Inhibitors of menin-MLL interaction

Abstract

To provide inhibitors of the interaction of menin and MLL that are useful in the treatment of diseases or disorders associated with menin-MLL interaction, such as cancer.SOLUTION: Provided are compounds and pharmaceutical compositions inhibiting / blocking menin-MLL interaction represented by the following structural formula, methods of treating diseases or disorders associated with menin-MLL interaction, and methods of synthesizing these compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 287,716, entitled "Inhibitors of Menin-MLL Interaction," filed December 9, 2021, U.S. Provisional Patent Application No. 63 / 306,399, entitled "Inhibitors of Menin-MLL Interaction," filed February 3, 2022, and U.S. Provisional Patent Application No. 63 / 397,322, entitled "Inhibitors of Menin-MLL Interaction," filed August 11, 2022, the disclosures of which are incorporated herein by reference in their entireties for all purposes.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates to inhibitors of the interaction between menin and MLL. The inhibitors described herein may be useful for treating diseases or disorders associated with menin-MLL interaction, such as cancer. In particular, the present 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) Translocations of the MLL (mixed lineage leukemia) gene occur frequently in aggressive human acute myeloid and lymphoid leukemia in both children and adults. Fusion of MLL with one of over 60 different genes results in chimeric MLL fusion proteins that promote proliferation and inhibit hematopoietic differentiation, ultimately leading to acute leukemia. Patients with leukemia harboring MLL translocations have an extremely poor prognosis and rarely respond to currently available treatments. The risk of relapse with conventional chemotherapy and stem cell transplantation is very high, with an overall 5-year survival rate of only approximately 35% of patients.

[0004] Menin is an essential cofactor for oncogenic MLL fusion proteins, and the menin-MLL interaction is critical 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 peptidomimetic inhibitors, demonstrate the feasibility of targeting the menin-MLL interaction. However, biochemical and structural studies have revealed that MLL binds to menin in a complex bivalent mode involving two MLL motifs, making inhibition of this protein-protein interaction challenging.

[0005] Chromosomal rearrangements of the MLL gene, located at chromosome band 11q23, are observed in patients with de novo acute myeloid (AML) and acute lymphoblastic (ALL) leukemia, as well as in patients with therapy-related leukemia or myelodysplastic syndromes (MDS). As a result of chromosomal translocations, the MLL gene fuses with one of over 60 different protein partners, most frequently AF4, AF9, ENL, AF6, ELL, and AF10. Disruption of MLL by gene fusion upregulates the expression of the HOXA9 and MEIS1 genes, which are critical for leukemogenesis. The role of HOXA genes in leukemic transformation has been validated in both in vitro and in vivo models, showing that MLL fusion protein-mediated upregulation of HOXA9 and MEIS1 leads to increased proliferation and blockage of hematopoietic differentiation, ultimately leading to acute leukemia. The extremely poor prognosis for patients with MLL translocation leukemia (3-year event-free survival of 20%) and poor response to available treatments highlight the need for new therapies.

[0006] The oncogenic function of MLL fusion proteins critically depends on direct interaction with menin. Menin is a 67-kDa protein encoded by the MEN1 (multiple endocrine neoplasia type 1) gene located on chromosome 11q13. Menin is a ubiquitously 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 key role in recruiting MLL and MLL fusions to target genes, including HOXA9. Loss of menin binding by MLL fusion proteins abolishes their oncogenic properties in vitro and in vivo. Mutations within the N-terminus of the MLL-ENL oncoprotein result in the protein's inability to bind menin, abolishing its ability to upregulate Hox gene expression and inducing leukemia in mice. Expression of a dominant-negative inhibitor consisting of the amino-terminal MLL sequence inhibits proliferation of MLL-AF9-transformed bone marrow cells and blocks leukemic transformation.

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

[0008] Blocking menin-MLL interactions is a viable approach to reversing the oncogenic activity of MLL fusion proteins in leukemia and may lead to new therapeutic approaches. Summary of the Invention

[0009] (overview) A first aspect of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein 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 is N; W is -CN; or W and ring B, together with the atoms to which they are attached and any intervening atoms, form a 5-10 membered heterocyclic ring; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, NH2, NHCH3, and N(CH3)2, and alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from 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, heterocycle, aryl, heteroaryl; Each R 2 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, 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 C(O); R 3 is hydrogen, deuterium, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 Selected from; L 4 teeth, [ka] and; L 5 is (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q C(O); Ring B is C3-C 14 cycloalkyl, 3- to 10-membered heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO, oxo, OH, NR 9 R 10 , optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl; R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 , heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH, C1-C6 alkyl, and C1-C6 alkoxy; Each R 5 is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10independently selected from cycloalkyl; R 6 is H, C1-C6 alkyl, -C(O)R 7 , -NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 selected from cycloalkyl, C1-C6 alkanediylheterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediylheteroaryl, wherein 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, heterocycle, aryl, and heteroaryl; R 7 is R 8 , OR 8 , N.R. 9 R 10 is selected from R 8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is selected from halogen, OH, CN, NO2, NR 9 R 10 optionally substituted with one or more substituents independently selected from: Each R 9 and R 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10a cycloalkyl, aryl, heteroaryl, or heterocycle, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NH, C-C alkyl, and C-C alkoxy; Alternatively, R 9 and R 10 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered heterocyclic ring; R 11 is C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from; m and n are each integers independently selected from 1, 2, and 3; 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; Cycloalkyl is a mono- or polycyclic saturated carbocyclic ring containing 3-18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) 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 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 the present 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 comprise an excipient, diluent, or surfactant.

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

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

[0014] Another aspect of the present 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 associated with the inhibition of the interaction between menin and MLL.

[0015] Another aspect of the present disclosure pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0016] Another aspect of the present disclosure relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0017] Another aspect of the present 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 present disclosure further provides a method of treating a disease or disorder associated with the interaction of menin and MLL, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] The present disclosure provides inhibitors of the interaction between menin and MLL that are therapeutic agents in the treatment of diseases and disorders.

[0020] The present disclosure further provides compounds and compositions with improved efficacy and safety profiles compared to known inhibitors of the interaction between menin and MLL. The present disclosure also provides agents with novel mechanisms of action on the interaction between menin and MLL in the treatment of various types of diseases.

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

[0022] The present disclosure provides inhibitors of the interaction between menin and MLL that are therapeutic agents in the treatment of diseases and disorders.

[0023] The present disclosure further provides a method of 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 said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] In some aspects, the disclosure provides compounds obtainable by or obtainable by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in General Procedures A or B).

[0025] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in the preparative examples described herein below).

[0026] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0027] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure, comprising one or more steps described herein.

[0028] 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.In this specification, the singular form also includes the plural form unless the context clearly dictates otherwise.Methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, and suitable methods and materials are described below.In addition, materials, methods, and examples are merely illustrative and are not intended to be limiting.If the chemical structure and name of a compound disclosed herein are inconsistent, the chemical structure shall prevail.

[0029] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0030] (Detailed explanation) The present disclosure provides methods for treating, preventing, or ameliorating a disease or disorder associated with inhibition of the interaction of menin and MLL1 by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0031] Details of the present disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will become apparent from the specification and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates 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] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

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

[0034] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, —OH, —CN, —COOH, —CHCN, —O—(C-C)alkyl, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, —O—(C-C)alkenyl, —O—(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, —OH, —OP(O )(OH), —OC(O)(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH((C-C)alkyl), —N((C-C)alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is described below.

[0035] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl indicates that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0036] As used herein, the term "unsubstituted" means that the particular group bears no 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. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, -NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0038] Unless otherwise defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 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. Polycyclic aromatic radicals can contain two or more fused rings and can further contain two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" refers to two rings that share two ring atoms. Unless otherwise specified, "spiro-fused" refers to two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radicals may be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, 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 ... lo[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, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, 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]pyrimidinyl, tetrahydropyridinyl Furo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl Lysinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[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]imidazol-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,

[0023] In addition, when containing two or more fused rings, the heteroaryl group 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 ring may be further fused with a saturated or partially unsaturated ring as described herein. In addition, when containing three or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings spiro-fused. Any saturated or partially unsaturated ring as described herein may be optionally substituted with one or more oxo. 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, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyra pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

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

[0040] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 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, neo-pentyl, and isohexyl.

[0041] "Alkoxy" refers to a straight or branched chain 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] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0043] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "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 term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

[0045] "Cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3-18 carbon atoms. Polycyclic cycloalkyls may be fused bicyclic cycloalkyls, bridged bicyclic cycloalkyls, or spiro-fused bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyl groups 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," "heterocycle," or "heterocycloalkyl" containing 3-24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, is monocyclic or polycyclic, and wherein the ring is not aromatic. The heterocycloalkyl ring structure may be substituted with one or more substituents. Polycyclic heterocycloalkyls contain at least one non-aromatic ring. Polycyclic heterocyclic compounds can be bridged, fused, or spirofused. The substituents may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, homotropanyl, 2-oxa-5-azabicyclo[2.2.2]octane, and 2,6-diazaspiro[3.3]heptanyl.

[0047] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of linked p-orbitals with delocalized electrons, which may contain lone pairs of electrons.

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

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

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

[0051] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-based bicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or may be identical in size and nature. 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 replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced with a heteroatom.

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

[0053] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For purposes of this disclosure, such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0054] As used herein, the term "alkyl-aryl" (and variations thereof, e.g., C1-C6 alkyl-aryl) refers to a chemical moiety comprising an alkyl group covalently bonded to an aryl group, where the bond to the rest of the molecule is on the first group described, i.e., the alkyl group. Similarly, alkyl-alkoxy refers to a chemical moiety comprising an alkyl group covalently bonded to an alkoxy group, where the bond to the rest of the molecule is 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, C alkyl-phenyl is: [ka] C2 alkenyl-furanyl refers to [ka] C1 alkyl-C2 alkoxy refers to [ka] For example, it refers to

[0056] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0057] The present disclosure also provides isotopically labeled compounds of Formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents in accordance with procedures similar to those disclosed in the following schemes and / or examples.

[0058] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "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, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, and hydrochloride. , hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0059] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0060] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject as described herein.

[0061] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0062] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

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

[0064] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, allowing an equivalent amount of active compound to form in the subject's body.

[0065] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0066] The term "salt" means a pharmaceutically acceptable salt.

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

[0068] As used herein, a "menin / 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 menin and MLL.

[0069] The amount of the compound of the composition described herein required to achieve a therapeutic effect can be empirically determined according to conventional procedures for a particular purpose. Generally, when administering a therapeutic agent (e.g., a compound of Formula I or a composition described herein (and / or an additional agent)) for therapeutic purposes, the therapeutic agent is given in a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or achieve a desired result, 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 symptoms of the disease), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse symptoms of a disorder or disease. For example, administering a therapeutic agent to a subject suffering from cancer provides a therapeutic benefit not only if the underlying condition is eradicated or improved, but also if the subject reports a decrease in the severity or duration of symptoms associated with the disease, such as a decrease in tumor burden, a decrease in circulating tumor cells, or an increase in progression-free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is achieved. Compounds of the Disclosure

[0070] In various embodiments, the inhibitor of menin-MML interaction is a compound having a structure represented by formula (I): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein 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 is N; W is -CN; or W and ring B, together with the atoms to which they are attached and any intervening atoms, form a 5-10 membered heterocyclic ring; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, OH, NH2, NHCH3, and N(CH3)2, and alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from 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, heterocycle, aryl, heteroaryl; Each R 2 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, 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 C(O); R 3 is hydrogen, deuterium, C1-C6 alkyl, C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 Selected from; L 4 teeth, [ka] and; L 5 is (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q C(O); Ring B is C3-C 14 cycloalkyl, 3- to 10-membered heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO, oxo, OH, NR 9 R 10 , optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl; R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 , 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, NH, C-C alkyl, and C-C alkoxy; Each R 5 is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 independently selected from cycloalkyl; R 6 is H, C1-C6 alkyl, -C(O)R 7 , -NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 selected from cycloalkyl, C1-C6 alkanediylheterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediylheteroaryl, wherein 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, heterocycle, aryl, and heteroaryl; R 7 is R 8 , OR 8 , N.R. 9 R 10 is selected from R 8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is selected from halogen, OH, CN, NO2, NR9 R 10 optionally substituted with one or more substituents independently selected from: Each R 9 and R 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 a cycloalkyl, aryl, heteroaryl, or heterocycle, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NH, C-C alkyl, and C-C alkoxy; Alternatively, R 9 and R 10 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered heterocyclic ring; R 11 is C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from; m and n are each integers independently selected from 1, 2, and 3; 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 a 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 to 3 aromatic rings; heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) 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 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.

[0072] In one aspect, the disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [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 compounds 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 can each be selected from groups described herein, where applicable; 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 It is understood that the groups described herein for any of m, n, p, r, q, and s can 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 one or more of the remaining , m, n, p, r, q, and 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 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 is N; W is -CN; or W and ring B, together with the atoms to which they are attached and any intervening atoms, form a 5-10 membered heterocyclic ring; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, 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; and alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from 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, heterocycle, aryl, heteroaryl; Each R 2 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, 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 C(O); R 3 is hydrogen, deuterium, C1-C6 alkyl, C3-C 10Cycloalkyl, heterocyclyl, aryl, heteroaryl and L 4 Selected from; L 4 teeth, [ka] and; L 5 is (CR 5 2) q , (CR 5 2) q O, (CR 5 2) q S(O) s and (CR 5 2) q C(O); Ring B is C3-C 14 cycloalkyl, 3- to 10-membered heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, CN, NO, oxo, OH, NR 9 R 10 , optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl; R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 , heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH, C1-C6 alkyl, and C1-C6 alkoxy; Each R 5 is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 independently selected from cycloalkyl; R 6is H, C1-C6 alkyl, -C(O)R 7 , -NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 selected from cycloalkyl, C1-C6 alkanediylheterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediylheteroaryl, wherein 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, heterocycle, aryl, and heteroaryl; R 7 is R 8 , OR 8 , N.R. 9 R 10 is selected from R 8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, wherein alkyl, alkenyl, alkynyl or cycloalkyl is selected from halogen, OH, CN, NO2, NR 9 R 10 optionally substituted with one or more substituents independently selected from: Each R 9 and R 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10a cycloalkyl, aryl, heteroaryl, or heterocycle, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, NH, C-C alkyl, and C-C alkoxy; Alternatively, R 9 and R 10 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered heterocyclic ring; R 11 is C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkoxy, NR 9 R 10 Selected from; m and n are each integers independently selected from 1, 2, and 3; 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 is independently selected from CH or N; 1 , X 2 , X 3 , X 4 , X 5 , and X 6 At least one of is N.

[0076] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 each is independently selected from CH or N; 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 is independently selected from CH or N; 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 is independently selected from CH or N; 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 is CH or N.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0107] In some embodiments, X 6 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 the is N and X 2 , X 3 , X 4 and X 5 each is CH, and each H is optionally R 1 is replaced by

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

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

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

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

[0114] In some embodiments, X 1 and X 6 Each of the is N and X 2 , X 3 , and X 5 Each of the is CH and X 4 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 the is N and X 1 , X 2 , X 3 and X 4 each is CH, and each H is optionally R 1 is replaced by

[0117] In some embodiments, X 5 and X 6 Each of the is N and X 1 , X 2 , X 3 and X 4 Each of these 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 the is N and X 2 , X 3 , X 4 and X 6 each is CH, and each H is optionally R 1 is replaced by

[0120] In some embodiments, X 1 and X 5 Each of the is N and X 2 , X 3 , X 4 and X 6 Each of these 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 the is N and X 2 , X 3 , and X 5 each is CH, and each H is optionally R 1 is replaced by

[0123] In some embodiments, X 1 , X 4 and X 6 Each of the is N and X 2 , X 3 , and X 5 Each of these 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 the is N and X 2 , X 4 , and X 5 each is CH, and each H is optionally R 1 is replaced by

[0126] In some embodiments, X 1 , X 3 and X6 Each of the is N and X 2 , X 4 , and X 5 Each of these 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 the is N and X 3 , X 4 , and X 5 each is CH, and each H is optionally R 1 is replaced by

[0129] In some embodiments, X 1 , X 2 and X 6 Each of the is N and X 3 , X 4 , and X 5 Each of these 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 the is N and X 3 and X 5 each is CH, and each H is optionally R 1 is replaced by

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

[0133] In some embodiments, each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, 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 and alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is independently selected from 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, heterocycle, aryl, heteroaryl;

[0134] In some embodiments, R 1 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 is I.

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

[0137] In some embodiments, each R 1 is C3-C 10In some embodiments, each R is independently selected from cycloalkyl, heterocycle, aryl, heteroaryl, C-C alkyl-aryl, C-C alkyl-heteroaryl, C-C alkenyl-aryl, C-C alkenyl-heteroaryl, C-C alkynyl-aryl, and C-C alkynyl-heteroaryl. 1 is C3-C 10 Independently selected from cycloalkyl, heterocycle, aryl, and heteroaryl.

[0138] In some embodiments, each R 1 is independently selected from C1-C6 alkyl and C1-C6 alkoxy. In some embodiments, each R 1 is C3-C 10 In some embodiments, each R 1 is independently selected from heterocycle and heteroaryl.

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

[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 iso-propyl. 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 pentyl. In some embodiments, R1 is hexyl.

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

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

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

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

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

[0146] In some embodiments, R 1 is a monocyclic C3-C 10 In some embodiments, R 1 is a polycyclic C3-C 10 It is cycloalkyl.

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

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

[0149] In some embodiments, R 1 is a fused polycyclic C3-C 10 In some embodiments, R 1 is a bridged polycyclic C3-C 10 In some embodiments, R 1 is C3-C 10 It is a spirocycloalkyl.

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

[0151] In some embodiments, R 1 is C alkenyl. In some embodiments, R 1 is C alkenyl. In some embodiments, R 1 is C4 alkenyl. In some embodiments, R 1 is C alkenyl. In some embodiments, R 1 is a C6 alkenyl.

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

[0153] In some embodiments, R 1 is C alkynyl. In some embodiments, R 1 is C alkynyl. In some embodiments, R 1 is C4 alkynyl. In some embodiments, R 1 is a C5 alkynyl. In some embodiments, R 1 is a C6 alkynyl.

[0154] In some embodiments, R 1 is a heterocycle. In some embodiments, R 1 is a 3-10 membered heterocycle. In some embodiments, R 1 is a heterocycle containing 1, 2, or 3 heteroatoms. In some embodiments, R 1 is a 3-10 membered heterocycle containing 1, 2 or 3 heteroatoms.

[0155] In some embodiments, R 1 is a monocyclic heterocycle. In some embodiments, R 1 is a polycyclic heterocycle.

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

[0157] In some embodiments, R 1 is a 5- to 6-membered heterocycle.

[0158] In some embodiments, R 1 is aryl.

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

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

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

[0162] In some embodiments, R 1 is methyl-aryl. In some embodiments, R 1 is ethyl-aryl. In some embodiments, R 1 is propyl-aryl. In some embodiments, R 1 is n-propyl-aryl. 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 is isobutyl-aryl. 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 is hexyl-aryl.

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

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

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

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

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

[0168] In some embodiments, R 1 is C alkenyl-heteroaryl. In some embodiments, R 1 is C alkenyl-heteroaryl. In some embodiments, R 1 is C4 alkenyl-heteroaryl. In some embodiments, R 1 is C alkenyl-heteroaryl. In some embodiments, R 1 is a C6 alkenyl-heteroaryl.

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

[0170] In some embodiments, R 1 is C alkynyl-aryl. In some embodiments, R 1 is C alkynyl-aryl. In some embodiments, R 1 is C4 alkynyl-aryl. In some embodiments, R 1 is a C5 alkynyl-aryl. In some embodiments, R 1 is a C6 alkynyl-aryl.

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

[0172] In some embodiments, R 1 is C alkynyl-heteroaryl. In some embodiments, R 1 is a C 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 is a C6 alkynyl-heteroaryl.

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

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

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

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

[0177] In some embodiments, R 1 is C1-C6 alkyl substituted with one or more F. In some embodiments, R 1 is methyl substituted with one or more F. In some embodiments, R 1 is ethyl substituted with one or more F. In some embodiments, R 1 is propyl substituted with one or more F. In some embodiments, R 1 is n-propyl substituted with one or more F. In some embodiments, R 1 is iso-propyl 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 pentyl substituted with one or more F. In some embodiments, R 1 is hexyl substituted with one or more F.

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

[0179] In some embodiments, R 1 is —CH 2 CF 3 . In some embodiments, R 1 is -CF2CF3.

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

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

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

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

[0184] In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more halogens. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more F. In some embodiments, R 1is C1-C6 alkoxy substituted with one or more Cl. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more Br. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more I. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more OH. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more NH2. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more C1-C6 alkoxy. In some embodiments, R 1 is one or more NR 12 R 13 In some embodiments, R 1 is one or more C3-C 10 In some embodiments, R is C1-C6 alkoxy substituted with cycloalkyl. 1 is C1-C6 alkoxy substituted with one or more C2-C6 alkenyl. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more C2-C6 alkynyl. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more heterocycles. In some embodiments, R 1 is C1-C6 alkoxy substituted with aryl. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more heteroaryls.

[0185] In some embodiments, R 1 is a C3-C substituted with one or more halogens 10 In some embodiments, R 1 is C3-C substituted with one or more F 10In some embodiments, R 1 is C3-C substituted with one or more Cl groups 10 In some embodiments, R 1 is C3-C substituted with one or more Br 10 In some embodiments, R 1 is C3-C substituted with one or more I 10 In some embodiments, R 1 is C3-C substituted with one or more OH 10 In some embodiments, R 1 is a C3-C substituted with one or more NH2 10 In some embodiments, R 1 is a C3-C substituted with one or more C1-C6 alkyls 10 In some embodiments, R 1 is a C3-C substituted with one or more C1-C6 alkoxy groups 10 In some embodiments, R 1 is one or more NR 12 R 13 C3-C substituted with 10 In some embodiments, R 1 is one or more C3-C 10 Cycloalkyl-substituted C3-C 10 In some embodiments, R 1 is a C3-C substituted with one or more C2-C6 alkenyls 10 In some embodiments, R 1 is a C3-C substituted with one or more C2-C6 alkynyls 10 In some embodiments, R 1 is a C3-C substituted with one or more heterocycles 10 In some embodiments, R 1 is a C3-C substituted with one or more aryls 10In some embodiments, R 1 is a C3-C substituted with one or more heteroaryls 10 It is cycloalkyl.

[0186] In some embodiments, R 1 is C-C alkenyl substituted with one or more halogens. In some embodiments, R 1 is C2-C6 alkenyl substituted with F. In some embodiments, R 1 is C-C alkenyl substituted with one or more Cl. In some embodiments, R 1 is C-C 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. In some embodiments, R 1 is a C-C alkenyl substituted with one or more NH. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more C1-C6 alkyl. In some embodiments, R 1 is C-C alkenyl substituted with one or more C-C alkoxy. In some embodiments, R 1 is one or more NR 12 R 13 In some embodiments, R is a C-C alkenyl substituted with 1 is one or more C3-C 10 In some embodiments, R is a C-C alkenyl substituted with cycloalkyl. 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 C-C alkenyl substituted with one or more heterocycles. In some embodiments, R 1is a C2-C6 alkenyl substituted with one or more aryl. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more heteroaryls.

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

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

[0189] In some embodiments, R 1 is aryl substituted with one or more halogens. In some embodiments, R 1 is an aryl substituted with one or more heteroaryls.

[0190] In some embodiments, R 1 is heteroaryl substituted with one or more halogens. In some embodiments, R 1 is heteroaryl substituted with one or more heteroaryls.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0207] In some embodiments, R 1 is unsubstituted C1-C6 alkyl. In some embodiments, R 1 is unsubstituted C1-C6 alkoxy. In some embodiments, R 1 is unsubstituted C3-C 10 In some embodiments, R 1 is unsubstituted C-C alkenyl. In some embodiments, R 1 is an unsubstituted C2-C6 alkynyl. In some embodiments, R 1 is an unsubstituted heterocycle. In some embodiments, R 1 is unsubstituted aryl. In some embodiments, R 1 is unsubstituted heteroaryl. In some embodiments, R 1 is an unsubstituted C1-C6 alkyl-aryl. In some embodiments, R 1 is an unsubstituted C1-C6 alkyl-heteroaryl. In some embodiments, R 1 is an unsubstituted C-C alkenyl-aryl. In some embodiments, R 1 is an unsubstituted C-C alkenyl-heteroaryl. In some embodiments, R 1 is an unsubstituted C2-C6 alkynyl-aryl. In some embodiments, R 1 is an unsubstituted C2-C6 alkynyl-heteroaryl.

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

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

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

[0211] In some embodiments, R 1 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 C(O).

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

[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 is.

[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's 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 It is 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: [ka] .

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

[0226] In some embodiments, L is (CR 5 2) q S(O) s and the compound is of formula I-3: [ka] s is an integer selected from 0, 1, or 2 for different oxidation stages of the sulfur atom;

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

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

[0229] In some embodiments, L is (CR 5 2) q C(O) and the compound 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 bond.

[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] In some embodiments, each R 5 is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl.

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

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

[0242] In some embodiments, R 5 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 )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 )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 )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 )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] In some embodiments, each R 2 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 9 R 10 , C3-C 10 Independently selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0296] In some embodiments, R 2 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 is hexyl.

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

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

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

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

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

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

[0312] In some embodiments, R 2 is butoxy.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0326] In some embodiments, R 2 is aryl.

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

[0328] In some embodiments, R 3 is hydrogen, deuterium, C1-C6 alkyl, C3-C 10 cycloalkyl, and L 4 is selected from.

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

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

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

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

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

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

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

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

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

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

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

[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's S.

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

[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 is (CR5 2) q C(O).

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

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

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

[0351] In some embodiments, L 5 is (CR 5 2) q S(O)2 and the compound is 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 is a bond.

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

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

[0361] In some embodiments, each R 5 is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0425] In some embodiments, Ring B is an aryl, heteroaryl, a 3- to 8-membered heterocycle, or a C3-C 14 cycloalkyl, and the aryl, heteroaryl, heterocycle or cycloalkyl is halogen, CN, NO2, oxo, OH, NR 9 R 10、 Optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0426] In some embodiments, Ring B is aryl, and aryl is selected from halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0427] In some embodiments, Ring B is phenyl, and phenyl is selected from the group consisting of halogen, CN, NO, oxo, OH, NR 9 R10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0428] In some embodiments, ring B is benzenediyl, and benzenediyl is selected from the group consisting of halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0429] In some embodiments, ring B is benzenediyl-1,4, wherein benzenediyl-1,4 is selected from the group consisting of halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0430] In some embodiments, ring B is benzenediyl-1,3, wherein benzenediyl-1,3 is selected from the group consisting of halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0431] In some embodiments, Ring B is benzenediyl-1,2, wherein benzenediyl-1,2 is selected from the group consisting of halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[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 heteroaryl, wherein the heteroaryl is halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

[0438] In some embodiments, Ring B is heteroaryl.

[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 the ring heteroatom and the remaining ring atoms are C.

[0441] In some embodiments, Ring B is a monocyclic 5-membered heteroaryl containing two N as ring heteroatoms and the remaining ring atoms are 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 atoms being C.

[0443] In some embodiments, Ring B is a monocyclic 5-membered heteroaryl containing one O as a ring heteroatom and the remaining ring atoms are C.

[0444] In some embodiments, Ring B is a monocyclic 5-membered heteroaryl containing one S as a ring heteroatom and the remaining ring atoms are 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 the 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 atoms are C.

[0448] In some embodiments, Ring B is a monocyclic 6-membered heteroaryl containing three N as ring heteroatoms, and the remaining ring atoms are 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 as ring heteroatoms, and the remaining ring atoms are C.

[0452] In some embodiments, Ring B is a bicyclic 9-membered heteroaryl containing three N as ring heteroatoms, and the remaining ring atoms are C.

[0453] In some embodiments, Ring B is a bicyclic 9-membered heteroaryl containing one O as a ring heteroatom and the remaining ring atoms are C.

[0454] In some embodiments, Ring B is a bicyclic 9-membered heteroaryl containing one S as a ring heteroatom and the remaining ring atoms are 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 as ring heteroatoms, and the remaining ring atoms are C.

[0458] In some embodiments, Ring B is a bicyclic 10-membered heteroaryl containing three N as ring heteroatoms, and the remaining ring atoms are C.

[0459] In some embodiments, ring B is a 3- to 8-membered heterocycle, and the heterocycle is selected from the group consisting of halogen, CN, NO, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

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

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

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

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

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

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

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

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

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

[0469] In some embodiments, Ring B is a 5-membered heterocycle containing two N as ring heteroatoms, and the remaining ring atoms are C.

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

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

[0472] In some embodiments, Ring B is a 5-membered heterocycle containing one S as a ring heteroatom and the remaining ring atoms are C.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0490] In some embodiments, ring B is a 6-membered heterocycle 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] is.

[0492] In some embodiments, Ring B is a 7-membered heterocycle.

[0493] In some embodiments, Ring B is a monocyclic 7-membered heterocycle.

[0494] In some embodiments, Ring B is a monocyclic 7-membered heterocycle containing one N as the ring heteroatom and the remaining ring atoms are C.

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

[0496] In some embodiments, Ring B is a monocyclic 7-membered heterocycle containing two N as ring heteroatoms, and the remaining ring atoms are C.

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

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

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

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

[0501] In some embodiments, Ring B is a bicyclic 7-membered heterocycle.

[0502] In some embodiments, Ring B is a bicyclic 7-membered heterocycle containing two N as ring heteroatoms, and the remaining ring atoms are C.

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

[0504] In some embodiments, ring B is C3-C 14 Cycloalkyl, where cycloalkyl is halogen, CN, NO2, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle.

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

[0506] In some embodiments, Ring B is a fused bicyclic cycloalkyl.

[0507] In some embodiments, Ring B is a bridged bicyclic cycloalkyl.

[0508] In some embodiments, Ring B is a spiro bicyclic cycloalkyl.

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

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

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

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

[0513] In some embodiments, Ring B is a bridged bicyclic 5-membered cycloalkyl.

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

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

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

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

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

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

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

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

[0522] In some embodiments, R 6 is H, C1-C6 alkyl, -C(O)R 7 , -NHC(O)R 7 , S(O) s R 11 , -NHS(O) s R 11 , -NHS(O)NR 9 R 10 , [ka] , C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkanediyl C3-C 10 and selected from cycloalkyl, C1-C6 alkanediylheterocyclyl, C1-C6 alkanediylaryl, and C1-C6 alkanediylheteroaryl, wherein alkyl, cycloalkyl, aryl, or heteroaryl is selected from halogen, CN, NO2, oxo, OH, NR 9 R 10 , C 1 Optionally substituted with one or more substituents independently selected from -C6 alkyl, C1-C6 alkoxy, cycloalkyl, heterocycle, aryl, and heteroaryl.

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

[0524] In some embodiments, R 6 is C1-C6 alkyl, and alkyl is halogen, OH, CN, NR 9 R 10 , cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0542] In some embodiments, R 7 is R 8 , OR 8 , N.R. 9 R 10 is selected from.

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

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

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

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

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

[0548] In some embodiments, R 8 is C1-C6 alkyl, where alkyl is halogen, OH, CN, NO2, NR 9 R 10 and optionally substituted with one or more substituents independently selected from:

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

[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(CH). In some embodiments, R 8 is -CH2CH2CH2CH3. In some embodiments, R 8 is —CHCH(CH)2. In some embodiments, R 8 is pentyl. In some embodiments, R 8 is hexyl.

[0551] In some embodiments, R 8is C2-C6 alkenyl, where alkenyl is halogen, OH, CN, NO2, NR 9 R 10 and optionally substituted with one or more substituents independently selected from:

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

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

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

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

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

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

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

[0559] In some embodiments, R 8 is C3-C 10Cycloalkyl, where cycloalkyl is halogen, OH, CN, NO2, NR 9 R 10 and optionally substituted with one or more substituents independently selected from:

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

[0561] In some embodiments, R 7 is R 8 , OR 8 , N.R. 9 R 10 is selected from.

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

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

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

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

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

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

[0568] In some embodiments, R 8 is C1-C6 alkyl, where alkyl is halogen, OH, CN, NO2, NR 9 R 10 and optionally substituted with one or more substituents independently selected from:

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

[0570] In some embodiments, R 8 Methyl.

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

[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 is.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0598] In some embodiments, R 11 is a bicyclic C5-C 10 It is cycloalkyl.

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

[0600] In some embodiments, R 11 is a bicyclic bridged C5-C 10 It is cycloalkyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0618] In some embodiments, L 4 is selected from Table 1. JPEG2025170331000091.jpg200150JPEG2025170331000092.jpg223150JPEG2025170331000093.jpg66150

[0619] In some embodiments, R 4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C(O)R 7 , aryl, heteroaryl, or heterocycle, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle is selected from halogen, OH, NR 9 R 10 , C1-C6 alkyl, and C1-C6 alkoxy.

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

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

[0622] In some embodiments, R 4 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 attached and any intervening atoms, form a 5-10 membered heterocyclic ring.

[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 is halogen, CN, NO2, oxo, OH, NR 9 R 10 , C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycle; b is an integer selected from 0, 1, 2, 3, 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. JPEG2025170331000097.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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are as defined herein.

[0655] In some embodiments, the compound is of formula (I-II): JPEG2025170331000108.jpg65170, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are 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, where all variables are as defined herein.

[0676] In some embodiments, the compound is selected from Table 3, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein. JPEG2025170331000129.jpg184150JPEG2025170331000130.jpg218150JPEG2025170331000131.jpg217150JPEG2025170331000132.jpg211150JPEG2025170331000133.jpg218150JPEG2025170331000134.jpg218150JPEG2025170331000135.jpg218150JPEG2025170331000136.jpg218150JPEG2025170331000137.jpg218150JPEG2025170331000138.jpg218150JPEG2025170331000139.jpg218150JPEG2025170331000140.jpg218150JPEG2025170331000141.jpg200150JPEG2025170331000142.jpg221150JPEG2025170331000143.jpg212150JPEG2025170331000144.jpg221150JPEG2025170331000145.jpg221150JPEG2025170331000146.jpg212150JPEG2025170331000147.jpg221150JPEG2025170331000148.jpg221150JPEG2025170331000149.jpg212150JPEG2025170331000150.jpg221150JPEG2025170331000151.jpg221150JPEG2025170331000152.jpg187150JPEG2025170331000153.jpg198150JPEG2025170331000154.jpg198150JPEG2025170331000155.jpg198150JPEG2025170331000156.jpg198150JPEG2025170331000157.jpg198150JPEG2025170331000158.jpg198150JPEG2025170331000159.jpg198150JPEG2025170331000160.jpg198150JPEG2025170331000161.jpg198150JPEG2025170331000162.jpg198150JPEG2025170331000163.jpg198150JPEG2025170331 000164.jpg198150JPEG2025170331000165.jpg198150JPEG2025170331000166.jpg198150JPEG2025 170331000167.jpg198150JPEG2025170331000168.jpg216150JPEG2025170331000169.jpg216150JP EG2025170331000170.jpg216150JPEG2025170331000171.jpg216150JPEG2025170331000172.jpg21 6150JPEG2025170331000173.jpg216150JPEG2025170331000174.jpg216150JPEG202517033100017 5.jpg216150JPEG2025170331000176.jpg216150JPEG2025170331000177.jpg216150JPEG202517033 1000178.jpg216150JPEG2025170331000179.jpg216150JPEG2025170331000180.jpg216150JPEG202 5170331000181.jpg216150JPEG2025170331000182.jpg216150JPEG2025170331000183.jpg164150.

[0677] In some embodiments, the compound is selected from Table 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein. JPEG2025170331000184.jpg186150JPEG2025170331000185.jpg220150JPEG2025170331000186.jpg183150JPEG2025170331000187.jpg183150JPEG2025170331000188.jpg220150JPEG2025170331000189.jpg220150JPEG2025170331000190.jpg220150JPEG2025170331000191.jpg220150JPEG2025170331000192.jpg220150JPEG2025170331000193.jpg220150JPEG2025170331000194.jpg220150JPEG2025170331000195.jpg220150JPEG2025170331000196.jpg220150JPEG2025170331000197.jpg218150JPEG2025170331000198.jpg221150JPEG2025170331000199.jpg221150JPEG2025170331000200.jpg212150JPEG2025170331000201.jpg221150JPEG2025170331000202.jpg221150JPEG2025170331000203.jpg212150JPEG2025170331000204.jpg221150JPEG2025170331000205.jpg222150JPEG2025170331000206.jpg210150JPEG2025170331000207.jpg200150JPEG2025170331000208.jpg189150JPEG2025170331000209.jpg198150JPEG2025170331000210.jpg198150JPEG2025170331000211.jpg193150JPEG2025170331000212.jpg193150JPEG2025170331000213.jpg198150JPEG2025170331000214.jpg198150JPEG2025170331000215.jpg198150JPEG2025170331000216.jpg198150JPEG2025170331000217.jpg198150JPEG2025170331000218.jpg198150JPEG20251703310002 19.jpg198150JPEG2025170331000220.jpg198150JPEG2025170331000221.jpg198150JPEG20251703310 00222.jpg198150JPEG2025170331000223.jpg207150JPEG2025170331000224.jpg216150JPEG20251703 31000225.jpg216150JPEG2025170331000226.jpg219150JPEG2025170331000227.jpg216150JPEG202517 0331000228.jpg216150JPEG2025170331000229.jpg216150JPEG2025170331000230.jpg216150JPEG202 5170331000231.jpg216150JPEG2025170331000232.jpg216150JPEG2025170331000233.jpg216150JPEG2 025170331000234.jpg216150JPEG2025170331000235.jpg216150JPEG2025170331000236.jpg216150JP EG2025170331000237.jpg216150JPEG2025170331000238.jpg216150JPEG2025170331000239.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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 is selected from H, C1-C6 alkyl, aryl, heteroaryl, and all other variables are as defined herein.

[0748] In some embodiments, the compound is of 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, aryl, and heteroaryl).

[0769] In some embodiments, the compound is of 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 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 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 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, wherein G is selected from CH, O, S, NH, and all other variables are as defined herein.

[0774] In some embodiments, the compound is of 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, aryl, heteroaryl, and all other variables are as defined herein.

[0941] In some embodiments, the compound is of formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein 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 and M is selected from CH2, O, and NH, and all other variables are as defined herein.

[0943] In some embodiments, the compound is of the formula (In): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof (each R B is selected from H, C1-C6 alkyl, 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 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 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 set forth in Table 5, and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0959] In some embodiments, the compound is selected from the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0960] In some embodiments, the compound is selected from the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0961] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 5 and pharmaceutically acceptable salts thereof.

[0962] In some embodiments, the compound is selected from the compounds listed in Table 5.

[0963] JPEG2025170331000520.jpg219156JPEG2025170331000521.jpg211156JPEG2025170331000522.jpg218156JPEG2025170331000523.jpg21115 6JPEG2025170331000524.jpg204156JPEG2025170331000525.jpg211156JPEG2025170331000526.jpg182156JPEG2025170331000527.jpg18915 6JPEG2025170331000528.jpg211159JPEG2025170331000529.jpg211159JPEG2025170331000530.jpg211159JPEG2025170331000531.jpg21115 9JPEG2025170331000532.jpg211159JPEG2025170331000533.jpg211159JPEG2025170331000534.jpg175159JPEG2025170331000535.jpg89159

[0964] In some embodiments, the compound is the neutral form (ie, 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 set forth in Table 5.

[0966] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 5.

[0967] In some embodiments, the compound is the sodium or potassium salt of any one of the compounds listed in Table 5.

[0968] In some embodiments, the compound is the sodium salt of any one of the compounds listed in Table 5.

[0969] In some embodiments, the compound is the potassium salt of any one of the compounds listed in Table 5.

[0970] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0971] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 5, and prodrugs and pharmaceutically acceptable salts thereof.

[0972] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 5 and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0974] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5.

[0975] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0976] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0977] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0978] The term "isotopic derivative" as used herein refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched or labeled with respect to one or more atoms selected from S). 2 H).

[0979] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 5, and prodrugs and pharmaceutically acceptable salts thereof.

[0980] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 5, and pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof.

[0982] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 5.

[0983] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium 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 for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio of deuterium abundance to the natural abundance of deuterium.

[0985] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[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. 2 H) may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0987] In some embodiments, the compound is 18 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, 135I-labeled compounds, or any combination thereof.

[0989] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, 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 will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds generally utilize S-labeled compounds in place of non-isotopic labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 S-labeled reagents can be prepared by carrying out the procedures disclosed in the schemes 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 containing one or more S atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0992] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group encompasses the broadest definition appearing first, as well as each and every specific definition associated with that group.

[0993] The various functional groups and substituents that make up the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More usually, 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 the present disclosure are, for example, acid addition salts of compounds of the present 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, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0995] It will be understood that compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

[0996] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality 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" refers to a compound having at least one chiral center. Compounds with multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center were ranked according to the rules of Cahn, Ingold, and Prelog ordering. (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" refers to diastereomers that exist due to hindered rotation about 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, which indicate groups on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[1000] It is understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers, and when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude all isomeric forms, and it is understood that not all isomers have the same level of activity.

[1001] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers have the same level of activity.

[1002] As used herein, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist because of restricted rotation of large groups around a central bond, which prevents rotation. Such atropic isomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropic isomers in selected cases.

[1003] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. 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 interconvert by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) of a sugar molecule reacts with one of the hydroxyl groups (-OH) of the same molecule to give a cyclic (ring-shaped) form, as shown in glucose.

[1004] It should be understood that the compounds of the present disclosure can be represented as different tautomers. When a compound has tautomers, it is intended that all tautomers are included within the scope of the present disclosure, and it should also be understood that the naming of a compound does not exclude any tautomers. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[1005] Compounds of any one of the formulas disclosed herein can exist in many different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nevertheless encompassed by formula (I) or (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acid-nitro. [ka]

[1006] A non-limiting example of tautomerism in compounds of formula (I) is when the substituent R 1 Examples of compounds include compounds having the formula: [ka]

[1007] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called diastereomers, and stereoisomers that are not superimposable mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are called dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1008] The compounds of the present disclosure may have one or more asymmetric centers; such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is 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 resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

[1009] The present disclosure also encompasses compounds of the disclosure as defined herein that contain one or more isotopic substitutions.

[1010] It should be understood that the compounds of any formula described herein include, if applicable, the compounds themselves, as well as their salts and solvates.For example, salts can be formed between an anion on the substituted compounds disclosed herein and a positively charged group (e.g., amino).Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[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 and a negatively charged group (e.g., carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[1012] It is understood that compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc., and non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[1013] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.Some compounds tend to trap a certain molar ratio of solvent molecules in crystalline solid state to form solvates.When the solvent is water, the solvate that is formed is a hydrate; when the solvent is alcohol, the solvate that is formed is an alcoholate.Hydrates are formed by the combination of one molecule of a substance with one or more molecules of water, with water retaining its molecular state as HO.

[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., the replacement of one atom with an atom of a different element, or the replacement of one atom with the presence of a particular functional group, or the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but differs from the reference compound in structure or origin.

[1015] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[1016] As used herein, the term "bioisomer" 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 bioisosteric substitution is to generate a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be based on physicochemical or topology. Examples of carboxylic acid bioisosteres 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 also be understood that any one particular compound of formula disclosed herein can exist in solvated form and unsolvated form, for example, hydrated form.Suitable pharmaceutically acceptable solvate is, for example, hydrate such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[1018] It should also be understood that any one particular compound of the formula disclosed herein may exhibit polymorphism, and the present 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 analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, 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 containing an amine functional group can also form N-oxides. Herein, a reference to a compound of formula (I) or (II) containing an amine functional group also includes the N-oxide. When 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 the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be generated by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[1020] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is broken down in the human or animal body to release the disclosed compound.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.When the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached, a prodrug can be formed.Examples of prodrugs include derivatives of any one of the formulas disclosed herein that contain an alkyl or acyl substituent that can be cleaved in vivo on the ester or amide group.

[1021] Thus, the present disclosure includes those compounds of any of the above-defined formulas disclosed herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes those compounds of any of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, and the compounds of any of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[1022] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein are those that are based on sound medical judgment and are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, 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 Prodrugs”, by H. Bundgaard, pp. 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] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, their in vivo cleavable esters or ethers. In vivo cleavable esters or ethers containing a hydroxy group of compounds of any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 10 Examples of ring substituents for phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[1024] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C group such as methylamine, 1-4 alkylamines, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amides formed with amino acids such as glycine or its esters.

[1025] Suitable pharmaceutically acceptable prodrugs of any compound of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of ring substituents for the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[1026] The in vivo effects of a compound of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body after administration of a compound of any of the formulas disclosed herein. As mentioned above, the in vivo effects of a compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug). Compound synthesis method

[1027] The compounds of the present disclosure may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes shown below.

[1028] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed as needed in accordance with 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 of the compound synthesis using methods readily apparent to those skilled in the art. The presence or absence of a stereocenter in compounds of formula (I) will be recognizable to those skilled in the art by the selection process and reaction conditions and sequences. Therefore, the present disclosure (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When 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 can be affected 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 made from commercially available starting materials or can be synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[1030] The compounds of the present disclosure can be prepared by many methods well known to those skilled in the art of organic synthesis.For example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or by modifications thereof that will be understood by those skilled in the art.Suitable methods include, but are not limited to, those methods described below.The compounds of the present disclosure can be synthesized according to the steps outlined in General Procedure A or B, involving assembly intermediates or compounds of different sequences.Starting materials are commercially available or can be prepared by any of the known procedures reported in the literature, or as shown below. General Procedure

[1031] In general, compounds of formula (I) can be prepared using a reductive amination reaction between 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, compounds 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 from commercially available reagents. Compounds (A) and (B) can be prepared using one-step or multi-step synthetic methods, including but not limited to those described in the preparation section of this specification.

[1034] A non-limiting example of the preparation of compounds of formula (I) can be presented by reacting any one of compounds (A) with any one of compounds (B) listed in Table 6 under the conditions described herein or any other conditions for reductive amination known in the art. Table 6 JPEG2025170331000539.jpg216170JPEG2025170331000540.jpg255165JPEG2025170331 000541.jpg255170JPEG2025170331000542.jpg255168JPEG2025170331000543.jpg72170

[1035] It will be apparent to those skilled in the art that any of the compounds of formula (I) obtained according to the above procedures may be subject to further transformations and modifications leading to other compounds of formula (I).

[1036] As a specific, non-limiting example of further transformation of compounds of formula (I), the reaction of preparation of compound 97 (Example 15) from compound 68 (Example 9) can be presented: [ka] Biological assays

[1037] Once compounds designed, selected, and / or optimized by the above methods are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[1038] Furthermore, high-throughput screening can be used to speed up the analysis using such assays. As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the 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 can use one or more different assay technologies, 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 of the present disclosure, including, but 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 aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 5.

[1041] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[1042] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[1043] The formulation of the present disclosure may be in the form of an aqueous solution containing 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, isotonicity agents, viscosity / suspension agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[1044] Any suitable solubility enhancer can be used, including 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, and examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[1046] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[1047] In some embodiments, exemplary preservatives include quaternary ammonium salts, such as those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[1048] The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tonicity agent is selected from the group consisting of glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[1049] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and 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 adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and 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 a target acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, the mixture can be adjusted to the desired pH range by simply adding either an acid or a base.

[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 a salt thereof including disodium tetraborate), citrate buffer (such as citric acid or a salt thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[1052] The formulation may further comprise 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, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[1053] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can also be enclosed 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, troches, 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, swished, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose, a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, orange flavoring, and the like.

[1054] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present 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 can further comprise one or more additional pharmaceutically active agents.

[1056] The compositions of the disclosure may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel, aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by inhalation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[1057] The disclosed compositions can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[1058] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the MLL-associated conditions referred to herein.

[1059] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with an MLL-associated condition referred to herein.

[1060] The magnitude of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles. How to use

[1061] In some aspects, the present disclosure provides a method of inhibiting the interaction of menin and MLL (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[1062] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1063] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1064] In some embodiments, the disease or disorder is associated with MLL, ie, a disease or disorder involving menin-MLL binding.

[1065] The compounds of the present disclosure are inhibitors of the interaction between menin and MLL or MLL fusion proteins. In some embodiments, the present disclosure relates to methods for inhibiting the interaction between menin and MLL or MLL fusion proteins by contacting the menin and MLL or MLL fusion proteins with a compound of the present disclosure. The contacting can be performed in vitro or in vivo. In some embodiments, the compounds of the present disclosure can bind to menin, thereby preventing MLL from binding to menin. In some embodiments, the present disclosure provides methods for inhibiting the activity of menin by contacting menin with a compound of the present disclosure in the presence of MLL or MLL fusion proteins. In further embodiments, the present disclosure provides methods for inhibiting the binding of MLL or MLL fusion proteins to menin, comprising contacting menin with a compound of the present disclosure in the presence of MLL or MLL fusion proteins.

[1066] The compounds of the present disclosure are also useful for treating diseases associated with menin-MLL interaction or menin-MLL fusion protein interaction. For example, diseases and conditions treatable according to the methods of the present disclosure include cancer, such as leukemia, and other diseases or disorders mediated by menin-MLL interaction or menin-MLL fusion protein interaction, such as diabetes.

[1067] In some embodiments, the disease or disorder is selected from the group consisting of leukemia, hematological malignancies, solid tumor cancers, prostate cancer, breast cancer, liver cancer, brain cancer, and diabetes. In some embodiments, the leukemia is selected from the group consisting of AML, ALL, mixed lineage leukemia, and leukemia with partial tandem duplication of MLL.

[1068] In some embodiments, the disease or disorder is cancer.

[1069] In some embodiments, the cancer is selected from blood cancers (e.g., leukemia and lymphoma), bladder cancer, brain cancer (e.g., glioma), diffuse intrinsic pontine glioma (DIPG), breast cancer (e.g., triple-negative breast cancer), colon cancer, cervical cancer, gastrointestinal cancer (e.g., colon cancer, gastric cancer), genitourinary cancer, head and neck cancer, 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 cancer. In some embodiments, the cancer is a cardiac cancer, e.g., a sarcoma (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; a lung cancer, e.g., a bronchial carcinoma (e.g., squamous cell, small undifferentiated cell, large undifferentiated cell, and adenocarcinoma), alveolar carcinoma and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitinoma, mesothelioma, non-small cell lung carcinoma, small cell lung carcinoma, bronchial adenoma / carcinoid, and pleural gastrointestinal cancers, such as 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 vipoma), cancer of the small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), colorectal cancer or colon cancer , (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma), other cancers of the gastrointestinal tract (e.g., anal cancer, anorectal cancer, appendix cancer, anal canal cancer, tongue cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); genitourinary cancers, including kidney cancer (e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia), bladder cancer and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, cancer, including cancer of the bladder, bladder cancer, urinary tract, urethra, bladder cancer, urinary tract ...Bone cancers, including osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, including cancers of the skull (e.g., osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans); cancers of the meninges (e.g., meningioma, meningeal sarcoma, and gliomatosis); cancers of the brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors); cancers of the spinal cord (e.g., neurofibroma, meningioma, glioma, and sarcoma), and other cancers of the nervous system (e.g., brainstem glioma, diffuse intrinsic 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 lysoma, gynecologic cancers, including uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical carcinoma and preneoplastic cervical dysplasia), ovarian cancer (e.g., ovarian carcinoma, mucinous cystadenocarcinoma including serous cystadenocarcinoma, unclassified carcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, and malignant teratoma), cancer of the vulva (e.g., squamous cell carcinoma, uterine fibroids, thyroid cancer ... epithelial carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, and malignant melanoma); vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma); fallopian tube cancer (e.g., carcinoma); other reproductive organ cancers, including endometrial cancer, uterine carcinoma, germ cell tumor, gestational trophoblastic tumor, gestational trophoblastic tumor glioma, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumor, extragonadal germ cell tumor, uterine cancer, endometrial cancer, and uterine sarcoma;Cancers of the lymphatic and hematologic systems, including, for example, cancers of the blood (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia), and other cancers of the lymphatic or hematologic systems, including, for example, childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasms / multiple myeloma, myelodysplasia, myelodysplastic syndromes, cutaneous T-cell lymphoma, lymphomas, AIDS-related 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, sebaceous glands, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, Merkel cell carcinoma, Merkel cell skin cancer, malignant melanoma, and carcinoid tumors; adrenal gland cancer, including neuroblastoma; other cancers related to the endocrine system, including adrenocortical carcinoma, multiple endocrine neoplasia (e.g., multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid carcinoma, pituitary tumor, pheochromocytoma, pancreatic islet cell carcinoma, and pancreatic islet cell tumor Cancers of the head, neck, and mouth (e.g., head and neck cancer, paranasal sinus and nasal cancer, metastatic squamous cell neck cancer, oral cavity cancer, throat cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, and salivary gland cancer) are included, including mixed tissue cancers (e.g., bone cancer, bone and joint cancer, osteosarcoma, and malignant fibrous histiocytoma); cancers associated with the head, neck, and mouth (e.g., head and neck cancer, paranasal sinus and nasal cancer, metastatic squamous cell neck cancer, oral cavity cancer, throat cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, and salivary gland cancer); and cancers associated with the eye (e.g., eye 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 by the compounds of the present disclosure include mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangements or LJ gene rearrangements, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphocytic leukemia (ALL) (also called acute lymphoblastic leukemia or acute lymphocytic leukemia), acute myeloid leukemia (AML) (also called acute myeloid leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also called chronic lymphoblastic leukemia and acute myeloblastic leukemia), acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also called chronic lymphoblastic leukemia and acute myeloblastic leukemia), acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute lymphocy ... leukemia (also called chronic myelogenous leukemia (CML)), therapy-related leukemia, myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasms (MPN), plasma cell neoplasms, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasms, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, mycosis fungoides, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia.

[1071] In some embodiments, diseases and conditions treatable with compounds of the present disclosure include insulin resistance, prediabetes, diabetes (e.g., type 2 diabetes or type 1 diabetes), and risk of diabetes. In some embodiments, diseases and conditions treatable with compounds of the present disclosure include hyperglycemia. In some embodiments, hyperglycemia is associated with diabetes, such as type 2 diabetes. In some embodiments, compounds of the present disclosure are used to treat loss of response to other antidiabetic drugs and / or reduced beta cell function in a patient or subject. In some embodiments, compounds of the present disclosure are used to restore response to other antidiabetic drugs, and / or restore beta cell function, and / or reduce the need for insulin in a patient or subject. In some embodiments, compounds of the present disclosure are used to reduce insulin resistance, reduce the risk of diabetes, or reduce the rise in blood glucose levels caused by statins in subjects taking statins. In some embodiments, compounds of the present disclosure are used to treat diabetes in subjects taking statins or to prevent diabetes in subjects taking statins. The disclosed methods include decreasing, reducing, suppressing, inhibiting, limiting, or controlling elevated blood glucose levels in a subject. In a further aspect, the methods of the present invention include increasing, stimulating, enhancing, promoting, inducing, or activating insulin sensitivity in a subject. Statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[1072] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1073] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1074] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting the interaction of menin and MLL (e.g., in vitro or in vivo).

[1075] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[1076] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[1077] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject in need thereof.

[1078] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[1079] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the interaction of menin and MLL (e.g., in vitro or in vivo).

[1080] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[1081] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[1082] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[1083] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

[1084] The present disclosure provides compounds that function as inhibitors of the interaction between menin and MLL (e.g., in vitro or in vivo). Accordingly, the present disclosure provides a method of inhibiting the interaction between menin and MLL in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[1085] In some embodiments, the menin / MLL interaction inhibitor is a compound of the present disclosure.

[1086] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models as described in the art and as found in the current general knowledge.

[1087] The present disclosure also provides a method of treating a disease or disorder in which the interaction of menin and MLL is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[1088] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human. Route of administration

[1089] The compounds of the present disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., to the desired site of action).

[1090] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., using aerosols, e.g., inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.; [Example]

[1091] Abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG2025170331000545.jpg195150JPEG2025170331000546.jpg118150General synthetic procedures and examples of 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) was added BocO (26.5 g, 0.122 mol), triethylamine (62 g, 0.61 mol), and DMAP (4 g, 0.033 mol). The solution was stirred at ambient temperature for 17 hours. 250 ml of water was then added, and potassium hydrogen sulfate was added portionwise with stirring until a pH of 3 was reached. The aqueous phase was washed with dichloromethane (200 ml), the organic solution was concentrated, and the residue was purified using 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)diboron (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 min under an argon atmosphere. Pd(dppf)Cl2 (3.2 g) was then added, and the reaction mixture was stirred at 100 °C for an additional 3 h (TLC control). The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was then concentrated, and the residue was purified by silica gel column chromatography (dichloromethane) to give 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 under an argon atmosphere for 30 minutes. 1,1,1 trifluoro-2-iodo-ethane (18.6 g, 89 mmol), Pd2(dba)3 (2.6 g), and Xantphos (2.6 g) were then added. The reaction mixture was stirred at 82 °C for 18 hours, after which the mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane-hexane-1:1) to give the product (P3) as a white solid (5.85 g, 59% yield). 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 3 M 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 h (NMR control) and concentrated to dryness to give the product (P4, 4.6 g, 100%) 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] Preparation 5. 2-Amino-5-(2,2,2-trifluoroethyl)benzoic acid (P5) [ka] A solution (35 ml) of lithium hydroxide (2 g, 83 mmol) in water was added to a solution (100 ml) 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 with stirring and quenched with cold water until pH = 3. The resulting precipitate was filtered, washed with water (15 ml), and dried to give 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)quinazolin-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 and 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 that formed was filtered off, washed with water (55 mL), and dried to give the 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 h. The solution was cooled and poured into an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred for 30 min and then extracted with DCM (2 × 50 ml). After evaporation of dichloromethane, the residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate-10:1) to give 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 (LCMS control). The product was then purified by column chromatography on silica (ethyl acetate-methanol 10:1) to give P8 (5.1 g, 96%) as a white solid. 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)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P8, 5.1 g, 11.7 mmol) was added a solution of 3 M dioxane-HCl (120 ml). The reaction mixture was stirred at room temperature for 3 hours (LCMS control) and then evaporated to dryness under reduced pressure to give 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)quinazolin-4(3H)-one (230 mg, 1 mmol, prepared as described in US 2005 / 54626, 2005, A1) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (263 mg, 1 mmol) in DMAA (4 mL) was added DBU (610 mg, 4 mmol) and PyBOP (564 mg, 1.5 mmol). The reaction mixture was stirred at 50 °C for 48 h, 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 with ethyl acetate afforded tert-butyl 2-[6-(trifluoromethoxy)quinazolin-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)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)phenyl]amine (P11) [ka] To tert-butyl 2-[6-(trifluoromethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P10, 350 mg, 0.8 mmol) was added TFA (3 mL). The reaction mixture was stirred at 20° C. for 1 hour, then concentrated aqueous sodium bicarbonate (20 mL) was added, and the mixture was extracted with DCM (2×10 mL). The DCM was evaporated to dryness to give 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 Pd-C 10% (0.5 g) under hydrogen (70 bar) for 18 h. The reaction mixture was filtered and evaporated to dryness to give 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) was added DIPEA (131 mg, 1.02 mmol) and MsCl (116 mg, 1.02 mmol). The mixture was stirred at 50 °C for 45 min, and then 2-cyano-4-methyl-5-formylindole (P97, 78 mg, 0.42 mmol) and potassium carbonate (300 mg, 2.2 mmol) were added. The mixture was stirred at 90 °C for 48 h. The product was extracted from water (10 mL) with 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 give 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-oxoimidazolidin-1-yl)ethyl]-1H-indole-5-carbaldehyde (P14) [ka]

[1105] Preparation 14. 2-Ethynyl-4-methyl-1-[2-(2-oxoimidazolidin-1-yl)ethyl]-1H-indole-5-carbaldehyde (P14) [ka] To a solution of 1-(2-hydroxyethyl)imidazolidin-2-one (130 mg, 1 mmol) in DMAA (3 ml) was added DIPEA (258 mg, 2 mmol) and MsCl (132 mg, 1.15 mmol). The mixture was stirred at 50° C. for 45 min, 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 h. The product was extracted from water (40 ml) with 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 give pure 2-ethynyl-4-methyl-1-[2-(2-oxoimidazolidin-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-carbonitrile (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) was added DIPEA (405 mg, 3.14 mmol) and MsCl (300 mg, 2.02 mmol). The mixture was stirred at 50 °C for 45 min, 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 an additional 48 h. After the reaction was complete, water was added (40 ml), 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 give 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-piperazin-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 (P17) [ka]

[1107] Preparation 16. 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-indol-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-indol-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). An aqueous solution of sodium bicarbonate was then added with stirring. The mixture was stirred for 30 minutes and separated. The aqueous phase was extracted with DCM (100 ml). The combined DCM extracts were concentrated and the residue was purified by column chromatography on silica with ethyl acetate-methanol (10:2) to give tert-butyl 4-{2-[2-cyano-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}-1H-indol-1-yl]ethyl}piperazine-1-carboxylate (P16, 190 mg, 51%) as a white solid. LCMS (ESI) [MH] + : 703.

[1108] Preparation 17. 1-(2-piperazin-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 (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-indol-1-yl]ethyl}piperazine-1-carboxylate (P16, 190 mg, 0.27 mmol) was added to a solution of HCl (3 M 12 ml) in dioxane. The reaction mixture was stirred at room temperature for 3 hours (LCMS control) and then evaporated to dryness under reduced pressure to give 1-(2-piperazin-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-piperazin-1-ylpropyl)-5-[[2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]indole-2-carbonitrile (P20) [ka]

[1109] Preparation 18. 5-Formyl-4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazin-1-yl]propyl}-1H-indole-2-carbonitrile (P18) [ka] To a mixture of 2-[4-(tert-butylcarboxylate)piperazin-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), DIAD (273 mg, 1.35 mmol) was added, and the resulting mixture was stirred at ambient temperature overnight. The solvent was evaporated. The residue after evaporation was subjected to column chromatography on silica gel eluting with dichloromethane / ethyl acetate (0→20%) to give 5-formyl-4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazin-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)piperazin-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) [ka] Molecular sieves, 3 Å (200 mg) were added to a mixture of 5-formyl-4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazin-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). NaBH3CN (42 mg, 0.67 mmol) was then added, and the reaction mixture was stirred overnight at ambient temperature. Saturated aqueous sodium bicarbonate and dichloromethane were added, and 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 give the target compound 4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazin-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-piperazin-1-ylpropyl)-5-[[2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]indole-2-carbonitrile (P20) [ka] To 4-methyl-1-{2-[4-(tert-butylcarboxylate)piperazin-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 added TFA (1 ml). The solution was stirred at room temperature for 2 hours (LCMS control), then evaporated to dryness, aqueous sodium bicarbonate (5 ml) was added, and the product was extracted with DCM (3 × 5 ml). The organic phase dried over sodium sulfate was concentrated to dryness to give product P20 (31 mg, 100%). LCMS (ESI) [MH + ]: 631. Synthesis of 4-(7-{[2-ethynyl-4-methyl-1-(4-piperazin-1-ylbutyl)-1H-indol-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-carbonitrile (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 was added 1,4-dichlorobutane (1.27 g, 10 mmol), KCO (2 g), and NaI (0.5 g). The reaction mixture was stirred at 80° C. for 24 h, then evaporated to dryness, washed with water (15 mL), dried under vacuum, and washed with hexane (3 mL) to give 1-(4-chlorobutyl)-5-formyl-4-methyl-1H-indole-2-carbonitrile (P21, 244 mg, 89%). 1H 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) [ka] To a solution of 1-(4-chlorobutyl)-5-formyl-4-methyl-1H-indole-2-carbonitrile (P21, 244 mg, 0.89 mmol) in MeCN (3 ml) was added Boc-piperazine (215 mg, 1.16 mmol) and K2CO3 (0.4 g). The mixture was stirred at 80 °C for 24 h, then filtered and concentrated. After evaporation of the solvent, the residue was subjected to column chromatography on silica gel eluting with dichloromethane / ethyl acetate (0 → 50%) to give compound P22 (238 mg, 63%). LCMS [MH + ]: 425. 1 H NMR (400 MHz, CDCl3), δ: 10.44 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J=8.2 Hz, 1H), 4,36 (t, J=7.1 Hz, 2H), 3.48-3.34 (m, 4H), 2.90 (s, 3H), 2.43-2.29 (m, 5H), 1.98-1.89 (m, 2H), 1.60-1.52 (m, 2H), 1.43 (s, 9H).

[1114] Preparation 23. 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-indol-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), tert-butyl 4-[4-(2-cyano-5-formyl-4-methyl-1H-indol-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 h (LCMS control), then washed with saturated aqueous NaHCO3 and extracted with DCM (2 × 5 mL). The residue after solvent evaporation was subjected to column chromatography on silica gel eluting with ethyl acetate-methanol (0 → 30%) to give 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-piperazin-1-ylbutyl)-1H-indol-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-indol-1-yl]butyl}piperazine-1-carboxylate (P23, 167 mg, 0.224 mmol) in TFA (1 ml) was stirred at room temperature for 2 h (LCMS control), then evaporated to dryness, aqueous sodium bicarbonate (5 ml) was added, and the product was extracted with dichloromethane (3 × 5 ml). The organic phase, dried over sodium sulfate, was concentrated to dryness to give 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)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-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)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-4-methyl-1H-indol-1-yl]methyl}cyclohexyl)carbamate (P25) [ka] To a solution of {trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}methyl methanesulfonate (118 mg, 0.4 mmol) and 4-methyl-5-[[2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]-1H-indole-2-carbonitrile (150 mg, 0.30 mmol) prepared according to WO 2018 / 67422, 2018, A1 in MeCN (3 ml) was added potassium carbonate (138 mg, 1 mmol). The reaction mixture was stirred at 50 °C for 24 h, then filtered and concentrated. The residue after evaporation of the solvent was subjected to column chromatography on silica gel eluting with ethyl acetate-methanol (0 → 30%) to give 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)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]-1H-indole-2-carbonitrile hydrochloride (P26) [ka] tert-Butyl (trans-4-{[2-cyano-5-({2-[6-(2,2-dimethylpropyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-4-methyl-1H-indol-1-yl]methyl}cyclohexyl)carbamate To P25 (70 mg, 0.1 mmol) was added 2 ml of a 3 M solution of HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours (LCMS control) and then evaporated to dryness to give 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) was added DIPEA (7.9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate hydrochloride (3.2 g, 12.2 mmol). The reaction mixture was stirred at room temperature for 18 hours (LCMS control). After completion of the reaction, the solvent was evaporated and the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:1) to give 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)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (P27, 5.1 g, 11.7 mmol) was added to a dioxane-HCl solution (3 M, 120 ml). The reaction mixture was stirred at room temperature for 3 hours (LCMS control) and then evaporated to dryness under reduced pressure to give 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. LCMS (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) was added DIPEA (7.9 g, 61 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.5 g, 12.2 mmol). The reaction mixture was stirred at room temperature for 18 hours (LCMS control). After evaporation of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) to give the product P29 (5.1 g, 92%) as a white solid. 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 a 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 to dryness under reduced pressure to give 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) was added dropwise a solution of bromine (1.01 ml, 39 mmol) in DCM (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with sodium hydrogen sulfate solution (50 ml) and extracted with DCM (2×40 ml). The combined organic layers were washed with brine (40 ml), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 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] Preparation 32. 2-Amino-5-bromonicotinic acid (P32) [ka] To a solution of P31 (2.76 g, 11.95 mmol) in DCM (100 ml) was added a solution of LiOH (1.72 g, 71.7 mmol) in water, and the reaction mixture was refluxed for 1 h, then evaporated under reduced pressure, dissolved in water, and the pH adjusted to about 3 with HCl. The residue was filtered and washed with water to give 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-Bromopyrido[2,3-d]pyrimidin-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 solution of sodium bicarbonate (30 ml) and stirred to shred the residue. The precipitate was then filtered and washed with water to give 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-bromopyrido[2,3-d]pyrimidin-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 h. The reaction mixture was then cooled to room temperature, extracted with EtOAc (2×10 ml), washed with brine (40 ml), dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient from EtOAc to 1% MeOH in EtOAc) to give 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]pyrimidin-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 h. The reaction mixture was then cooled to room temperature, extracted with EtOAc and water, dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (gradient from EtOAc to 1% MeOH in EtOAc) to give the title compound (P35) as a white solid (130 mg, 99%). LCMS (ESI) [MH] + : 382.

[1127] Preparation 36. tert-Butyl-2-(6-formylpyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P36) [ka] To a solution of P35 (130 mg, 0.3 mmol), 2,6-lutidine (58 mg, 0.48 mmol), and NaIO (241 mg, 0.99 mmol) in a mixture of dioxane (6 mL) and water (2 mL) was filled with argon and a solution of OsO (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 EtOAc to 1% MeOH in EtOAc) to give 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]pyrimidin-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) was added dropwise an aqueous solution of hydrazine hydrate (39 mg, 0.72 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to give the title compound (P37) as a white solid (87 mg, 84%). LCMS (ESI) [MH] + : 398.

[1129] Preparation 38. tert-Butyl-2-[6-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidin-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 flushed with argon. The reaction mixture was stirred at 50° C. for 24 hours. The reaction mixture was extracted with EtOAc, and the combined organic layers were evaporated under reduced pressure and purified by silica gel column chromatography (gradient from EtOAc to 50% MeOH in EtOAc) to give 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 h. The reaction mixture was evaporated under reduced pressure, followed by the addition of an aqueous solution of potassium carbonate, extraction with DCM (2 × 10 mL), drying over sodium sulfate, filtration, and concentration to give 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-bromophthalazin-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) was added DIPEA (7.9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.67 g, 6.37 mmol). 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 give the title compound 40 (1.3 g, 47%) as a white solid. LCMS (ESI) [MH + ]: 434.

[1132] Preparation 41. tert-Butyl 2-(7-vinylphthalazin-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P41) [ka] To a solution of tert-butyl 2-[7-bromophthalazin-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P40, 0.30 g, 0.69 mmol) in EtOH (10 mL) was added water (0.5 mL) and TEA (140 mg, 1.39 mmol). 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 h. The reaction mixture was treated with EtOAc and HO, and the layers were separated. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated. The crude material was purified on silica (gradient elution, 0-40% EtOAc / hexanes) to give the title compound P41 as a white solid (210 mg, 80%). + ]: 381.

[1133] Preparation 42. tert-Butyl 2-(7-formylphthalazin-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P42) [ka] To a solution of tert-butyl 2-(7-vinylphthalazin-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) was added 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). The reaction mixture was stirred at room temperature for 24 h. Upon completion of the reaction, the solution was cooled and added to an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred at 15 °C for 30 min, 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 give 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)phthalazin-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P43) [ka] To a solution of tert-butyl 2-(7-formylphthalazin-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P42, 145 mg, 0.38 mmol) in MeOH (1 mL) was added hydrazine hydrate (38 mg, 0.76 mmol). The solution was stirred at room temperature for 2 hours (TLC control), and then the reaction mixture was evaporated to dryness to give the crude hydrazone (150 mg), which was used in the next step without purification. The 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 x 25 ml), and the combined organic layers were washed with water (3 x 60 ml) and brine (25 ml), and dried over NaSO. The organic layer was concentrated, and the residue was separated by HPLC (silica C-18, MeCN-HO) to give P43 (75 mg, 45%). LCMS (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)phthalazin-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (P43, 75 mg, 0.17 mmol) was added TFA (1 mL). The solution was stirred at room temperature for 2 hours (LCMS control), then evaporated to dryness, aqueous sodium bicarbonate (5 mL) was added, and the product was extracted with DCM (3 × 5 mL). The organic phase was dried over NaSO and concentrated to dryness to give 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)cinnoline (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-chlorocinnoline (prepared according to the procedure described in US2015 / 259331; 1.55 g, 6.37 mmol) in dichloroethane (40 ml) was added DIPEA (7.9 g, 61 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (1.67 g, 6.37 mmol). 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 give the title compound P45 (1.3 g, 47%) as a white solid. 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) was added water (0.5 mL) and TEA (140 mg, 1.39 mmol). 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 h. The reaction mixture was treated with EtOAc and HO, and the layers were separated. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated. The crude material was purified on silica (gradient elution, 0-40% EtOAc / hexanes) to give the title compound P46 as a white solid (210 mg, 80%). LCMS (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) was added 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). The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the solution was cooled and added to an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred at 15 °C for 30 min, 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 give 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)cinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P48) [ka] To a solution of tert-butyl 2-(6-phospomylcinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P47, 145 mg, 0.38 mmol) in MeOH (1 mL) was added hydrazine hydrate (38 mg, 0.76 mmol). The reaction mixture was stirred at room temperature for 2 h (TLC control). The reaction mixture was then evaporated to dryness to give crude hydrazone (150 mg), which was used in the next step without purification. The 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 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 x 25 ml), and the combined organic layers were washed with water (3 x 60 ml) and brine (25 ml), and dried over NaSO. The organic layer was concentrated, and the residue was separated by HPLC (silica C-18, MeCN-HO) to give P48 (75 mg, 45%). LCMS (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)cinnoline (P49) [ka] To tert-butyl 2-(6-(2,2,2-trifluoroethyl)cinnolin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P48, 75 mg, 0.17 mmol) was added TFA (1 ml). The solution was stirred at room temperature for 2 hours (LCMS control) and then evaporated to dryness. 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 to dryness to give 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)cinnoline P49 (57 mg, 100%). LCMS (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 equiv.) in methanol (4.0 mL) and DCM (16 mL) was added trimethylsilyldiazomethane (7.23 mL, 14.5 mmol, 2.0 equiv.) at room temperature. The mixture was then stirred at room temperature for 16 hours, treated with water, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO(s), filtered, and concentrated in vacuo to give 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] To a solution of P50 (5.00 g, 32.8 mmol, 1.0 equiv.) in 2 M sulfuric acid (101 mL) was added a solution of bromine (1.68 mL, 32.8 mmol, 1.0 equiv.) in acetic acid (12.6 mL) at room temperature. The mixture was then stirred at room temperature for 4 hours, and the solution was then diluted with NaSO. 3(aq) and extracted with EtOAc. The organic layer was collected, washed with brine, and 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give P51 (5.56 g, 73%) as an orange solid. 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 equiv.) in n-butanol (10 ml), potassium vinyltrifluoroborate (435 mg, 3.25 mmol, 1.5 equiv.) and trimethylamine (1.51 ml, 10.8 mmol, 5.0 equiv.) were added at room temperature. The solution was degassed with argon, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex was added. The reaction mixture was then stirred at 80 °C for 16 h, after which it was cooled to room temperature and filtered through a pad of Celite. The solution was treated with water and extracted with EtOAc. The organic layer was collected, washed with brine, and diluted with MgSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc:n-hexane=1:2) to give P52 (230 mg, 60%) as a yellow solid. 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 equiv) in DCM (10 ml) was added di-tert-butyl dicarbonate (0.890 ml, 3.87 mol, 3.0 equiv) and 4-dimethylaminopyridine (15.7 mg, 0.129 mmol, 0.1 equiv) 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 (EtOAc:n-hexane = 1:3) to give P53 (432 mg, 88%) as a white solid. 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-formylpicolinate (P54) [ka] To a solution of P53 (432 mg, 1.14 mmol, 1.00 equiv.) 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 equiv.), sodium periodate (977 mg, 4.56 mmol, 4.00 equiv.), and 2,6-lutidine (265 mL, 2.28 mmol, 2.00 equiv.) were added at room temperature and stirred for 2 hours. The mixture was filtered through Celite and extracted with EtOAc. The organic layer was collected, washed with brine, and then filtered with MgSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc:dichloromethane=1:4) to give P54 (402 mg, 93%) as a yellow solid. 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-(hydrazinylidenemethyl)-picolinate (P55) [ka] To a solution of P54 (402 mg, 1.06 mmol, 1.0 equiv) in methanol (9 mL) was added hydrazine monohydrate (63.5 mg, 1.27 mol, 1.2 equiv) at room temperature, and the mixture was stirred at room temperature for 4 h. The solution was concentrated in vacuo to give 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 equiv) in DMSO (10 ml) was added 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (377 mg, 1.19 mmol, 1.1 equiv), and the mixture was stirred for 10 min. Triethylamine (0.197 ml, 1.41 mmol, 1.3 equiv) was added to the reaction mixture, and the solution was stirred at 50 °C for 16 h. After the solution was cooled to room temperature, it was diluted with water and extracted with EtOAc. The organic layer was washed with brine and diluted with MgSO 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc:n-hexane=1:2) to give P56 (258 mg, crude) as a yellow solid. 1LRMS (ESI) [MH] + : 435.1.

[1148] Preparation 57. Methyl 3-amino-6-(2,2,2-trifluoroethyl)picolinate (P57) [ka] To a solution of P56 (3.6 g, 8.29 mmol, 1.0 equiv.) in DCM (20 ml) was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and purified by flash column chromatography (EtOAc:n-hexane = 1:1) to give P57 (1.9 g, 98%) as a yellow solid. 1 LCMS (ESI) [MH] + : 235.1.

[1149] Preparation 58. 3-Amino-6-(2,2,2-trifluoroethyl)picolinamide (P58) [ka] A solution of P57 (1.90 g, 8.11 mmol, 1.0 equiv) in 28% ammonia in water (50 ml) was stirred at room temperature for 16 hours. The solution was diluted with water and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO(s), filtered, and concentrated in vacuo to give P58 (1.45 g, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 7.82 (br. s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.98 (br. s, 2H), 5.42 (br. s, 1H), 3.45 (q, J = 10.8 Hz, 2H).

[1150] Preparation 59. 6-(2,2,2-trifluoroethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (P59) [ka] A solution of P58 (50.0 mg, 0.114 mmol, 1.0 equiv) in trimethyl orthoformate (5.0 ml) in a sealed tube was stirred at 150 °C for 5 h. After the solution was cooled to room temperature, it was diluted with water and extracted with EtOAc. The organic layer was collected, washed with brine, and added with MgSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (methanol:DCM=1:10) to give P59 (38 mg, 73%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 12.30 (br. s, 1H), 8.23 ​​(s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 3.91 (q, J = 10.4 Hz, 2H); LCMS (ESI) [MH] + : 230.1.

[1151] Preparation 60. tert-Butyl 2-(6-(2,2,2-trifluoroethyl)pyrido[3,2-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P60) [ka] To a solution of P59 (410 mg, 1.79 mmol, 1.0 equiv.) in anhydrous N,N-dimethylformamide (10 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (564 mg, 2.15 mmol, 1.2 equiv.), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.86 g, 3.58 mmol, 2.0 equiv.), and N,N-diisopropylethylamine (0.934 mg, 5.36 mmol, 3.0 equiv.). The reaction mixture was stirred at 60 °C for 3 h, after which it was cooled to room temperature and directly purified by C18 flash column chromatography (0-100% methanol in HO) to give P60 as an orange solid (580 mg, 74%). 1 H NMR (400 MHz, CDCl3), δ: 8.55 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 4.61 (s, 2H), 4.08 (s, 2H), 3.69 (q, J = 10.4 3.53-3.48 (m, 2H), 3.41-3.36 (m, 2H), 1.85-1.83 (m, , 4H), 1.47 (s, 9H); LCMS (ESI) [MH] + : 438.2.

[1152] Preparation 61. 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[3,2-d]pyrimidine (P61) [ka] To a stirred solution of P60 (330 mg, 0.68 mmol) in DCM (3 ml) was added TFA (0.860 g, 10 equiv.). After stirring the reaction at room temperature overnight, the solution was treated with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with MgSO 4(s) The mixture was dried at 77°C, filtered, and concentrated to give the product P61 as a yellow solid (240 mg, 94%). LCMS (ESI) [M−H] + : 338.4. Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pteridine (P71) [ka]

[1153] Preparation 62. Methyl 3-amino-6-vinyl-pyrazine-2-carboxylate (P62) [ka] To a stirred solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (12.0 g, 51.72 mmol) in dioxane (120 mL) was added potassium vinyltrifluoroborate (10.4 g, 77.6 mmol) and triethylamine (37.7 mL, 259 mmol). The solution was purged with argon for 30 minutes, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (4.23 g, 5.17 mmol) was added and purged again. The mixture was stirred at reflux for 16 hours. TLC monitoring indicated the reaction was complete. The solution was treated with ethyl acetate and NaHCO 3(aq) The organic phase was washed with MgSO 4(s) The residue was purified by silica gel column chromatography (25% EtOAc in n-hexane) to give methyl 3-amino-6-vinylpyrazine-2-carboxylate (P62, 7.5 g, 75% yield) as a yellow solid.

[1154] Preparation 63. Methyl 3-(di(tert-butoxycarbonyl)amino)-6-vinylpyrazine-2-carboxylate (P63) [ka] To a solution of P62 (7.5 g, 41.9 mmol) in tetrahydrofuran (100 ml) was added di-tert-butyl-dicarbonate (48.2 ml, 209.5 mmol) and 4-dimethylaminopyridine (512 mg, 4.19 mmol). The reaction was stirred overnight at room temperature. The starting material was shown to be consumed. The solvent was concentrated to remove the product. The mixture was extracted with EtOAc / water and purified by silica-gel column chromatography (25% ethyl acetate in n-hexane) to give P63 as a yellow solid (14.57 g, 92% yield). 1 H NMR (400 MHz, CDCl3), δ: 8.67 (s, 1H), 6.92 (dd, J = 17.6 Hz, 11.0 Hz, 1H), 6.41 (d, J = 17.6 Hz, 1H), 5.75 (d, J = 11.0 Hz, 1H), 3.98 (s, 3H), 1.39 (s, 18H).

[1155] Preparation 64. Methyl 3-(di(tert-butoxycarbonyl)amino)-6-formylpyrazine-2-carboxylate (P64) [ka] To a stirred solution of P63 (14.0 g, 36.9 mmol) in dioxane (400 mL) and HO (100 mL), 2,6-lutidine (8.6 mL, 73.8 mmol), a solution of 2.5% osmium tetroxide in tert-butanol (188 mg, 0.74 mmol), and sodium periodate (31.59 g, 147.6 mmol) were added at room temperature. The mixture was stirred for 16 h at room temperature. TLC monitoring indicated the reaction was complete. The resulting mixture was filtered, and the filtrate was treated with water and extracted with EtOAc. The organic layer was dried over MgSO(s), filtered, and concentrated in vacuo to give the crude product. The residue was purified by silica gel column chromatography (25% EtOAc in n-hexane) to give P64 (9.96 g, 71% yield) as a brown solid. 1H NMR (400 MHz, CDCl3), δ: 10.23 (s, 1H), 9.18 (s, 1H), 4.03 (s, 3H), 1.42 (s, 18H).

[1156] Preparation 65. Methyl (E)-3-(di(tert-butoxycarbonyl)amino)-6-(hydrazinylidenemethyl)pyrazine-2-carboxylate (P65) [ka] To a solution of P64 (9.96 g, 26.1 mmol) in methanol (50 ml) was added hydrazine monohydrate (1.52 ml, 31.3 mmol) at 0 °C and stirred for 10 min. The solution was warmed to room temperature and stirred for an additional 5 h. The solution was concentrated to give crude product P65, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 9.11 (s, 1H), 7.86 (s, 1H), 6.11 (br. s, 2H), 3.98 (s, 3H), 1.39 (s, 18H).

[1157] Preparation 66. Methyl 3-(di(tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroethyl)pyrazine-2-carboxylate (P66) [ka] To a solution of P65 (26.1 mmol) in DMSO (70 mL) was added 1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (1.52 mL, 31.3 mmol) and TFA (2.0 mL) at 0°...

Claims

1. A compound selected from: 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

2. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and a pharmaceutically acceptable carrier.

3. 3. The pharmaceutical composition of claim 2, further comprising one or more additional pharmaceutically active agents.

4. A method for inhibiting the interaction of menin and MLL in a cell, comprising contacting the cell with a compound of claim 1 or a pharmaceutical composition of claim 2.

5. A method for inhibiting the interaction of menin and MLL1 in a cell, comprising contacting the cell with a compound of claim 1 or a pharmaceutical composition of claim 2.

6. The method of claim 4 , wherein the contacting is in vitro or in vivo.

7. A method for treating or preventing a disease or disorder associated with the interaction of menin and MLL, comprising administering a compound described in claim 1 or a pharmaceutical composition described in claim 2 to a subject in need thereof.

8. 8. The method of claim 7, wherein the disease or disorder is selected from the group consisting of leukemia, hematological malignancies, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain cancer, and diabetes.

9. 9. The method of claim 8, wherein the leukemia is selected from the group consisting of AML, ALL, mixed lineage leukemia, and leukemia with partial tandem duplication of MLL.

10. The method of claim 7 , wherein the subject is a mammal.

11. The method of claim 10 , wherein the subject is a human.

Images