound itself, as well as their salts and solvates. For example, salts can be formed between an anion on a substituted compound disclosed herein and a positively charged group (e.g., amino). Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucuronates, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, and acetates (e.g., trifluoroacetates).

[1011] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a substituted compound disclosed herein and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[1012] It should be understood that the compounds of this disclosure, for example, salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates, and non-limiting examples of solvates include ethanol solvate and acetone solvate.

[1013] As used herein, the term “solvate” means a solvation form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture solvent molecules in a certain molar ratio in their crystalline solid state to form solvates. When the solvent is water, the solvate produced is a hydrate; when the solvent is an alcohol, the solvate produced is an alcoholate. Hydrates are formed by the bonding of one molecule of a substance in which water retains its molecular state as H2O with one or more molecules of water.

[1014] As used herein, the term “analog” refers to a compound that is structurally similar to another but has a slightly different composition (e.g., substitution of one atom with an atom of a different element, substitution of one atom in the presence of a particular functional group, or substitution of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance but different in structure or origin from the reference compound.

[1015] As used herein, the term “derivative” refers to a compound having a common core structure and substituted with various groups as described herein.

[1016] As used herein, the term “biological equivalent” refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of biological equivalent substitution is to produce a novel compound having similar biological properties to the parent compound. Biological equivalent substitution can be based on physicochemical or topological principles. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[1017] It should be understood that any particular compound of any of the formulas disclosed herein may exist in both solvated and unsolvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are hydrates, such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that this disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[1018] Furthermore, it should be understood that any particular compound of any one of the formulas disclosed herein may exhibit polymorphism, and that this disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be measured by Karl Fischer analysis.

[1019] Compounds of any one of the formulas disclosed herein that contain an amine functional group may also form an N-oxide. In this specification, references to compounds of formula (I) or (II) containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be produced by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), where the amine compound reacts with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[1020] Any compound of any of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compounds disclosed herein. A prodrug can be formed if the compounds disclosed contain suitable groups or substituents to which characterizing groups can be attached. Examples of prodrugs include derivatives of any of the formulas disclosed herein, which contain an alkyl or acyl substituent on the ester or amide group that is cleavable in vivo.

[1021] Accordingly, this disclosure includes any of these compounds of the formulas defined above as disclosed herein, whether made available by organic synthesis or made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure also includes any of these compounds of the formulas disclosed herein produced by organic synthesis means, and such compounds produced in the body of a human or animal by metabolism of precursor compounds, any of the compounds of the formulas disclosed herein may be compounds produced by synthesis or compounds produced by metabolism.

[1022] A suitable pharmaceutically acceptable prodrug of any compound of the formulas disclosed herein is based on reasonable medical judgment that it is suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity. Various forms of prodrugs are described in the following documents, for example: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1023] A suitable pharmaceutically acceptable prodrug of a compound having a hydroxyl group of any of the formulas disclosed herein is, for example, its ester or ether which is cleavable in vivo. A pharmaceutically acceptable ester or ether containing a hydroxyl group of any of the compounds of any of the formulas disclosed herein is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the body of a human or animal to produce a parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include C1-C groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C6 groups such as alkanoyl groups, ethoxycarbonyl groups, N,N-(C1-C6 alkyl)2-carbamoyl groups, 2-dialkylaminoacetyl groups, and 2-carboxyacetyl groups. 10 Examples include alkoxycarbonyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxyl groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[1024] A suitable pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein having a carboxyl group is, for example, its in vivo cleavable amide, such as an amine like ammonia, or a C-amine like methylamine. 1-4 These are amides formed from alkylamines, dimethylamines, (C1-C4 alkyl)2-amines such as N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[1025] A suitable pharmaceutically acceptable prodrug of any compound of the formulas disclosed herein having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, acetyl, benzoyl, phenylacetyl, and C1-C such as substituted benzoyl and phenylacetyl groups. 10 Examples of amides formed by alkanoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[1026] The in vivo effect of any compound of any of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of any compound of any of the formulas disclosed herein. As stated above, the in vivo effect of any one of the compounds of any of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug). Methods for synthesizing compounds

[1027] The compounds of this disclosure can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are shown in the scheme below.

[1028] The compound of formula (I) can be prepared by methods known in the art of organic synthesis, as partially defined by the following synthetic scheme. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed as needed, according to general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Wuts, " (Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. Whether a stereocenter is present in a compound of formula (I) can be determined by the selection process, as well as the reaction conditions and sequence, to those skilled in the art. Thus, this disclosure includes both possible stereoisomers (unless otherwise specified in synthesis) and not only racemic compounds but also individual enantiomers and / or diastereomers. Where a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, intermediate, or starting material may be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[1029] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[1030] The compounds of this disclosure can be prepared by many methods well known to those skilled in the art of organic synthesis. For example, the compounds of this disclosure can be synthesized by the methods described below, along with synthetic methods known in the art of organic synthesis, or by modifications thereof that will be understood by those skilled in the art. Suitable methods include, but are not limited to, those described below. The compounds of this disclosure can be synthesized by following the steps outlined in general procedure A or B, which include aggregate intermediates or compounds of different sequences. Starting materials are commercially available or prepared by any known procedure in the reported literature or as shown below. General Procedure

[1031] Generally, compounds of formula (I) can be prepared by the reduction-amination reaction of a carbonyl compound (A) and an amine (B) in the presence of a suitable reducing agent ([H]): AC(O)H + B-NH2 + [H] → Compound of formula (I)

[1032] In a more specific embodiment, the compound of formula (I) can be obtained according to the scheme shown below: [ka]

[1033] Reagents (A) and (B) may be commercially available compounds themselves or synthetic products derived from commercially available reagents. One-step or multi-step synthetic methods, including but not limited to those described in the preparation section of this specification, may be used to prepare compounds (A) and (B).

[1034] Examples of the preparation of the compounds of formula (I) can be presented by the reaction of any one of the compounds (A) listed in Table 6 with any one of the compounds (B) under the conditions described herein or any other conditions of reduction amination known in the art. Table 6 JPEG2026143650000539.jpg216170JPEG2026143650000540.jpg255165JPEG2026143650 000541.jpg255170JPEG2026143650000542.jpg255168JPEG2026143650000543.jpg72170

[1035] It will be obvious to experts in this field that any of the compounds of formula (I) obtained by following the above procedure can be subject to further transformations and modifications that could lead to obtaining other compounds of formula (I).

[1036] A specific, non-limiting example of further transformation of the compound of formula (I) can be presented by the reaction of preparing compound 97 (Example 15) from compound 68 (Example 9): [ka] Biological assays

[1037] Compounds designed, selected, and / or optimized by the methods described above can be characterized after production using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[1038] Furthermore, high-throughput screening can accelerate analysis using such assays. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in this art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays may utilize one or more different assay techniques, including but not limited to those described below.

[1039] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical composition

[1040] In some embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 5.

[1041] As used herein, the term “composition” is intended to encompass any product containing a specified amount of a specified component, as well as any product resulting directly or indirectly from a specified amount of a specified combination of specified components.

[1042] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (including sustained-release or time-release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, in any form familiar to those skilled in the pharmaceutical art.

[1043] The formulations of this disclosure may be in the form of aqueous solutions comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity / suspension agents, buffers, and pH adjusters, as well as mixtures thereof.

[1044] Any suitable dissolution accelerator can be used. Examples of dissolution accelerators include cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[1045] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[1046] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as sorbic acid and mixtures thereof.

[1047] In some embodiments, examples of preservatives include those selected from the group consisting of quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as sorbic acid and mixtures thereof.

[1048] Furthermore, the aqueous vehicle may contain an isotonic agent to adjust its tonicity (osmotic pressure). The isotonic agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof. In some embodiments, the isotonic agent is selected from the group consisting of glycols (such as propylene glycol and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

[1049] The aqueous vehicle may also contain a viscosity / suspension agent. Suitable viscosity / suspension agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol (Carbopol - e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), as well as mixtures thereof.

[1050] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjusters are typically mineral acids or metal hydroxide bases selected from potassium hydroxide, sodium hydroxide, hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, adding only one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[1051] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or its salts containing disodium tetraborate), citrate buffer (such as citric acid or its salts containing sodium citrate), and ε-aminocaproic acid, as well as mixtures thereof.

[1052] The formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylene-sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapole), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, as well as mixtures thereof.

[1053] Oral compositions typically contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They can also be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth, the mouth is rinsed, and the mixture is spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[1054] Further aspects of this disclosure provide pharmaceutical compositions comprising a compound of the disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[1055] In some embodiments, the pharmaceutical compositions described herein may further include one or more additional pharmaceutically active agents.

[1056] The compositions of this disclosure may be in forms suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by inhalation (e.g., as finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[1057] The disclosed compositions can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Accordingly, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[1058] A therapeutically effective dose of the compounds of this disclosure for therapeutic use is sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with, the MLL-related conditions referred to herein.

[1059] A therapeutically effective dose of the compounds of this disclosure for use in treatment is sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with the MLL-related conditions referred to herein.

[1060] The size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes naturally varies according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration. How to use

[1061] In some embodiments, the Disclosure provides a method for inhibiting the interaction between menine and MLL (e.g., in vitro or in vivo), comprising contacting cells with a therapeutically effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[1062] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering a therapeutically effective amount of the Compounds Disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, to a subject.

[1063] In some embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering a therapeutically effective amount of the Compounds Disclosed or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, to a subject.

[1064] In some embodiments, the disease or disorder is associated with MLL. In some embodiments, the disease or disorder involves menin-MLL binding.

[1065] The compounds of this disclosure are inhibitors of the interaction between menin and MLL and MLL fusion proteins. In some embodiments, this disclosure relates to a method for inhibiting the interaction between menin and MLL or MLL fusion proteins by contacting menin and MLL or MLL fusion proteins with the compounds of this disclosure. The contact can be performed in vitro or in vivo. In some embodiments, the compounds of this disclosure can bind to menin, thereby interfering with the binding of MLL to menin. In some embodiments, this disclosure provides a method for inhibiting the activity of menin by contacting menin with the compounds of this disclosure in the presence of MLL or MLL fusion proteins. In further embodiments, this disclosure provides a method for inhibiting the binding of MLL or MLL fusion proteins to menin, comprising contacting menin with the compounds of this disclosure in the presence of MLL or MLL fusion proteins.

[1066] The compounds of this disclosure are also useful in treating diseases associated with menin-MLL interactions or menin-MLL fusion protein interactions. For example, diseases and conditions treatable according to the methods of this disclosure include cancers such as leukemia, and other diseases or disorders mediated by menin-MLL interactions or menin-MLL fusion protein interactions, such as diabetes.

[1067] In some embodiments, the disease or disorder is selected from the group consisting of leukemia, hematological malignancies, solid tumor carcinomas, prostate cancer, breast cancer, liver cancer, brain tumors, and diabetes. In some embodiments, leukemia is selected from the group consisting of AML, ALL, mixed-series leukemia, and leukemia with partial tandem overlap of MLL.

[1068] In some embodiments, the disease or disorder is cancer.

[1069] In some embodiments, cancer is selected from hematological cancers (e.g., leukemia and lymphoma), bladder cancer, brain cancer (e.g., glioma), diffuse endogenous pontine glioma (DIPG), breast cancer (e.g., triple-negative breast cancer), colorectal cancer, cervical cancer, gastrointestinal cancers (e.g., colorectal cancer, gastric cancer), genitourinary cancers, head and neck cancers, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid carcinoma), testicular cancer, sarcoma (e.g., Ewing's sarcoma), and AIDS-related cancers. In some embodiments, cancers include cardiac cancer, e.g., sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers, e.g., bronchial cancers (e.g., squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, and adenocarcinoma), alveolar carcinoma and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrodysartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, bronchial adenoma / carcinoid, and pleura This includes pulmonary blastoma; gastrointestinal cancers, e.g., esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), gastric cancer (e.g., carcinoma, lymphoma, and leiomyosarcoma), pancreatic cancer (e.g., ductal carcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and bipoma), small intestine cancer (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), colorectal cancer or colon cancer. This includes cancers of the gastrointestinal tract (e.g., adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, and leiomyoma), other cancers of the gastrointestinal tract (e.g., anal cancer, anorectal cancer, appendiceal cancer, anal canal cancer, tongue cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST) colorectal cancer, colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); genitourinary cancers, such as kidney cancer (e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia), bladder cancer, and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma). Cancers, including adenocarcinomas, prostate cancers (e.g., adenocarcinomas and sarcomas), testicular cancers (e.g., seminomas, teratomas, fetal carcinomas, teratocarcinomas, choriocarcinomas, sarcomas, stromal cell carcinomas, fibromas, fibroadenomas, adenomatous tumors, and lipomas), as well as transitional cell carcinomas, transitional cell carcinomas of the renal pelvis and ureters and other urinary tracts, urethral cancers, and bladder cancers; liver cancers, including hepatocellular carcinomas (e.g., hepatocellular carcinomas), cholangiocarcinomas, hepatoblastomas, angiosarcomas, hepatocellular adenomas, and hemangiomas;Bone cancers, including, for example, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral osteoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, including, for example, cancers of the skull (e.g., osteoma, hemangioma, granuloma, xanthomas, and osteoosteitis); cancers of the meninges (e.g., meningioma, meningiosarcoma, and gliomas); and cancers of the brain. (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors); cancers of the spinal cord (e.g., neurofibroma, meningioma, glioma, and sarcoma), and cancers of the nervous system (e.g., brainstem glioma, diffuse endogenous pontine glioma (DIPG) brain tumor, central nervous system cancer, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, primary central nervous system phosphate This includes cancers of the visual pathway and hypothalamic glioma, lymphoma of the nervous system, supratentorial primordial neuroectodermal tumors, pineal blastoma and supratentorial primordial neuroectodermal tumors; gynecological cancers, e.g., uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical cancer and pretumoral cervical dysplasia), ovarian cancer (e.g., ovarian cancer, mucinous cystadenocarcinoma including serous cystadenocarcinoma, unclassifiable cancer, granulosa cell tumor, Sertli-Leydig cell tumor, undifferentiated germ cell tumor, and malignant teratoma), and vulvar cancer (e.g., squamous genital cancer). This includes cancers of other reproductive organs, such as endometrial cancer, germ cell tumors, gestational trophoblastic tumors, ovarian epithelial carcinoma, ovarian germ cell tumors, low-grade ovarian tumors, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumors, extragonadal germ cell tumors, uterine cancer, endometrial cancer, and uterine sarcoma; and cancers of other reproductive organs, such as endometrial cancer, germ cell tumors, gestational trophoblastic tumors, gestational trophoblastic tumors, ovarian epithelial carcinoma, ovarian germ cell tumors, low-grade ovarian tumors, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumors, extragonadal germ cell tumors, uterine cancer, endometrial cancer, and uterine sarcoma.Cancers of the lymphatic and hematological systems, including, for example, blood cancers (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia), as well as other cancers of the lymphatic or hematological systems, including, for example, childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasms / multiple myeloma, myelodysplasia, myelodysplastic syndrome, cutaneous T-cell lymphoma, lymphoma, AIDS-associated lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, and Sézary syndrome; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, and sebaceous gland cancers. This includes lipomas, hemangiomas, dermatofibromas, keloids, psoriasis, Merkel cell carcinoma, Merkel cell carcinoma, malignant melanoma, and carcinoid tumors; adrenal carcinomas, such as neuroblastoma; and other cancers related to the endocrine system, such as adrenocortical carcinoma, multiple endocrine neoplasia (e.g., multiple endocrine neoplasia type 1), multiple endocrine neoplasia syndrome, parathyroid carcinoma, pituitary tumors, pheochromocytoma, islet cell carcinoma, and islet cell tumors. This includes composite tissue cancers (e.g., bone cancer, bone and joint cancer, osteosarcoma, and malignant fibrous histiocytoma); cancers related to the head, neck, and mouth (e.g., head and neck cancer, paranasal sinus cancer and nasal cavity cancer, metastatic squamous cell carcinoma of the neck, oral cancer, pharyngeal cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, and salivary gland cancer); and cancers related to the eye (e.g., ocular cancer, intraocular melanoma). In some embodiments, the cancer is Ewing's sarcoma.

[1070] In some embodiments, the cancer is a blood cancer such as leukemia or lymphoma. Examples of leukemias and lymphomas treatable with the compounds disclosed herein include mixed leukemia (MLL), MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed leukemia (MLL-r), leukemia associated with MLL rearrangement or LJ gene rearrangement, acute leukemia, chronic leukemia, painless leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL) (also known as acute lymphoblastic leukemia or acute lymphoblastic leukemia), acute myeloid leukemia (AML) (also known as acute myeloid leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute nonlymphoblastic leukemia, chronic lymphocytic leukemia (CLL) (also known as chronic lymphoblastic leukemia and These include chronic myeloid leukemia (CML), treatment-associated leukemia, myelodysplastic syndromes (MDS), myeloproliferative disorders (MPDs) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasms (MPNs), plasma cell tumors, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasms, AIDS-associated lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Aribert-Bazan syndrome, mycosis fungoides, Sézary syndrome, hairy cell leukemia, pre-T-cell lymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic molluscum meningitis, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia.

[1071] In some embodiments, diseases and conditions treatable with the compounds of the Disclosure include insulin resistance, prediabetes, diabetes (e.g., type 2 diabetes or type 1 diabetes), and the risk of diabetes. In some embodiments, diseases and conditions treatable with the compounds of the Disclosure include hyperglycemia. In some embodiments, hyperglycemia is associated with diabetes, such as type 2 diabetes. In some embodiments, the compounds of the Disclosure are used to treat loss of response to other antidiabetic drugs and / or decreased β-cell function in a patient or subject. In some embodiments, the compounds of the Disclosure are used to restore response to other antidiabetic drugs and / or restore β-cell function and / or reduce the need for insulin in a patient or subject. In some embodiments, the compounds of the Disclosure are used in subjects taking statins to reduce insulin resistance, reduce the risk of diabetes, or reduce the rise in blood glucose levels caused by statins. In some embodiments, the compounds of the Disclosure are used to treat diabetes in subjects taking statins or to prevent diabetes in subjects taking statins. The methods of this disclosure include reducing, lowering, suppressing, limiting, or controlling elevated blood glucose levels in a subject. In further embodiments, the methods of the present invention include increasing, stimulating, enhancing, promoting, inducing, or activating insulin sensitivity in a subject. Examples of statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[1072] In some embodiments, the Disclosure provides a method for treating or preventing cancer in a subject requiring treatment or prevention of cancer, comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of the Disclosure, to the subject.

[1073] In some embodiments, the Disclosure provides a method for treating cancer in a subject requiring treatment of cancer, comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of the Disclosure, to the subject.

[1074] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in inhibiting the interaction between menine and MLL (e.g., in vitro or in vivo).

[1075] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[1076] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders disclosed herein.

[1077] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer in subjects requiring treatment or prevention of cancer.

[1078] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of cancer in subjects requiring treatment for cancer.

[1079] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for inhibiting the interaction between menine and MLL (e.g., in vitro or in vivo).

[1080] In some aspects, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing the diseases or disorders disclosed herein.

[1081] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating diseases or disorders disclosed herein.

[1082] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing cancer in subjects requiring treatment or prevention of cancer.

[1083] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating cancer in subjects requiring cancer treatment.

[1084] This disclosure provides compounds that function as inhibitors of the interaction between menin and MLL (e.g., in vitro or in vivo). Accordingly, this disclosure provides a method for inhibiting the interaction between menin and MLL in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as defined herein.

[1085] In some embodiments, the menin / MLL interaction inhibitor is a compound of the present disclosure.

[1086] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models, as described in the art and as can be found in current general knowledge.

[1087] The disclosure also provides a method for treating a disease or disorder involving a subject requiring such treatment, wherein the interaction between menine and MLL comprises administering a therapeutically effective amount of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition as defined herein to the subject.

[1088] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Route of administration

[1089] The compounds of this disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, regardless of whether it is systemic, peripheral, or topical (i.e., the desired site of action).

[1090] The routes of administration are not limited to, but include, oral (e.g., by oral ingestion); cheek; sublingual; transdermal (e.g., including by patches, bandages, etc.); transmucosal (e.g., including by patches, bandages, etc.); intranasal (e.g., nasal spray); ocular (e.g., by eye drops); lung (e.g., via mouth or nose, using aerosols, e.g., inhalation or inhalation therapy); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral administration by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal; and, for example, by implanting a storage unit or reservoir subcutaneously or intramuscularly. [Examples]

[1091] The following are the abbreviations used in the following examples and elsewhere in this specification: JPEG2026143650000545.jpg195150JPEG2026143650000546.jpg118150Examples of general synthesis procedures and compound preparation. Building block synthesis Synthesis of 4-chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7) [ka]

[1092] Preparation 1. Methyl 5-bromo-2-[(tert-butoxycarbonyl)amino]benzoate (P1) [ka] To a solution of methyl 2-amino-5-bromobenzoate (25 g, 0.109 mol) in DCM (250 ml), Boc2O (26.5 g, 0.122 mol), triethylamine (62 g, 0.61 mol), and DMAP (4 g, 0.033 mol) were added. The solution was stirred at ambient temperature for 17 hours. Then, 250 ml of water was added, and potassium bisulfate was added in small amounts while stirring until the pH reached 3. The aqueous phase was washed with dichloromethane (200 ml), the organic solution was concentrated, and the residue was purified by silica gel column chromatography (30% dichloromethane in hexane). 5-bromo-2-[(tert-butoxycarbonyl)amino]benzoate (P1) was isolated as a white solid (14.3 g, 40%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.02 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 9.0, 2.4 Hz, 1H), 3.84 (s, 3H), 1.43 (s, 9H).

[1093] Preparation 2. Methyl 2-[(tert-butoxycarbonyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (P2) [ka] 5-Bromo-2-[(tert-butoxycarbonyl)amino]benzoate (P1, 14.3 g, 0.043 mol) and bis(pinacolato)diborone (22 g, 0.087 mol) were dissolved in dioxane (120 ml). Potassium acetate (12.6 g, 0.129 mol) was added to the solution. The mixture was stirred at 70°C for 30 minutes under an argon atmosphere. Then, Pd(dppf)Cl2 (3.2 g) was added, and the reaction mixture was stirred at 100°C for a further 3 hours (TLC control). The mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was then concentrated, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain the product (P2) as a white solid (1 g, 99% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 10.31 (s, 1H), 8.26 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 1.48 (s, 9H), 1.29 (s, 12H).

[1094] Preparation 3. Methyl 2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroethyl)benzoate (P3) [ka] Methyl 2-[(tert-butoxycarbonyl)amino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (P2, 11.2 g, 30 mmol) was dissolved in dioxane (100 ml), and cesium carbonate (32.6 g, 118 mmol) in water (8 ml) was added. The mixture was stirred at 70°C for 30 minutes under an argon atmosphere. Then, 1,1,1-trifluoro-2-iodoethane (18.6 g, 89 mmol), Pd2(dba)3 (2.6 g), and xanthophos (2.6 g) were added. The reaction mixture was stirred at 82°C for 18 hours, then the mixture was cooled and filtered through a Celite pad. The filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane-hexane-1:1) to obtain the product (P3) as a white solid (5.85 g, yield 59%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.10 (s, 1H), 8.20 (t, J = 20.8 Hz, 1H), 7.92 (s, 1H), 7.50 (d, J = 23.8 Hz, 1H), 3.86 (s, 3H), 3.74 - 3.48 (m, 2H), 1.48 (s, 9H).

[1095] Preparation 4. Methyl 2-amino-5-(2,2,2-trifluoroethyl)benzoate (P4) [ka] A 3M solution of HCl in dioxane was added to methyl 2-[(tert-butoxycarbonyl)amino]-5-(2,2,2-trifluoroethyl)benzoate (P3, 5.85 g, 17.6 mmol). The reaction mixture was stirred at room temperature for 2 hours (NMR control), concentrated to dryness, and the product (P4, 4.6 g, 100%) was obtained as the hydrochloride salt. 1 H NMR (400 MHz, DMSO-d6), δ: 7.62-7.70 (m, 1H), 7.19-7.27 (m, 1H), 6.86-6.84 (m, 1H), 3.79 (s, 3H), 4.03 - 3.58 (m, 2H).

[1096] Prepared 5,2-amino-5-(2,2,2-trifluoroethyl)benzoic acid (P5) [ka] A 35 ml aqueous solution of lithium hydroxide (2 g, 83 mmol) was added to a 100 ml solution of methyl 2-amino-5-(2,2,2-trifluoroethyl)benzoate (P4, 4.6 g, 17.6 mmol) in methanol. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was then cooled, concentrated to dryness, and water (50 ml) was added. Concentrated HCl was added to the resulting solution while stirring, and the mixture was cooled with cold water to pH=3. The resulting precipitate was filtered, washed with water (15 ml), and dried to obtain product P5 as a white solid (3 g, 78%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.62-7,70 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 3.55 - 3.33 (m, 2H).

[1097] Preparation 6.6-(2,2,2-trifluoroethyl)quinazoline-4(3H)-one (P6) [ka] 2-amino-5-(2,2,2-trifluoroethyl)benzoic acid (P5, 3 g, 13.7 mmol) and formamide (2.2 g, 49 mmol) were stirred in a vial at 155°C for 1.5 hours, then at 165°C for 40 minutes. The reaction mixture was cooled, a saturated solution of sodium bicarbonate (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate formed was removed by filtration, washed with water (55 ml), and dried to obtain product P6 as a white solid (2.52 g, 85%). 1H NMR (400 MHz, DMSO-d6), δ: 12.30 (s, 1H), 8.4 - 8,16 (m, 1H), 8,07-8,16 (m, 1H), 7.78 (d, J = 8.6 Hz, 1H),7.68 (d, J=7.8 Hz, 1H), 3.79 - 3.90 (m, 2H).

[1098] Preparation 7.4-Chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7) [ka] POCl3 (35 nl) was added to 6-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (P6, 2.52 g, 11 mmol), and the reaction mixture was stirred and refluxed for 1 hour. The solution was cooled and poured into an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred for 30 minutes and then extracted with DCM (2 × 50 ml). After evaporating the dichloromethane, the residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate-10:1) to obtain the product (P7, 1.9 g, 70%) as a brown solid. 1 H NMR (400 MHz, CDCl3), δ: 9.12-9.07 (m, 1H), 8.25-8.22 (m, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.1, Hz, 1H), 3.70 - 3.60 (m, 2H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9) [ka]

[1099] Preparation 8. tert-butyl 2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P8) [ka] DIPEA (7 / 9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (3.2 g, 12.2 mmol) were added to 4-chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7, 3 g, 12.2 mmol) in dichloromethane (60 ml). The reaction solution was stirred at room temperature for 18 hours (LC-MS control). The product was then purified by silica (ethyl acetate-methanol 10:1) column chromatography to obtain P8 as a white solid (5.1 g, 96%). 1 H NMR (400 MHz, DMSO-d6), δ: 8.47-8.43 (m, 1H), 7.99-7.95 (m, 1H), 7.68 (m, 2H), 4.65-3.96 (m, 4H), 3.96-3.75 (m, 2H), 3.48-3.40 (m, 4H), 2.63-2.48 (m,4H),1.86 - 1.63 (m, 4H), 1.41 (s, 9H).

[1100] Preparation 9.4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9) [ka] To tert-butyl 2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P8, 5.1 g, 11.7 mmol), dioxane-HCl solution (3 M, 120 ml) was added. The reaction mixture was stirred at room temperature for 3 hours (LC-MS control), and then evaporated to dryness under reduced pressure to obtain 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline hydrochloride (P9, 4.4 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.44 (s,1H), 9.29 (s,1H), 8.85-8.80 (m, 1H), 8.14-8.08 (m, 1H), 8.06-7.98 (m, 2H), 4.90-4.76 (m, 2H), 4.38-4.24 (m,2H), 4.03-3.89 (m,2H), 3.18-2.97 (m, 4H), 2.20-2.02 (m, 4H). Synthesis of 4-(2,7-diazaspiro[3.5]nonan-2-yl)-6-(trifluoromethoxy)quinazoline (P11) [ka]

[1101] Preparation 10. tert-butyl 2-[6-(trifluoromethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P10) [ka] To a solution of 6-(trifluoromethoxy)quinazoline-4(3H)-one (230 mg, 1 mmol, prepared as described in US2005 / 54626, 2005, A1) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (263 mg, 1 mmol) in DMAA (4 ml), DBU (610 mg, 4 mmol) and PyBOP (564 mg, 1.5 mmol) were added. The reaction mixture was stirred at 50°C for 48 hours, then water (30 ml) was added, and the product was extracted with ethyl acetate (2 × 5 ml). The extract was washed with brine and concentrated. Flash chromatography on silica gel using ethyl acetate yielded tert-butyl 2-[6-(trifluoromethoxy)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P10, 350 mg, 80%). 1H NMR (400 MHz, DMSO-d6), δ: 8.45 (s, 1H), 7.88 (m, 3H), 3.33 (m, 6H), 2.08 (m, 2H), 1.75 (m, 4H). LCMS (ESI) [MH] + : 439.

[1102] Preparation 11. [4-({2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)phenyl]amine (P11) [ka] To tert-butyl 2-[6-(trifluoromethoxy)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P10, 350 mg, 0.8 mmol), TFA (3 ml) was added. The reaction mixture was stirred at 20°C for 1 hour, then a concentrated aqueous solution of sodium bicarbonate (20 ml) was added, and the mixture was extracted with DCM (2 × 10 ml). The DCM was evaporated to dryness to obtain 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(trifluoromethoxy)quinazoline (P11, 270 mg, 100%). 1 H NMR (400 MHz, DMSO-d6), δ: 8.87 (s, 1H), 8.13 (m, 2H), 7.94 (m, 1H), 4.84 (m, 3H), 3.90 (m, 2H), 3.85 (m, 2H), 3.70 (m, 2H), 2.08 (m, 4H). LCMS (ESI) [MH] + : 339. Synthesis of 5-formyl-4-methyl-1-[(3-oxo-1,4-oxazepan-7-yl)methyl]indole-2-carbonitrile (P13) [ka]

[1103] Preparation 12.7-(hydroxymethyl)-1,4-oxazepan-3-one (P12) [ka] 7-[(benzyloxy)methyl]-1,4-oxazepan-3-one (2.25 g, 10 mmol, prepared according to WO2016 / 75240, 2016, A1) was dissolved in MeOH (70 ml) and stirred with 10% Pd-C (0.5 g) under hydrogen (70 bar) for 18 hours. The reaction mixture was filtered and evaporated to dryness to obtain 7-(hydroxymethyl)-1,4-oxazepan-3-one (P12, 1.45 g, 100%). 1 H NMR (400 MHz, DMSO-d6), δ: 10.2 (s, 1H), 7.63 (s, 1H), 4.70 (m, 1H), 4.40 (m, 2H), 3.55 (m, 1H), 3.38 (m, 1H), 3.19 (m, 2H), 1.87 (m, 1H), 1.53 (m, 1H).

[1104] Preparation 13.5-Formyl-4-methyl-1-[(3-oxo-1,4-oxazepan-7-yl)methyl]indole-2-carbonitrile (P13) [ka] To a solution of 7-(hydroxymethyl)-1,4-oxazepan-3-one (P12, 123 mg, 0.85 mmol) in DMAA (2 ml), DIPEA (131 mg, 1.02 mmol) and MsCl (116 mg, 1.02 mmol) were added. The mixture was stirred at 50°C for 45 minutes, then 2-cyano-4-methyl-5-formylindole (P97, 78 mg, 0.42 mmol) and potassium carbonate (300 mg, 2.2 mmol) were added, and the mixture was stirred at 90°C for 48 hours. The product was extracted with water (10 ml) and ethyl acetate (3 × 5 ml), and the ethyl acetate was evaporated to dryness. The residue was washed with dry ethyl acetate (4 ml), filtered, and dried to obtain the pure product (P13, 53 mg, 41%). 1H NMR (400 MHz, DMSO-d6), δ: 10.38 (s, 1H), 7.82 (m, 2H), 7.70 (m, 2H), 4.45 (m, 1H), 4.41 (m, 1H), 3.98 (m, 2H), 3.30 (m, 3H), 3.20 (m, 2H), 2.86 (m, 3H). LCMS (ESI) [MH] + : 312. Synthesis of 2-ethynyl-4-methyl-1-[2-(2-oxoimidazolidine-1-yl)ethyl]-1H-indole-5-carbaldehyde (P14) [ka]

[1105] Preparation 14. 2-Ethinyl-4-methyl-1-[2-(2-oxoimidazolidine-1-yl)ethyl]-1H-indole-5-carbaldehyde (P14) [ka] To a solution of 1-(2-hydroxyethyl)imidazolidine-2-one (130 mg, 1 mmol) in DMAA (3 ml), DIPEA (258 mg, 2 mmol) and MsCl (132 mg, 1.15 mmol) were added. The mixture was stirred at 50°C for 45 minutes, then 2-cyano-4-methyl-5-formylindole (P97, 92 mg, 0.5 mmol) and potassium carbonate (400 mg, 2.9 mmol) were added, and the mixture was stirred at 90°C for 48 hours. The product was extracted with water (40 ml) and ethyl acetate (3 × 5 ml), and the ethyl acetate was evaporated to dryness. The residue was washed with dry ethyl acetate (4 ml), filtered, and dried to obtain pure 2-ethynyl-4-methyl-1-[2-(2-oxoimidazolidine-1-yl)ethyl]-1H-indole-5-carbaldehyde (P14, 47 mg, 32%). 1H NMR (400 MHz, CDCl3), δ: (8.9 (s, 1H), 6.85 (n, 1H), 6.40 (m, 3H), 3.46 (m, 3H), 3.02 (m, 2H), 2.20 (m, 2H), 1.75 (m, 4H). LCMS (ESI) [MH] + : 297. Synthesis of 5-formyl-4-methyl-1-[(7-oxoazepan-4-yl)methyl]-1H-indole-2-carbonitrile (P15) [ka]

[1106] Preparation 15.5-Formyl-4-methyl-1-[(7-oxoazepan-4-yl)methyl]-1H-indole-2-carbonitride (P15) [ka] To a solution of 5-(hydroxymethyl)azepan-2-one (312 mg, 2.2 mmol, prepared as described in CN113277991, 2021, A) in DMAA (3 ml), DIPEA (405 mg, 3.14 mmol) and MsCl (300 mg, 2.02 mmol) were added. The mixture was stirred at 50°C for 45 minutes, then 2-cyano-4-methyl-5-formylindole (P97, 92 mg, 0.5 mmol) and potassium carbonate (400 mg, 2.9 mmol) were added, and the mixture was stirred at 90°C for a further 48 hours. After the reaction was complete, water (40 ml) was added, and the product was extracted with ethyl acetate (3 × 5 ml). The ethyl acetate was evaporated to dryness. The residue was washed with dry ethyl acetate (4 ml), filtered, and dried to obtain pure 5-formyl-4-methyl-1-[(7-oxoazepan-4-yl)methyl]-1H-indole-2-carbonitrile (P15, 128 mg, 83%). 1H NMR (400 MHz, CDCl3), δ: 10.45 (s, 1H), 7.85 (m, 1H), 7.40 (m,1H), 6.15 (m, 1H), 4.18 (m,1H), 3.45 (m,2H), 3.2 (m, 2H), 2.95 (m, 3H), 2.45 (m,2H), 1.35 (m, 4H). LCMS (ESI) [MH] + : 310. Synthesis of 1-(2-piperazine-1-ylethyl)-5-({2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (P17) [ka]

[1107] Preparation 16. tert-butyl 4-{2-[2-cyano-5-({2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-1-yl]ethyl}piperazine-1-carboxylate (P16) [ka] A mixture of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline hydrochloride (P9, 200 mg, 0.535 mmol), tert-butyl 4-[2-(2-cyano-5-formyl-1H-indole-1-yl)ethyl]piperazine-1-carboxylate (P89, 306 mg, 0.8 mmol), and triacetoxyborohydride (227 mg, 1.07 mmol) in DCM (10 ml) was stirred at room temperature for 24 hours (LCMS control). Then, an aqueous solution of sodium bicarbonate was added while stirring. The mixture was stirred for 30 minutes and separated. The aqueous phase was extracted with DCM (100 ml). The combined DCM extract was concentrated, and the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:2) to obtain tert-butyl 4-{2-[2-cyano-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}-1H-indole-1-yl]ethyl}piperazine-1-carboxylate (P16, 190 mg, 51%) as a white solid. LCMS (ESI) [MH] + : 703.

[1108] Preparation 17.1-(2-piperazine-1-ylethyl)-5-({2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (P17) [ka] tert-butyl 4-{2-[2-cyano-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-1-yl]ethyl}piperazine-1-carboxylate (P16, 190 mg, 0.27 mmol) was added to a dioxane solution in HCl (3M 12 ml). The reaction mixture was stirred at room temperature for 3 hours (LCMS control), and then evaporated to dryness under reduced pressure to obtain 1-(2-piperazine-1-ylethyl)-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile hydrochloride (P17, 172 mg, 100%) as a white solid. LCMS (ESI) [MH] + : 603. Synthesis of 4-methyl-1-(2-piperazine-1-ylpropyl)-5-[[2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-yl]methyl]indole-2-carbonitrile (P20) [ka]

[1109] Preparation 18.5-Formyl-4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazine-1-yl]propyl}-1H-indole-2-carbonitrile (P18) [ka] A mixture of 2-[4-(tert-butylcarboxylate)piperazine-1-yl]propan-1-ol (200 mg, 0.9 mmol), 5-formyl-4-methyl-1H-indole-2-carbonitrile P97 (165 mg, 0.9 mmol), and triphenylphosphine (354 mg, 1.35 mmol) in toluene (5 ml) was mixed with DIAD (273 mg, 1.35 mmol), and the resulting mixture was stirred overnight at ambient temperature. The solvent was evaporated. The residue after evaporation was subjected to column chromatography on silica gel eluted with dichloromethane / ethyl acetate (0 → 20%) to obtain 5-formyl-4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazine-1-yl]propyl}-1H-indole-2-carbonitrile (P18, 130 mg, 37%). LCMS [MH + ]: 411. 1 H NMR (400 MHz, DMSO-d6), δ: 10.37 (s, 1H), 7.82-7.78 (m, 2H), 7.63 (d, J=7.0 Hz, 1H), 4.82-4.73 (m, 1H), 4.39-4.31 (m, 1H), 4.27-4.20 (m, 1H), 3.25-3.10 (m, 4H), 2.85 (s, 3H), 2.64-2.52 (m, 2H), 2.25-2.19 (m, 2H), 1.38 (s, 9H), 1,18-1,12 (m, 3H).

[1110] Preparation 19.4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazine-1-yl]propyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (P19) [ka] Molecular sieves, 3 Å (200 mg), were added to a mixture of 5-formyl-4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazine-1-yl]propyl}-1H-indole-2-carbonitrile (P18, 130 mg, 0.34 mmol) and 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9, 113 mg, 0.34 mmol) in methanol (1 ml). Then, NaBH3CN (42 mg, 0.67 mmol) was added, and the reaction mixture was stirred overnight at ambient temperature. Saturated aqueous sodium bicarbonate and dichloromethane were added, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated. The residue after evaporation was subjected to HPLC to obtain the target compound 4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazine-1-yl]propyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (P19, 39 mg, 17%). LCMS (ESI) [MH + ]: 731.

[1111] Preparation 20.4-methyl-1-(2-piperazine-1-ylpropyl)-5-[[2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-yl]methyl]indole-2-carbonitrile (P20) [ka] 4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazine-1-yl]propyl}-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-2-carbonitrile (P19, 39 mg, 5.8 mmol) was mixed with TFA (1 ml). The solution was stirred at room temperature for 2 hours (LCMS control), then evaporated until dry, and sodium bicarbonate aqueous solution (5 ml) was added. The product was extracted with DCM (3 × 5 ml). The organic phase, dried over sodium sulfate, was concentrated and dried to obtain product P20 (31 mg, 100%). LCMS (ESI) [MH + ]: 631. Synthesis of 4-(7-{[2-ethynyl-4-methyl-1-(4-piperazine-1-ylbutyl)-1H-indole-5-yl]methyl}2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P24) [ka]

[1112] Preparation 21. 1-(4-chlorobutyl)-5-formyl-4-methyl-1H-indole-2-carbonitride (P21) [ka] To a solution of 5-formyl-4-methyl-1H-indole-2-carbonitrile P97 (184 mg, 1.0 mmol) in 10 ml of MeCN, 1,4-dichlorobutane (1.27 g, 10 mmol), K2CO3 (2 g), and NaI (0.5 g) were added. The reaction mixture was stirred at 80°C for 24 hours, then evaporated to dryness, washed with water (15 ml), dried under reduced pressure, and washed with hexane (3 ml) to obtain 1-(4-chlorobutyl)-5-formyl-4-methyl-1H-indole-2-carbonitrile (P21, 244 mg, 89%). 1¹H NMR (400 MHz, DMSO-d₆), δ: 10.37 (s, 1H), 7.89-7.81 (m, 2H), 7.68 (d, J=6.8 Hz, 1H), 4.42 (t, J=7.0 Hz, 2H), 3.64 (t, J=6.8 Hz, 2H), 2.85 (s, 3H), 1.95-1.79 (m, 2H), 1.79-1.63 (m,2H).

[1113] Preparation 22. tert-butyl 4-[4-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)butyl]piperazine-1-carboxylate (P22)

Chemical Formula

[1114] Preparation 23. tert-butyl 4-{4-[2-ethynyl-4-methyl-5-({2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-1-yl]butyl}piperazine-1-carboxylate (P23) [ka] To a solution of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9, 182 mg, 0.54 mmol) and tert-butyl 4-[4-(2-cyano-5-formyl-4-methyl-1H-indole-1-yl)butyl]piperazine-1-carboxylate (P22, 230 mg, 0.54 mmol) in DCM (5 ml), DIPEA (210 mg, 1.63 mmol) and STAB (345 mg, 1.63 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours (LCMS control), then washed with saturated aqueous solution of NaHCO3, and extracted with DCM (2 × 5 ml). The residue after solvent evaporation was subjected to column chromatography on silica gel eluted with ethyl acetate-methanol (0 → 30%) to obtain compound P23 (167 mg, 43%). LCMS (ESI) [MH + ]: 745. 1 H NMR (400 MHz, CDCl3), δ: 8.59 (s, 1H), 7.83-7.72 (m, 2H), 7.60 (d, J=6.0 Hz, 1H), 7.34 (d, J=9.6 Hz, 1H), 7.23-7.11 (m, 2H), 4.39-4.17 (m, 6H), 4.17-4.08 (m, 2H), 2.54 (s, 3H), 2.49-2.33 (m, 2H), 2.33-2.27 (m, 6H), 1.95-1.82 (m, 6H), 1.57-1.47 (m, 2H), 1.43 (s, 9H).

[1115] Preparation 24.4-(7-{[2-ethynyl-4-methyl-1-(4-piperazine-1-ylbutyl)-1H-indole-5-yl]methyl}-2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P24) [ka] A solution of tert-butyl 4-{4-[2-ethynyl-4-methyl-5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1H-indole-1-yl]butyl}piperazine-1-carboxylate (P23, 167 mg, 0.224 mmol) in TFA (1 ml) was stirred at room temperature for 2 hours (LCMS control), then evaporated to dryness, and sodium bicarbonate aqueous solution (5 ml) was added. The product was extracted with dichloromethane (3 × 5 ml). The organic phase dried over sodium sulfate was concentrated to dryness to obtain the target compound P24 (144 mg, 100%). LCMS (ESI) [MH + ]: 644. 1 H NMR (400 MHz, DMSO-d6), δ: 8.44 (s, 1H), 8.20-7.95 (m, 1H), 7.74-7.68 (m, 2H), 7.42 (d, J=6.0 Hz, 1H), 7.31 (d, J=9.5 Hz, 1H), 4.35-4.28 (m, 3H), 3.92-3.81 (m, 2H), 3.54-3.48 (m, 2H), 3.43-3.31 (m, 4H), 2.64-2.56 (m, 4H), 2.45-2.30 (m, 4H), 2.25-2.16 (m, 6H), 1.82-1.73 (m, 6H), 1.42-1.31 (m, 2H). Synthesis of 1-[(trans-4-aminocyclohexyl)methyl]-4-methyl-5-[[2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-yl]methyl]-1H-indole-2-carbonitrile hydrochloride (P26) [ka]

[1116] Preparation 25. tert-butyl (trans-4-{[2-cyano-5-({2-[6-(2,2-dimethylpropyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-4-methyl-1H-indole-1-yl]methyl}cyclohexyl)carbamate (P25) [ka] Potassium carbonate (138 mg, 1 mmol) was added to a solution of {trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}methylmethanesulfonate (118 mg, 0.4 mmol) and 4-methyl-5-[[2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-7-yl]methyl]-1H-indole-2-carbonitrile (150 mg, 0.30 mmol) prepared according to WO2018 / 67422, 2018, A1 in MeCN (3 ml). The reaction mixture was stirred at 50°C for 24 hours, then filtered and concentrated. The residue after solvent evaporation was subjected to column chromatography on silica gel eluted with ethyl acetate-methanol (0 → 30%) to obtain the title compound P25 (70 mg, 30%). LCMS (ESI) [MH + ]: 716.

[1117] Preparation 26.1-[(trans-4-aminocyclohexyl)methyl]-4-methyl-5-[[2-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-7-yl]methyl]-1H-indole-2-carbonitride hydrochloride (P26) [ka] To tert-butyl (trans-4-{[2-cyano-5-({2-[6-(2,2-dimethylpropyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-4-methyl-1H-indole-1-yl]methyl}cyclohexyl)carbamate P25 (70 mg, 0.1 mmol), 2 ml of 3 M HCl solution in dioxane was added. The reaction mixture was stirred at room temperature for 2 hours (LCMS control), and then evaporated to dryness to obtain P26 (68 mg, 100%). LCMS (ESI) [MH + ]: 616. Synthesis of 4-(2,7-diazaspiro[3.5]non-7-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P28) [ka]

[1118] Preparation 27. tert-butyl 7-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (P27) [ka] To a solution of 4-chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7, 3 g, 12.2 mmol) in DCM (60 ml), DIPEA (7.9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate hydrochloride (3.2 g, 12.2 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours (LCMS control). After the reaction was complete, the solvent was evaporated, and the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:1) to obtain 5.1 g of product P27 as a white solid. LCMS (ESI) [MH] + : 437.

[1119] Preparation 28.4-(2,7-diazaspiro[3.5]non-7-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P28) [ka] tert-butyl 7-[6-(2,2,2-trifluoroethyl)quinazoline-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (P27, 5.1 g, 11.7 mmol) was added to dioxane-HCl solution (3 M, 120 ml). The reaction mixture was stirred at room temperature for 3 hours (LC-MS control), and then evaporated to dryness under reduced pressure to obtain 4-(2,7-diazaspiro[3.5]non-7-yl)-6-(2,2,2-trifluoroethyl)quinazoline hydrochloride (P28, 4.4 g, 100%) as a white solid. LC-MS (ESI) [MH] + : 337. Synthesis of 3-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane (P30) [ka]

[1120] Preparation 29. tert-butyl 9-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (P29) [ka] To a solution of 4-chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7, 3 g, 12.2 mmol) in dichloroethane (60 ml), DIPEA (7.9 g, 61 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.5 g, 12.2 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours (LCMS control). After solvent evaporation, the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:1) to obtain product P29 as a white solid (5.1 g, 92%). LCMS (ESI) [MH] + : 465.

[1121] Preparation 30.3-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane (P30) [ka] tert-butyl 9-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (P29, 5.1 g, 11.7 mmol) was added to HCl / dioxane solution (3 M, 120 ml). The reaction mixture was stirred at room temperature for 3 hours (LCMS control), and then the solvent was evaporated under reduced pressure to dry and obtain 3-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane (P30, 4.4 g, 100%) as a white solid. LCMS (ESI) [MH] + : 364. Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine (P39) [ka]

[1122] Preparation 31. Methyl 2-amino-5-bromonicotinate (P31) [ka] To a stirred solution of methyl 2-aminonicotinate (2 g, 13.15 mmol) and sodium bicarbonate (2.2 g, 26.31 mmol) in DCM (30 ml), a solution of bromine (1.01 ml, 39 mmol) in DCM (20 ml) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with sodium bisulfate solution (50 ml) and extracted with DCM (2 × 40 ml). The combined organic layer was washed with brine (40 ml), dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain the title compound (P31) as a yellow solid (2.7 g, 91%).1 H NMR (400 MHz, DMSO-d6), δ: 8.29 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.32 (s, 2H), 3.82 (s, 3H).

[1123] Prepared 32,2-amino-5-bromonicotinic acid (P32) [ka] To a solution of P31 (2.76 g, 11.95 mmol) in DCM (100 ml), a solution of LiOH (1.72 g, 71.7 mmol) in water was added. The reaction mixture was refluxed for 1 hour, then evaporated under reduced pressure, dissolved in water, and the pH was adjusted to approximately 3 with HCl. The residue was filtered and washed with water to obtain the title compound (P32) as a white solid (2.05 g, 79%). 1 H NMR (400 MHz, DMSO-d6), δ: 13.30 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.38 (s, 1H).

[1124] Preparation 33.6-bromopiride[2,3-d]pyrimidine-4(3H)-one (P33) [ka] A solution of P32 (2 g, 9.22 mmol) in formamide (1.66 g, 36.88 mmol) was refluxed at 165°C for 1 hour, then at 175°C for 1 hour. The residue was washed with water and added to a sodium bicarbonate solution (30 ml), and the mixture was stirred to shred the residue. The precipitate was then filtered and washed with water to obtain the title compound (P33) as a white solid (2.03 g, 97%). 1 H NMR (400 MHz, DMSO-d6), δ: 12.69 (s, 1H), 9.03 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 8.35 (s, 1H).

[1125] Preparation 34. tert-butyl-2-(6-bromopirido[2,3-d]pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P34) [ka] A mixture of P33 (144 mg, 0.64 mmol), amine (205 mg, 0.78 mmol), PyBOP (416 mg, 1.11 mmol), and DBU (474 ​​mg, 3.12 mmol) in DMAA (2 ml). The reaction mixture was stirred at 60°C for 48 hours. The reaction mixture was then cooled to room temperature, extracted with HCl (2 x 10 ml), washed with brine (40 ml), dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient from HCl to 1% MeOH in HCl) to obtain the title compound (P34) as a white solid (150 mg, 44%). 1 H NMR (400 MHz, DMSO-d6), δ: 9.03 (d, J = 2.4 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 3.35 (br. s, 2H), 3.29 (br. s, 2H), 2.51 (br. s, 2H), 2.49 (br. s, 2H), 1.74 (s, 4H), 1.40 (s, 9H).

[1126] Preparation 35. tert-butyl-2-(6-vinylpyrido[2,3-d]pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P35) [ka] To a solution of P34 (150 mg, 0.35 mmol) in EtOH (2 ml), DIPEA (87 mg, 0.75 mmol) and vinyl-BF3 (92 mg, 0.70 mmol) were added. The mixture was then filled with argon, and Pddppf (30 mg) was added. The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was then cooled to room temperature, extracted with RINKAN and water, dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient from RINKAN to 1% MeOH in RINKAN) to obtain the title compound (P35) as a white solid (130 mg, 99%). LCMS (ESI) [MH] + : 382.

[1127] Preparation 36. tert-butyl-2-(6-formylpirido[2,3-d]pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P36) [ka] A solution of P35 (130 mg, 0.3 mmol), 2,6-lutidine (58 mg, 0.48 mmol), and NaIO4 (241 mg, 0.99 mmol) in a mixture of dioxane (6 ml) and water (2 ml) was packed with argon, and a solution of OsO4 (17 mg, 0.06 mmol) in t-BuOH (1 ml) was added. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was extracted with DCM (2 × 10 ml) and purified by silica gel column chromatography (gradient from SiO to 1% MeOH in SiO) to obtain the title compound (P36) as a white solid (110 mg, 84%). 1 H NMR (400 MHz, CDCl3), δ: 10.19 (s, 1H), 9.46 (d, J = 2.2 Hz, 1H), 8.83 (s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 4.36 (br. s, 2H), 3.17 (d, J = 3.4 Hz, 2H), 1.89 (t, J = 5.4 Hz, 4H), 1.72 (s, 2H), 1.62 (s, 2H), 1.49 (s, 9H).

[1128] Preparation 37. tert-butyl-2-{6-[(E)-hydrazonomethyl]pyrido[2,3-d]pyrimidine-4-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (P37) [ka] To a stirred solution of P36 (100 mg, 0.26 mmol) in MeOH (1 ml), an aqueous solution of hydrazine hydrate (39 mg, 0.72 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to obtain the title compound (P37) as a white solid (87 mg, 84%). LC-MS (ESI) [MH] + : 398.

[1129] Preparation 38. tert-butyl-2-[6-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P38) [ka] A solution of P37 (87 mg, 0.22 mmol), 3-(trifluoromethyl)-2-benzofuran-1(3H)-one (97 mg, 0.31 mmol), and TFA (25 mg, 0.22 mmol) in DMSO (2 ml) was filled with argon. The reaction mixture was stirred at 50°C for 24 hours. The reaction mixture was extracted with ethyl acetate, and the combined organic layer was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (gradient from ethyl acetate to 50% MeOH in ethyl acetate) to obtain the title compound (P38) as a white solid (39 mg, 41%). 1 H NMR (400 MHz, CDCl3), δ: 8.95 (s, 1H), 8.78 (s, 1H), 8.12 (s, 1H), 4.29 (s, 4H), 3.55 (d, J = 10.4 Hz, 2H), 3.47 (s, 4H), 1.94 - 1.84 (m, 4H), 1.48 (s, 9H).

[1130] Preparation 39.4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine (P39) [ka] A solution of P38 (39 mg, 0.09 mmol) and TFA (3 ml) in DCM (1 ml) was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, then an aqueous solution of potassium carbonate was added, and the mixture was extracted with DCM (2 × 10 ml), dried over sodium sulfate, filtered, and concentrated to obtain the title compound (P39) as a white solid (25 mg, 83%). 1 H NMR (400 MHz, CDCl3), δ: 8.94 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.14 - 8.08 (m, 1H), 4.27 (s, 4H), 3.58 - 3.49 (m, 2H), 3.17 (d, J = 3.0 Hz, 1H), 2.89 (s, 4H), 1.93 - 1.86 (m, 4H). Synthesis of 1-(2,7-diazaspiro[3.5]non-2-yl)-7-(2,2,2-trifluoroethyl)phthalazine (P44) [ka]

[1131] Preparation 40. tert-butyl 2-[7-bromophthalazine-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P40) [ka] To a solution of crude 7-bromo-1-chlorophthalazine (1.55 g, 6.37 mmol) (synthesized according to US2015 / 259331, 2015) in dichloroethane (40 ml), DIPEA (7.9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.67 g, 6.37 mmol) were added. The reaction solution was stirred at room temperature for 18 hours (LCMS control). The product was then purified by column chromatography on silica using ethyl acetate-methanol (10-1) to obtain the title compound 40 as a white solid (1.3 g, 47%). LCMS (ESI) [MH] + ]: 434.

[1132] Preparation 41. tert-butyl 2-(7-vinylphthalazine-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P41) [ka] To a solution of tert-butyl 2-[7-bromophthalazine-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P40, 0.30 g, 0.69 mmol) in EtOH (10 ml), water (0.5 ml) and TEA (140 mg, 1.39 mmol) were added. Potassium vinyltrifluoroborate (140 mg, 1.03 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(H) dichloromethane adduct (0.17 g, 0.21 mmol) were then added, and the reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was treated with siRNA and H2O, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified with silica (gradient elution, 0-40% siRNA / hexane) to obtain the title compound P41 as a white solid (210 mg, 80%). LCMS (ESI) [MH] + ]: 381.

[1133] Preparation 42. tert-butyl 2-(7-formylphthalazine-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P42) [ka] To a solution of tert-butyl 2-(7-vinylphthalazine-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P41, 210 mg, 0.55 mmol) in dioxane (2 ml) and water (0.42 ml), 2,6-lutidine (113 mg, 1.1 mmol), a solution of osmium tetroxide (10 mg) in tert-BuOH (0.5 ml), and sodium periodate (354 mg, 1.65 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the solution was cooled and added to an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred at 15°C for 30 minutes, then extracted with DCM (2 × 50 ml), the DCM was evaporated, and the residue was purified by silica gel column chromatography (DCM-ethyl acetate-1:1) to obtain the title product P42 as a brown solid (145 mg, 65%). LCMS (ESI) [MH + ]: 383.

[1134] Preparation 43. tert-butyl 2-[7-(2,2,2-trifluoroethyl)phthalazine-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P43) [ka] To a solution of tert-butyl 2-(7-formylphthalazine-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P42, 145 mg, 0.38 mmol) in MeOH (1 ml), hydrazine hydrate (38 mg, 0.76 mmol) was added. The solution was stirred at room temperature for 2 hours (TLC control), and then the reaction mixture was evaporated to dryness to obtain crude hydrazone (150 mg) for use in the next step without purification. Hydrazone (150 mg, 0.38 mmol) was dissolved in DMSO (1 ml) under an argon atmosphere, and then Togni reagent (144 mg, 0.456 mmol) and TFA (43 mg, 0.38 mmol) were added. The resulting mixture was stirred at 50°C for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 25 ml), the combined organic layer was washed with water (3 × 60 ml) and brine (25 ml), and then dried over Na₂SO₄. The organic layer was concentrated, and the residue was separated by HPLC (silica C-18, MeCN-H₂O) to obtain P43 (75 mg, 45%). LC-MS (ESI) [MH] + ]: 437. 1 H NMR (400 MHz, CDCl3), δ: 9.96 (s, 1H), 7.78-7.82 (m, 2H), 7.71 (d, J=10.6 Hz, 1H), 4.33-4,26 (m, 4H), 3.64-3.54 (m, 2H), 3.53-3.42 (m, 4H), 1.94-1.84 (m, 4H), 1.48 (s, 9H).

[1135] Preparation 44.1-(2,7-diazaspiro[3.5]non-2-yl)-7-(2,2,2-trifluoroethyl)phthalazine (P44) [ka] To tert-butyl 2-[7-(2,2,2-trifluoroethyl)phthalazine-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P43, 75 mg, 0.17 mmol), TFA (1 ml) was added. The solution was stirred at room temperature for 2 hours (LCMS control), then evaporated until dry, and sodium bicarbonate aqueous solution (5 ml) was added. The product was extracted with DCM (3 × 5 ml). The organic phase was dried over Na2SO4 and concentrated until dry to obtain 1-(2,7-diazaspiro[3.5]non-2-yl)-7-(2,2,2-trifluoroethyl)phthalazine P44 (57 mg, 100%). LCMS (ESI) [MH + ]: 337. 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.25-8.17(m, 2H), 8.17-8.08 (m, 1H), 4.60-4.40 (m, 4H), 4.11-3.98 (m, 2H), 3.17-3,08 (m, 4H), 2.12-2.03 (m, 4H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)sinnoline (P49) [ka]

[1136] Preparation 45. tert-butyl 2-(6-bromosinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P45) [ka] To a solution of crude 6-bromo-4-chlorosinnoline (prepared according to the procedure described in US2015 / 259331; 1.55 g, 6.37 mmol) in dichloroethane (40 ml), DIPEA (7.9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.67 g, 6.37 mmol) were added. The reaction solution was stirred at room temperature for 18 hours (LCMS control). The product was purified by column chromatography on silica using ethyl acetate-methanol (10:1) to obtain the title compound P45 as a white solid (1.3 g, 47%). LCMS (ESI) [MH] + : 434.

[1137] Preparation 46. tert-butyl 2-(6-vinylcinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P46) [ka] To a solution of tert-butyl 2-(6-bromosinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P45, 0.30 g, 0.69 mmol) in EtOH (10 ml), water (0.5 ml) and TEA (140 mg, 1.39 mmol) were added. Then, potassium vinyltrifluoroborate (140 mg, 1.03 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(H) dichloromethane adduct (0.17 g, 0.21 mmol) were added, and the reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was treated with toluene and H2O, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified with silica (gradient elution, 0-40% siRNA / hexane) to obtain the title compound P46 as a white solid (210 mg, 80%). LC-MS (ESI) [MH] + : 381.

[1138] Preparation 47. tert-butyl 2-(6-fopmylcinnolin)-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P47) [ka] To a solution of tert-butyl 2-(6-vinylcinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P46, 210 mg, 0.55 mmol) in a mixture of dioxane (2 ml) and water (0.42 ml), 2,6-lutidine (113 mg, 1.1 mmol), a solution of osmium tetroxide (10 mg) in tert-BuOH (0.5 ml), and sodium periodate (354 mg, 1.65 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the solution was cooled and added to an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred at 15°C for 30 minutes, then extracted with DCM (2 × 50 ml), the DCM was evaporated, and the residue was purified by silica gel column chromatography (DCM-ethyl acetate-1:1) to obtain the title product P47 as a brown solid (145 mg, 65%). LCMS (ESI) [MH] + : 383.

[1139] Preparation 48. tert-butyl 2-(6-(2,2,2-trifluoroethyl)sinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P48) [ka] To a solution of tert-butyl 2-(6-fopmylcinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P47, 145 mg, 0.38 mmol) in MeOH (1 ml), hydrazine hydrate (38 mg, 0.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours (TLC control), and then the reaction mixture was evaporated to dryness to obtain crude hydrazone (150 mg) for use in the next step without purification. Hydrazone (150 mg, 0.38 mmol) was dissolved in DMSO (1 ml) under an argon atmosphere, and Togni reagent (144 mg, 0.456 mmol) and TFA (43 mg, 0.38 mmol) were added. The resulting mixture was stirred at 50°C for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 × 25 ml), the combined organic layer was washed with water (3 × 60 ml) and brine (25 ml), and then dried under Na₂SO₄. The organic layer was concentrated, and the residue was separated by HPLC (silica C-18, MeCN-H₂O) to obtain P48 (75 mg, 45%). LC-MS (ESI) [MH] + : 437. 1 H NMR (400 MHz, CDCl3), δ: 8.35 (s, 1H), 8.29 (d, J=5.2 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 4.29-4.17 (m, 4H), 3.60-3.43 (m, 6H), 1.92-1.85 (m, 4H), 1.49 (s, 9H).

[1140] Preparation 49.4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)sinnoline (P49) [ka] tert-butyl 2-(6-(2,2,2-trifluoroethyl)sinnoline-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P48, 75 mg, 0.17 mmol) was mixed with TFA (1 ml). The solution was stirred at room temperature for 2 hours (LC-MS control) and then evaporated until dry. An aqueous solution of sodium bicarbonate (5 ml) was added to the residue, and the product was extracted with DCM (3 × 5 ml). The extract was dried over sodium sulfate and concentrated until dry to obtain 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)sinnoline P49 (57 mg, 100%). LC-MS (ESI) [MH] + : 337. 1 H NMR (400 MHz, DMSO-d6), δ: 8.35 (s, 1H), 8.14-8.07 (m, 1H), 8.03 (s, 1H), 7.73-7.66 (m, 1H), 4.25-4.14 (m, 4H), 4.09-3.82 (m, 6H), 2.10-1.94 (m, 4H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[3,2-d]pyrimidine (P61) [ka]

[1141] Preparation 50. Methyl 3-aminopicolinate (P50) [ka] To a solution of 3-aminopicolinic acid (1.00 g, 7.24 mmol, 1.0 equivalent) in methanol (4.0 ml) and DCM (16 ml), trimethylsilyldiazomethane (7.23 ml, 14.5 mmol, 2.0 equivalent) was added at room temperature. The mixed solution was then stirred at room temperature for 16 hours, treated with water, and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over MgSO4(s), filtered, and concentrated under vacuum to obtain P50 as an orange solid (555 mg, 50%).1 H NMR (400 MHz, CDCl3), δ: 8.06 (dd, J = 4.0, 1.4 Hz, 1H), 7.22 (dd, J = 8.4, 4.0 Hz, 1H), 7.05 (dd, J = 8.4, 1.4 Hz, 1H), 5.73 (br. s, 2H), 3.97 (s, 3H).

[1142] Preparation 51. Methyl 3-amino-6-bromopicolinate (P51) [ka] A solution of P50 (5.00 g, 32.8 mmol, 1.0 equivalent) in 2M sulfuric acid (101 ml) was mixed with a solution of bromine (1.68 ml, 32.8 mmol, 1.0 equivalent) in acetic acid (12.6 ml) at room temperature. The mixed solution was then stirred at room temperature for 4 hours, and the solution was converted to Na2S2O. 3(aq) It was treated with and then extracted with toluene. The organic layer was collected, washed with brine, and then MgSO 4(s) The solution was dried, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Â:n-hexane=1:3) to obtain P51 as an orange solid (5.56 g, 73%). 1 H NMR (400 MHz, CDCl3), δ: 7.34 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.82 (br. s, 2H), 3.95 (s, 3H).

[1143] Preparation 52. Methyl 3-amino-6-vinylpicolinate (P52) [ka] To a solution of P51 (500 mg, 2.16 mmol, 1.0 equivalent) in n-butanol (10 ml), potassium vinyltrifluoroborate (435 mg, 3.25 mmol, 1.5 equivalent) and trimethylamine (1.51 ml, 10.8 mmol, 5.0 equivalent) were added at room temperature. The solution was degassed with argon, and then the 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex was added. The reaction mixture was then stirred at 80°C for 16 hours, cooled to room temperature, and filtered through a Celite pad. The solution was treated with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and then filtered with MgSO4. 4(s) The solution was dried, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Â:n-hexane=1:2) to obtain P52 as a yellow solid (230 mg, 60%). 1 H NMR (400 MHz, CDCl3), δ: 7.47 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 17.6, 10.8 Hz, 1H), 5.86 (dd, J = 17.6, 0.8 Hz, LCMS (ESI) [MH] + : 179.1.

[1144] Preparation 53. Methyl 3-(di-tert-butoxycarbonylamino)-6-vinylpicolinate (P53) [ka] To a solution of P52 (230 mg, 1.29 mmol, 1.0 equivalent) in DCM (10 ml), di-tert-butyl dicarbonate (0.890 ml, 3.87 mol, 3.0 equivalent) and 4-dimethylaminopyridine (15.7 mg, 0.129 mmol, 0.1 equivalent) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (Â:n-hexane=1:3) to obtain P53 as a white solid (432 mg, 88%). 1 H NMR (400 MHz, CDCl3), δ: 7.54 (m, 2H), 6.91 (dd, J = 17.6, 11.2 Hz, 1H), 6.22 (d, J = 17.6 Hz, 1H), 5.60 (d, J = 11.2 Hz, 1H), 3.94 (s, 3H), 1.38 (s, 18H); LCMS (ESI) [MH] + : 379.2.

[1145] Preparation 54. Methyl 3-(di-tert-butoxycarbonylamino)-6-formyl picolinate (P54) [ka] To a solution of P53 (432 mg, 1.14 mmol, 1.00 equivalent) in 1,4-dioxane (10 ml) and water (2.5 ml), 2.5% osmium tetroxide in tert-butanol (0.226 ml, 0.0228 mmol, 0.02 equivalent), sodium periodate (977 mg, 4.56 mmol, 4.00 equivalent), and 2,6-lutidine (265 ml, 2.28 mmol, 2.00 equivalent) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixed solution was filtered through Celite and extracted with butyl. The organic layer was collected, washed with brine, and then MgSO4. 4(s) The solution was dried, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Â:dichloromethane = 1:4) to obtain P54 as a yellow solid (402 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.0 Hz, 1H), 4.00 (s, 3H), 1.39 (s, 18H).

[1146] Preparation 55. Methyl (E)-3-(di-tert-butoxycarbonylamino)-6-(hydrazineylidenemethyl)-picolinate (P55) [ka] To a solution of P54 (402 mg, 1.06 mmol, 1.0 equivalent) in methanol (9 ml), hydrazine monohydrate (63.5 mg, 1.27 mol, 1.2 equivalents) was added at room temperature, and the mixed solution was stirred at room temperature for 4 hours. The solution was concentrated under vacuum to obtain P55 (428 mg) as a yellow solid, which was used in the next step without purification.

[1147] Preparation 56. Methyl 3-(di-tert-butoxycarbonylamino)-6-(2,2,2-trifluoroethyl)picolinate (P56) [ka] To a solution of P55 (428 mg, 1.08 mmol, 1.0 equivalent) in DM...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula] X １ , X ２ , X ３ , X ４ , X ５ , and X ６ Each is independently selected from CH or N; X １ , X ２ , X ３ , X ４ , X ５ and X ６ at least one of which is N; W is -CN; Alternatively, W and ring B, together with the atoms to which they are bonded and any intervening atoms, form a 5-10 membered heterocycle; Each R １ is halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkynyl, heterocyclic, aryl, heteroaryl, OH, NH ２ , NHCH ３ , and N(CH ３ ) ２ Independently selected from, the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, chloroalkyl, aryl, or heteroaryl is halogen, OH, NR ９ R １０ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; Each R ２ These are halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR ９ R １０ , C ３ -C １０ Independently selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; L is (CR ５ ２ ) ｑ , (CR ５ ２ ) ｑ O, (CR ５ ２ ) ｑ S(O) ｓ and (CR ５ ２ ) ｑ Selected from C(O); R ３ is hydrogen, deuterium, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, heterocyclyl, aryl, heteroaryl and L ４ Selected from; L ４ teeth, 【Chemistry 2】 And; L ５ (CR ５ ２ ) ｑ , (CR ５ ２ ) ｑ O, (CR ５ ２ ) ｑ S(O) ｓ and (CR ５ ２ ) ｑ Selected from C(O); Ring B is C ３ -C １４ is selected from cycloalkyl, 3- to 10-membered heterocyclic ring, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic ring, aryl or heteroaryl is substituted with halogen, CN, NO ２ , oxo, OH, NR ９ R １０ , C １ -C ６ alkyl, C １ -C ６ is optionally substituted with one or more substituents independently selected from alkoxy, cycloalkyl, heterocyclic ring, aryl and heteroaryl; R ４ is selected from H, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C １０ cycloalkyl, C １ -C ６ alkyl-C １ -C ６ alkoxy, C(O)R ７ , heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH ２ , C １ -C ６ alkyl, and C １ -C ６ alkoxy; Each R ５ H, halogen, CN, OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Selected independently from cycloalkyl; R ６ H, C １ -C ６ Alkyl, -C(O)R ７ ,-NHC(O)R ７ , S(O) ｓ R １１ , -NHS(O) ｓ R １１ , -NHS(O) ２ NR ９ R １０ , 【Transformation 3】 , C ３ -C １０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ -C ６ Alkanjil C ３ -C １０ Cycloalkyl, C １ -C ６ Alkanediyl heterocyclyl, C １ -C ６ Alkanediylaryl and C １ -C ６ Selected from alkanediyl heteroaryls, alkyl, cycloalkyl, aryl, or heteroaryl, halogen, CN, NO ２ , oxo, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R ７ R ８ , OR ８ NR ９ R １０ Selected from, R ８ H, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Selected from cycloalkyl, alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH, CN, NO ２ NR ９ R １０ Optionally substituted with one or more substituents independently selected from; Each R ９ and R １０ H and C are independent of each other. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is a halogen, OH, or NH ２ , C １ -C ６ Alkyl and C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; Alternatively, R ９ and R １０ Together with the atoms to which they are bonded and any intervening atoms, they form a 3-14 membered heterocycle; R １１ C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkoxy, NR ９ R １０ Selected from; m and n are integers independently selected from 1, 2, and 3, respectively; p is an integer selected from 0, 1, and 2; r is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, 3, and 4; s is an integer selected from 0, 1, and 2; Cycloalkyls are monocyclic or polycyclic saturated carbocyclic rings containing 3–18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having one to three aromatic rings; A heterocyclyl is a saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridging, or spirocyclic), or 11-14 member tricyclic system (fused, bridging, or spirocyclic) having one or more heteroatoms selected from O, N, S, P, Se, or B; A heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being carbon.

2. The aforementioned compound is of formula (I'). 【Chemistry 4】 、 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

3. The compound is of formula (I-A), (I-B), (I-C), or (I-D): 【Transformation 5】 【Transformation 6】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

4. The compounds are those of the formulas (I-A'), (I-B'), (I-C'), and (I-D'): 【Transformation 7】 【Transformation 8】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

5. The compound is of the formula (I-I), (I-II), (I-III), (I-IV), (I-V), (I-VI), or (I-VII): 【Chemistry 9】 【Chemistry 10】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

6. The compound is of the formula (I-I'), (I-II'), (I-III'), (I-IV'), (I-V'), (I-VI'), or (I-VII'): 【Chemistry 11】 【Chemistry 12-1】 【Chemistry 12-2】 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

7. R ３ However, the following: A compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, selected from the above.

8. The compound is (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), or (I-i): 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

9. A compound selected from the following: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, further comprising one or more additional pharmaceutically active agents.

12. A method for inhibiting the interaction between menin and MLL in cells, comprising contacting the cells with a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11.

13. A method for inhibiting the interaction between menin and MLL1 in cells, comprising contacting the cells with a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11.

14. The method according to claim 12 or 13, wherein the contact is in vitro or in vivo.

15. A method for treating or preventing a disease or disorder related to the interaction of menin and MLL, comprising administering a compound according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 or 11, to a subject in need thereof.

16. The method according to claim 15, wherein the disease or disorder is selected from the group consisting of leukemia, hematological malignancies, solid tumors, prostate cancer, breast cancer, liver cancer, brain tumors, and diabetes.

17. The method according to claim 16, wherein the leukemia is selected from the group consisting of AML, ALL, mixed-series leukemia, and leukemia with partial tandem overlap of MLL.

18. The method according to any one of claims 12 to 17, wherein the subject is a mammal.

19. The method according to claim 18, wherein the subject is a human being.

20. The following compounds can be selected:

21. The following compounds can be selected:

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