Inhibitors of menin-MLL interaction

Abstract

The present invention relates to compounds of formula (I) - 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 invention relates to compounds and pharmaceutical compositions that inhibit / block menin-MLL interaction, methods of treating diseases or disorders associated with menin-MLL interaction, and methods of synthesizing these compounds. JPEG2024545511000352.jpg64170

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, filed December 9, 2021, entitled "INHIBITORS OF MENIN-MLL INTERACTION," the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention 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 invention 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] Translocations of the MLL (mixed lineage leukemia) gene occur frequently in aggressive human acute myeloid and lymphoid leukemias in both children and adults. Fusion of MLL with one of over 60 different genes results in a chimeric MLL fusion protein that promotes proliferation and blocks hematopoietic differentiation, ultimately resulting in acute leukemia. Patients with leukemias harboring MLL translocations have a very unfavorable prognosis and respond poorly to currently available treatments. The risk of relapse is very high using conventional chemotherapy and stem cell transplantation, and the overall 5-year survival rate for patients is only approximately 35%.

[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 represents 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, have demonstrated the feasibility of targeting the menin-MLL interaction. Meanwhile, biochemical and structural studies have revealed that MLL binds to menin in a complex bivalent manner, engaging two MLL motifs, and thus inhibiting this protein-protein interaction is 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 therapy-related leukemia or myelodysplastic syndromes (MDS). As a result of chromosomal translocations, the MLL gene is fused to 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, demonstrating that MLL fusion proteins mediate upregulation of HOXA9 and MEIS1, leading to enhanced proliferation and blockage of hematopoietic differentiation, ultimately leading to acute leukemia. Patients with leukemias harboring LML translocations have a very unfavorable prognosis (event-free survival of 20% at 3 years) and respond poorly to available treatments, demonstrating a clear 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 I) gene, located on chromosome 11q13. Menin is a ubiquitously expressed protein that is 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 the recruitment of 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, resulting in a protein unable to associate with menin, abolish its ability to upregulate Hox gene expression and induce leukemia in mice. Expression of a dominant-negative inhibitor composed of the amino-terminal MLL sequence inhibits the proliferation of MLL-AF9-transformed myeloid cells and blocks leukemic transformation.

[0007] Inhibition of the interaction between menin and the histone methyltransferase MLL1 (KMT2A) has recently emerged as a novel therapeutic strategy. Beneficial therapeutic effects have been hypothesized 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 the menin-MLL interaction may represent a viable approach to reversing the oncogenic activity of MLL fusion proteins in leukemia and may lead to novel therapeutic agents. Summary of the Invention

[0009] A first aspect of the present invention relates to compounds of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein: X 1 is N; each X1 ' is independently selected from CH2 and N; X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from CH or N; And X 2 , X 3 , X 4 , X 5 , and X 6 At least one of is N; X 7 is N; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, 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 12 R 13 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 , C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl; R 2 and R 3 are each independently selected from H or C1-C6 alkyl; or R 2 and R 3 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle, the heterocycle being selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R13 and optionally substituted with one or more substituents independently selected from: R 4 , R 4 ´, and R 5 are each independently selected from H and C1-C6 alkyl; or R 4 and R 5 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle or heteroaryl, and the heterocycle and heteroaryl are selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 or R 4 ´ and R 5 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle or heteroaryl, and the heterocycle and heteroaryl are selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 and optionally substituted with one or more substituents independently selected from: wherein at least (a) R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form the 3- to 8-membered heterocyclic ring; (b) R 4 and R5 together with the atoms to which they are attached and any intervening atoms form said 3- to 8-membered heterocycle or heteroaryl; or (c) R 4 ´ and R 5 together with the atom to which they are attached and any intervening atoms, form said 3- to 8-membered heterocycle or heteroaryl; L 1 is H or [ka] and; During the ceremony, R' and R" are both H; Ring A is an aryl and C3-C 14 cycloalkyl; L 2 is halogen, C1-C6 alkyl, NR 12 R 13 , -N(R 6 )S(O)2R 7 , -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7 , -S(O)NR 6 R 7 wherein the alkyl is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocyclyl; R 6 is selected from H, C1-C6 alkyl; R 7 is NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, —S(O)R 7 , N(R 6 )S(O)2R 7 , and N.R. 12 R 13 and optionally substituted with one or more substituents independently selected from: Each R 8 is halogen, OH, oxo, CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-NR 12 R 13 , -NR 12 R 13wherein the alkyl or alkoxy is selected independently from halogen, oxo, OH, NH, C-C alkyl, C-C alkoxy, NR 12 R 13 optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or L 2 and R 8 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered cycloalkyl, a 5- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 12 R 13 optionally substituted with one or more substituents independently selected from Each R 12 and R 13 are independently H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, -S(O)2R 7 , C1-C6 acyl, heterocyclyl, aryl, or heteroaryl; or R 12 and R 13 together with the atoms to which they are attached and any intervening atoms, form -S(O)R 7 forming a 5- to 14-membered heterocyclic ring optionally substituted with one or more substituents independently selected from m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1 and 2; s is an integer selected from 0, 1 and 2; v is 1; w is an integer selected from 0 and 1, and R 4 is part of an aromatic ring, then w is 0; During the ceremony, Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is 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.

[0010] Another aspect of the present invention 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, which may further comprise an excipient, diluent or surfactant.

[0011] Another aspect of the present invention 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 invention 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 invention 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 invention 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 diseases associated with the inhibition of the interaction between menin and MLL.

[0015] Another aspect of the present invention 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, as disclosed herein.

[0016] Another aspect of the present invention 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 invention 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 invention further provides a method for treating a disease or disorder associated with the interaction of menin and MLL, comprising administering to a patient suffering from at least one of the above 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 invention provides inhibitors of the interaction between menin and MLL that are therapeutic agents in the treatment of diseases and disorders.

[0020] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known inhibitors of the menin and MLL interaction. 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 invention further provides a method for treating a disease or disorder associated with the interaction of menin and MLL, comprising administering to a patient suffering from at least one of the above 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 invention provides inhibitors of the interaction between menin and MLL that are therapeutic agents in the treatment of diseases and disorders.

[0023] The present invention further provides a method of treating a disease, disorder, or condition selected from cancer, acute myeloid (AML) and acute lymphoblastic (ALL) leukemia, or myelodysplastic syndrome (MDS), comprising administering to a patient suffering from at least one of the above 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 embodiments, 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 Procedure A or B).

[0025] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods of preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Preparation Parts P1-P175).

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

[0027] In some embodiments, 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 to implement or test 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 conflict, the chemical structure shall control.

[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 Description of the Invention) The present disclosure provides methods for treating, preventing, or ameliorating a disease or disorder associated with inhibition of the interaction between 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 set forth 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 herein. Other features, objects, and advantages of the present disclosure will be apparent from the description 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 one of ordinary skill 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] The term "and / or" is used in this disclosure to mean 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, it can be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have additional functional groups. Suitable substituents used for the optional substitution of the groups described include 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 Examples of alkyl groups include, but are not limited to, (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” also refers to substitution or unsubstitution, the meaning of which is described below.

[0035] As used herein, the term "substituted" means that the specified group or moiety has one or more suitable substituents that may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is attached 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 specified group bears no substituents.

[0037] Unless otherwise specifically 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 joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). An aryl group can be optionally substituted at any point of attachment with one or more substituents, for example, 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. Exemplary 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 specifically 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 contain two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specifically defined, "fused" refers to two rings that share two ring atoms. Unless otherwise specifically defined, "spiro-fused" refers to two rings that share one ring atom. As defined herein, heteroaryl also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. As defined herein, heteroaryl 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 a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radicals are optionally substituted independently 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 ... Lysinyl, pyrrolo[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]pyridinyl imidinyl, tetrahydropyrrolo[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, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]thiazolyl, 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,Examples of heteroaryl groups include, but are not limited to, 3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused with a saturated or partially unsaturated ring as described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more spiro-fused saturated or partially unsaturated rings. Any saturated or partially unsaturated ring as described herein is 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]pyrazolo [4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyruro[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 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0041] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms containing 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-chain 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 may 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 may be unsubstituted or substituted. An alkenyl may be straight-chain or branched, as defined herein.

[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-, -CH2CH2CH2CH2-, and the like.

[0045] "Cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 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" monocyclic or polycyclic ring contains 3 to 24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, and is not aromatic. The heterocycloalkyl ring structure may be substituted with one or more substituents, which 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, and homotropanyl.

[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 connected p orbitals with delocalized electrons, which may include lone pairs.

[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, ie, C≡N.

[0051] "Spirocycloalkyl" or "spirocyclyl" refers to a bicarbonate 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, or spirodecane. One or both rings in a spiro ring can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spiro ring can 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 of which 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 variable stoichiometry formed by a solute and a solvent. For the purposes of this disclosure, such a solvent 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 called hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0054] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) can have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0055] The present disclosure also provides isotopically labeled compounds of Formula I, such as 2 H and 14 C) are also contemplated. 2 H or D) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dosage), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by procedures similar to those disclosed in the following schemes and / or examples herein, by using a suitable isotope-labeled reagent instead of a non-isotopically labeled reagent.

[0056] 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, tartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isopropyl alcohol, methyl methyl acrylate, methyl meth ... These include thionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theoclate, tosylate, triethionate, and valerate salts.

[0057] 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.

[0058] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease in a subject as described herein.

[0059] 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.

[0060] The term "treatment" with respect to a subject refers to ameliorating at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder.

[0061] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, symptom, or illness, unless otherwise indicated.

[0062] 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 the 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, which can form an equivalent amount of the active compound in the subject's body.

[0063] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0064] The term "salts" refers to pharmaceutically acceptable salts.

[0065] 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.

[0066] 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.

[0067] The amount of the compound of the compositions described herein required to achieve a therapeutic effect can be empirically determined according to conventional procedures for a particular purpose. Generally, for administering a therapeutic agent (e.g., a compound of Formula I or a composition described herein (and / or additional agents)) for therapeutic purposes, the therapeutic agent is administered at 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 a disease), reduce or eliminate one or more symptoms or manifestations of a disorder or disease, or reverse symptoms of a disorder or disease. For example, administration of a therapeutic agent to a subject suffering from cancer provides therapeutic benefit not only when the underlying disease is eradicated or ameliorated, but also when 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 realized. Compounds of the Disclosure

[0068] In various aspects of the disclosure, inhibitors of menin / MLL interaction are compounds having a structure represented by formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, X 1 is N; each X 1 ' is independently selected from CH2 and N; X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from CH or N; And X 2 , X 3 , X 4 , X 5 , and X 6 At least one of is N; X 7 is N; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, 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 12 R 13 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 , C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl; R 2 and R 3 are each independently selected from H or C1-C6 alkyl; or R 2 and R 3 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle, the heterocycle being selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 and optionally substituted with one or more substituents independently selected from: R 4 , R 4 ´, and R 5 are each independently selected from H and C1-C6 alkyl; or R4 and R 5 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle or heteroaryl, and the heterocycle and heteroaryl are selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 or R 4 ´ and R 5 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle or heteroaryl, and the heterocycle and heteroaryl are selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 and optionally substituted with one or more substituents independently selected from: wherein at least (a) R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form the 3- to 8-membered heterocyclic ring; (b) R 4 and R5 together with the atoms to which they are attached and any intervening atoms form said 3- to 8-membered heterocycle or heteroaryl; or (c) R 4 ´ and R 5 together with the atom to which they are attached and any intervening atoms, form said 3- to 8-membered heterocycle or heteroaryl; L 1 is H or [ka] and; During the ceremony, R' and R" are both H; Ring A is an aryl and C3-C 14 cycloalkyl; L 2 is halogen, C1-C6 alkyl, NR 12 R 13 , -N(R 6 )S(O)2R 7, -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7 , -S(O)NR 6 R 7 wherein the alkyl is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocyclyl; R 6 is selected from H, C1-C6 alkyl; R 7 is NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, —S(O)R 7 , N(R 6 )S(O)2R 7 , and N.R. 12 R 13 and optionally substituted with one or more substituents independently selected from: Each R 8 is halogen, OH, oxo, CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-NR 12 R 13 , -NR 12 R 13 wherein the alkyl or alkoxy is independently selected from halogen, oxo, OH, NH, C-C alkyl, C-C alkoxy, NR 12 R 13 optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or L 2and R 8 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered cycloalkyl, a 5- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 12 R 13 optionally substituted with one or more substituents independently selected from Each R 12 and R 13 are independently H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, -S(O)2R 7 , C1-C6 acyl, heterocyclyl, aryl, or heteroaryl; or R 12 and R 13 together with the atoms to which they are attached and any intervening atoms, form -S(O)R 7 forming a 5- to 14-membered heterocyclic ring optionally substituted with one or more substituents independently selected from m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1 and 2; s is an integer selected from 0, 1 and 2; v is 1; and w is an integer selected from 0 and 1, and R 4 is part of an aromatic ring, then w is 0.

[0069] In compounds according to formula (I), heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic) or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is 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, the remaining ring atoms being C.

[0070] In various aspects, 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 , R 4 ´, R 5 , X 1 , X 1 ´, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , L 1 , m, n, p, s, v and w are as described herein.

[0071] For compounds of formula (I), R 1 , R 2 , R 3 , R 4 , R 4 ´, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 ,R´,R”,A,X 1 , X 1 ´, X 2 , X 3 , X4 , X 5 , X 6 , X 7 , L 1 , L 2 , m, n, p, s, v, and w are each, where applicable, selected from the group described herein; R 1 , R 2 , R 3 , R 4 , R 4 ´, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 ,R´,R”,A,X 1 , X 1 ´, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , L 1 , L 2 Any group described herein for any of m, n, p, s, v and w, when applicable, may be R 1 , R 2 , R 3 , R 4 , R 4 ´, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 ,R´,R”,A,X 1 , X 1 ´, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , L 1 , L 2 It is understood that one or more of the remaining m, n, p, s, v and w can be combined with any group described herein.

[0072] In some embodiments, X 1 is N; each X 1 ' is independently selected from CH2 and N; X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from CH or N; And X 2 , X 3 , X 4 , X 5 , and X 6 At least one of is N; X 7 is N; Each R 1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, 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 12 R 13 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 , C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl; R 2 and R 3 are each independently selected from H or C1-C6 alkyl; or R 2 and R 3together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle, the heterocycle being selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 and optionally substituted with one or more substituents independently selected from: R 4 , R 4 ´, and R 5 are each independently selected from H and C1-C6 alkyl; or R 4 and R 5 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle or heteroaryl, and the heterocycle and heteroaryl are selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 or R 4 ´ and R 5 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocycle or heteroaryl, and the heterocycle and heteroaryl are selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 and optionally substituted with one or more substituents independently selected from: wherein at least (a) R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form the 3- to 8-membered heterocyclic ring; (b) R 4 and R5 together with the atoms to which they are attached and any intervening atoms form said 3- to 8-membered heterocycle or heteroaryl; or (c) R 4 ´ and R 5 together with the atom to which they are attached and any intervening atoms, form said 3- to 8-membered heterocycle or heteroaryl; L 1 is H or [ka] and; During the ceremony, R' and R" are both H; Ring A is an aryl and C3-C 14 cycloalkyl; L 2 is halogen, C1-C6 alkyl, NR 12 R 13 , -N(R 6 )S(O)2R 7 , -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7 , -S(O)NR 6 R 7 wherein the alkyl is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocyclyl; R 6 is selected from H, C1-C6 alkyl; R 7 is NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, —S(O)R 7 , N(R 6 )S(O)2R 7 , and N.R. 12 R 13 and optionally substituted with one or more substituents independently selected from: Each R 8is halogen, OH, oxo, CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-NR 12 R 13 , -NR 12 R 13 wherein the alkyl or alkoxy is independently selected from halogen, oxo, OH, NH, C-C alkyl, C-C alkoxy, NR 12 R 13 optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or L 2 and R 8 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered cycloalkyl, a 5- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 12 R 13 optionally substituted with one or more substituents independently selected from Each R 12 and R 13 are independently H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, -S(O)2R 7 , C1-C6 acyl, heterocyclyl, aryl, or heteroaryl; or R 12 and R 13 together with the atoms to which they are attached and any intervening atoms, form -S(O)R 7 forming a 5- to 14-membered heterocyclic ring optionally substituted with one or more substituents independently selected from m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1 and 2; s is an integer selected from 0, 1 and 2; v is 1; w is an integer selected from 0 and 1, and R 4 is part of an aromatic ring, then w is 0.

[0073] In some embodiments, L 1 is H.

[0074] In some embodiments, L 1 teeth [ka] is.

[0075] In some embodiments, X 1 is CH or N. In some embodiments, X 1 is CH. In some embodiments, X 1 is N.

[0076] In some embodiments, m is 0.

[0077] In some embodiments, m is 1. In some embodiments, m is 1 and X 1 In some embodiments, m is 1 and X 1 In some embodiments, m is 1 and X 1 ´ is N.

[0078] In some embodiments, m is 2. In some embodiments, m is 2 and each X 1 In some embodiments, m is 2 and both X' are independently selected from CH or N. 1 In some embodiments, m is 2 and both X' are CH. 1 In some embodiments, m is 2 and X′ is N. 1 X adjacent to 1 ´ is CH, and the other X 1In some embodiments, m is 2 and X′ is N. 1 X adjacent to 1 ´ is N, and the other X 1 ´ is CH.

[0079] In some embodiments, X 2 is CH or N. In some embodiments, X 2 is CH. In some embodiments, X 2 is N.

[0080] In some embodiments, X 3 is CH or N. In some embodiments, X 3 is CH. In some embodiments, X 3 is N.

[0081] In some embodiments, X 4 is CH or N. In some embodiments, X 4 is CH. In some embodiments, X 4 is N.

[0082] In some embodiments, X 5 is CH or N. In some embodiments, X 5 is CH. In some embodiments, X 5 is N.

[0083] In some embodiments, X 6 is CH or N. In some embodiments, X 6 is CH. In some embodiments, X 6 is N.

[0084] In some embodiments, X 7 is C, CH, or N. In some embodiments, X 7 is C and X 7 is part of an aromatic ring. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.

[0085] In some embodiments, each R 1 is independently selected from halogen, C-C alkyl, C-C alkoxy, C-C alkenyl, 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 are independently selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl.

[0086] In some embodiments, R 1 is a halogen.

[0087] In some embodiments, each R 1 is C3-C 10 In some embodiments, each R is independently selected from cycloalkyl, heterocyclyl, 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, heterocyclyl, aryl, and heteroaryl.

[0088] 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.

[0089] In some embodiments, R 1is C1-C6 alkyl.

[0090] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is n-propyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is n-butyl. In some embodiments, R 1 is isobutyl. 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, R 1 is hexyl.

[0091] In some embodiments, R 1 is C1-C6 alkoxy.

[0092] 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.

[0093] In some embodiments, R 1 is C3-C 10 It is cycloalkyl.

[0094] In some embodiments, R 1 is a monocyclic C3-C 10In some embodiments, R 1 is a polycyclic C3-C 10 It is cycloalkyl.

[0095] In some embodiments, R 1 is C5-C6 cycloalkyl.

[0096] In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 1 is cycloisopropyl. 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.

[0097] 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.

[0098] In some embodiments, R 1 is C2-C6 alkenyl.

[0099] In some embodiments, R 1 is C alkenyl. In some embodiments, R 1is C alkenyl. In some embodiments, R 1 is C4 alkenyl. In some embodiments, R 1 is C5 alkenyl. In some embodiments, R 1 is a C6 alkenyl.

[0100] In some embodiments, R 1 is C2-C6 alkynyl.

[0101] 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 C5 alkynyl. In some embodiments, R 1 is a C6 alkynyl.

[0102] In some embodiments, R 1 is heterocyclyl. In some embodiments, R 1 is a 3- to 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- to 10-membered heterocycle containing 1, 2, or 3 heteroatoms.

[0103] In some embodiments, R 1 is a monocyclic heterocycle. In some embodiments, R 1 is a polycyclic heterocycle.

[0104] 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 1is 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.

[0105] In some embodiments, R 1 is a 5- to 6-membered heterocycle.

[0106] In some embodiments, R 1 is aryl.

[0107] In some embodiments, R 1 is C6 aryl (e.g., phenyl).

[0108] In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is a 5- to 6-membered heteroaryl.

[0109] In some embodiments, R 1 is C1-C6 alkyl-aryl.

[0110] 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 isopropyl-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 1is tert-butyl-aryl. In some embodiments, R 1 is pentyl-aryl. In some embodiments, R 1 is hexyl-aryl.

[0111] In some embodiments, R 1 is C1-C6 alkyl-heteroaryl.

[0112] 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 isobutyl-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.

[0113] In some embodiments, R 1 is a C2-C6 alkenyl-aryl.

[0114] In some embodiments, R 1 is C alkenyl-aryl. In some embodiments, R 1 is C alkenyl-aryl. In some embodiments, R 1is C4 alkenyl-aryl. In some embodiments, R 1 is C alkenyl-aryl. In some embodiments, R 1 is a C6 alkenyl-aryl.

[0115] In some embodiments, R 1 is a C2-C6 alkenyl-heteroaryl.

[0116] 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.

[0117] In some embodiments, R 1 is a C2-C6 alkynyl-aryl.

[0118] 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.

[0119] In some embodiments, R 1 is and C2-C6 alkynyl-heteroaryl.

[0120] In some embodiments, R 1 is C alkynyl-heteroaryl. In some embodiments, R 1is a C alkynyl-heteroaryl. In some embodiments, R 1 is C4 alkynyl-heteroaryl. In some embodiments, R 1 is a C5 alkynyl-heteroaryl. In some embodiments, R 1 is a C6 alkynyl-heteroaryl.

[0121] In some embodiments, R 1 is NR 12 R 13 In some embodiments, R 1 is NHR 13 In some embodiments, R 1 is NHCH3.

[0122] In some embodiments, p is 2 and one R 1 is NR 12 R 13 and the other R 1 is C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, 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 12 R 13 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, C1-C6 alkyl, C1-C6 alkoxy, NR 12 R 13 , C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, aryl, heteroaryl.

[0123] 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 halogens. 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 fluoro. In some embodiments, one R 1 is NHCH3, and the other R 1 is CH2CF3.

[0124] 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 C1-C6 alkyl substituted with one or more NH2. 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 NRs 12 R 13 In some embodiments, R 1 is one or more C3-C 10 In some embodiments, R is C1-C6 alkyl substituted with cycloalkyl. 1is 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 1 is 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.

[0125] In some embodiments, R 1 is C1-C6 alkyl substituted with one or more F atoms. 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 isopropyl substituted with one or more F. In some embodiments, R 1 is butyl substituted with one or more F. In some embodiments, R 1 is n-butyl substituted with one or more F. In some embodiments, R 1 is isobutyl 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 It is hexyl substituted with one or more F.

[0126] In some embodiments, R 1 (CH2) 0-5 CF3. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CH2CF3.

[0127] In some embodiments, p is 1 and R 1 (CH2) 0-5 In some embodiments, p is 1 and R 1 is CF3. In some embodiments, p is 1 and R 1 is CH2CF3.

[0128] In some embodiments, p is 2 and at least 1, and R 1 (CH2) 0-5 In some embodiments, p is 2 and at least 1, and R 1 In some embodiments, p is 2 and at least 1, and R 1 is CH2CF3.

[0129] 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 1 is 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 1is 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 NRs 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 one or more aryl. In some embodiments, R 1 is C1-C6 alkoxy substituted with one or more heteroaryls.

[0130] 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 10 In 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 1is C3-C substituted with one or more I 10 In some embodiments, R 1 is a 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 alkyl 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 NRs 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 10 In some embodiments, R 1 is a C3-C substituted with one or more heteroaryls 10 It is cycloalkyl.

[0131] In some embodiments, R 1is a C-C alkenyl substituted with one or more halogens. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more F. In some embodiments, R 1 is C-C alkenyl substituted with one or more Cl. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more Br. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more I. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more OH. 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 a C2-C6 alkenyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 1 is one or more NRs 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 1 is a C-C alkenyl substituted with one or more aryls. In some embodiments, R 1 is a C2-C6 alkenyl substituted with one or more heteroaryls.

[0132] 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.

[0133] In some embodiments, R 1 is heterocyclyl substituted with one or more halogens. In some embodiments, R 1 is heterocyclyl substituted with one or more heteroaryls.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] In some embodiments, R 1 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.

[0142] 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 1is unsubstituted heterocyclyl. 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.

[0143] In some embodiments, R 4 ' is H. In some embodiments, R 4 In some embodiments, each R 4 ' is H. In some embodiments, at least one R 4 ´ is C1-C6 alkyl.

[0144] In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 In some embodiments, at least one R 4 ´ is hexyl.

[0145] In some embodiments, R 2 is H. In some embodiments, R 2 is C1-C6 alkyl.

[0146] 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 isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is isobutyl. 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, R 2 is hexyl.

[0147] In some embodiments, R 3 is H. In some embodiments, R 3 is C1-C6 alkyl.

[0148] In some embodiments, R 3 is methyl. In some embodiments, R 3is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is n-propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is n-butyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is sec-butyl. In some embodiments, R 3 is tert-butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl.

[0149] In some embodiments, R 2 and R 3 together with the atom to which they are attached and any intervening atoms, form a 3- to 8-membered heterocyclic ring, the heterocyclic ring being selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 is optionally substituted with one or more substituents independently selected from:

[0150] In some embodiments, R 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 3-membered heterocycle. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more halogens. 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form a 3-membered heterocycle substituted with one or more F. In some embodiments, R 2 and R 3are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more Cl. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more Br. In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 3-membered heterocycle substituted with one or more I. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more OH. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more NH2. 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more C1-C6 alkoxy. In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms a 3-membered heterocycle substituted with

[0151] In some embodiments, R 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 4-membered heterocyclic ring. In some embodiments, R 2 and R 3are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more halogens. 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form a 4-membered heterocycle substituted with one or more F. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more Cl. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more Br. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more I. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more NH2. 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more C1-C6 alkoxy. 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13Forms a 4-membered heterocycle substituted with

[0152] In some embodiments, R 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 5-membered heterocycle. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more halogens. 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 5-membered heterocycle substituted with one or more F. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more Cl. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more Br. In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 5-membered heterocycle substituted with one or more I. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more OH. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more NH. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 2 and R3 are taken together with the atom to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C1-C6 alkoxy. 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 5-membered heterocycle substituted with

[0153] In some embodiments, R 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 6-membered heterocycle. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more halogens. 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 6-membered heterocycle substituted with one or more F. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more Cl. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more Br. In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms form a 6-membered heterocycle substituted with one or more I. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more OH. In some embodiments, R 2 and R 3are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more NH. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more C-C alkoxy. In some embodiments, R 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 6-membered heterocycle substituted with

[0154] In some embodiments, R 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 7-membered heterocycle. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more halogens. 2 and R 3 taken together with the atoms to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more F. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more Cl. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more Br. In some embodiments, R 2 and R 3together with the atoms to which they are attached and any intervening atoms form a 7-membered heterocycle substituted with one or more I. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more OH. In some embodiments, R 2 and R 3 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more NH. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 2 and R 3 are taken together with the atom to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more C1-C6 alkoxy. 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 7-membered heterocycle substituted with

[0155] In some embodiments, R 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 3-membered heterocycle. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more halogens. 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form a 3-membered heterocycle substituted with one or more F. In some embodiments, R 4 and R 5are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more Cl. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more Br. In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms form a 3-membered heterocycle substituted with one or more I. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more OH. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more NH2. 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 3-membered heterocycle substituted with one or more C1-C6 alkoxy. In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms a 3-membered heterocycle substituted with

[0156] In some embodiments, R 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 4-membered heterocyclic ring. In some embodiments, R 4 and R 5are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more halogens. 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form a 4-membered heterocycle substituted with one or more F. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more Cl. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more Br. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more I. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more NH2. 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 4-membered heterocycle substituted with one or more C1-C6 alkoxy. 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13Forms a 4-membered heterocycle substituted with

[0157] In some embodiments, R 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 5-membered heterocycle. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more halogens. 4 and R 5 together with the atoms to which they are attached and any intervening atoms form a 5-membered heterocycle substituted with one or more F. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more Cl. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more Br. In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms form a 5-membered heterocycle substituted with one or more I. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more OH. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more NH. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 4 and R5 are taken together with the atom to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C1-C6 alkoxy. 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 5-membered heterocycle substituted with

[0158] In some embodiments, R 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 6-membered heterocycle. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more halogens. 4 and R 5 together with the atoms to which they are attached and any intervening atoms form a 6-membered heterocycle substituted with one or more F. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more Cl. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more Br. In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms form a 6-membered heterocycle substituted with one or more I. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more OH. In some embodiments, R 4 and R 5are taken together with the atoms to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more NH. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more C-C alkoxy. In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 6-membered heterocycle substituted with In some embodiments, R 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 7-membered heterocycle. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more halogens. 4 and R 5 taken together with the atoms to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more F. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more Cl. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more Br. In some embodiments, R 4 and R 5together with the atoms to which they are attached and any intervening atoms form a 7-membered heterocycle substituted with one or more I. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more OH. In some embodiments, R 4 and R 5 are taken together with the atoms to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more NH. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 4 and R 5 are taken together with the atom to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more C1-C6 alkoxy. 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 7-membered heterocycle substituted with

[0159] In some embodiments, R' and R" are both H.

[0160] In some embodiments, ring A is aryl or C-C 14 It is cycloalkyl.

[0161] In some embodiments, ring A is aryl.

[0162] In some embodiments, ring A is C6 aryl (eg, phenyl).

[0163] In some embodiments, ring A is C3-C 14 It is cycloalkyl.

[0164] In some embodiments, ring A is a monocyclic C-C 14 In some embodiments, ring A is a polycyclic C-C 14 It is cycloalkyl.

[0165] In some embodiments, ring A is C5-C6 cycloalkyl.

[0166] In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, or cyclotetradecyl. In some embodiments, Ring A is cycloisopropyl. In some embodiments, Ring A is cyclobutyl. In some embodiments, Ring A is cyclopentyl. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is cycloheptyl. In some embodiments, Ring A is cyclooctyl. In some embodiments, Ring A is cyclononyl. In some embodiments, Ring A is cyclodecyl.

[0167] In some embodiments, ring A is a fused polycyclic C-C 10 In some embodiments, Ring A is a bridged polycyclic C-C 10 In some embodiments, ring A is a C-C 10 It is a spirocycloalkyl.

[0168] In some embodiments, ring A is:

[0169] [ka] or [ka] .

[0170] In some embodiments, ring A is [ka] is.

[0171] In some embodiments, ring A is [ka] is.

[0172] In some embodiments, ring A is [ka] is.

[0173] In some embodiments, L 2 is -N(R 6 )S(O)2R 7 , -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7 , C(O)C 1-3 Alkenyl, C(O)C 1-3 Alkenyl-NR 6 R 7 , -S(O)2R 6 , or -S(O)NR 6 R 7 is.

[0174] In some embodiments, L 1 teeth [ka] and L 2 is -N(R 6 )S(O)2R 7 , -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7, C(O)C 1-3 Alkenyl, C(O)C 1-3 Alkenyl-NR 6 R 7 , -S(O)2R 6 , or -S(O)NR 6 R 7 is.

[0175] In some embodiments, L 2 is -N(R 6 )S(O)2R 7 , -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7 , -S(O)2R 6 , or -S(O)NR 6 R 7 is.

[0176] In some embodiments, L 1 teeth [ka] and L 2 is -N(R 6 )S(O)2R 7 , -N(R 6 )CH2R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 R 7 , -S(O)2R 6 , or -S(O)NR 6 R 7 is.

[0177] In some embodiments, L 2 -N(R 6 )S(O)2R 7 In some embodiments, L 1 teeth [ka] and L 2-N(R 6 )S(O)2R 7 is.

[0178] In some embodiments, L 2 -N(R 6 )CH2R 7 In some embodiments, L 1 teeth [ka] and L 2 -N(R 6 )CH2R 7 is.

[0179] In some embodiments, L 2 -N(R 6 )C(O)R 7 In some embodiments, L 1 teeth [ka] and L 2 -N(R 6 )C(O)R 7 is.

[0180] In some embodiments, L 2 is -C(O)NR 6 R 7 is.

[0181] In some embodiments, L 1 teeth [ka] and L 2 is -C(O)NR 6 R 7 is.

[0182] In some embodiments, L 2 is -C(O)C 1-3 In some embodiments, L is alkenyl. 1 teeth [ka] and L 2 is -C(O)C 1-3 It is alkenyl.

[0183] In some embodiments, L 2 is -C(O)C 1-3 Alkenyl-NR 6 R 7 In some embodiments, L 1 teeth [ka] and L 2 is -C(O)C 1-3 Alkenyl-NR 6 R 7 is.

[0184] In some embodiments, L 2 -S(O)2R 6 is.

[0185] In some embodiments, L 1 teeth [ka] and L 2 -S(O)2R 6 is.

[0186] In some embodiments, L 2 is -S(O)2NR 6 R 7 is.

[0187] In some embodiments, L 1 teeth [ka] and L 2 is -S(O)2NR 6 R 7 is.

[0188] In some embodiments, L1 is selected from:

[0189] [ka] [ka] [ka] [ka] .

[0190] In some embodiments, R 6 is NH. In some embodiments, R 6 is NR 12 R 13 In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C-C alkenyl. In some embodiments, R 6 is C2-C6 alkynyl. In some embodiments, R 6 is C3-C 10 In some embodiments, R 6 is aryl. In some embodiments, R 6 is a heterocycle. In some embodiments, R 6 is heteroaryl.

[0191] In some embodiments, R 6 is NH2 or NR 12 R 13 In some embodiments, R 6 is C-C alkyl, C-C alkenyl, or C-C alkynyl. In some embodiments, R 6 is C3-C 10 It is cycloalkyl, aryl, heterocycle, or heteroaryl.

[0192] In some embodiments, R6 is NH. In some embodiments, R 6 is NR 12 R 13 In some embodiments, R 6 is unsubstituted C1-C6 alkyl. In some embodiments, R 6 is unsubstituted C-C alkenyl. In some embodiments, R 6 is an unsubstituted C2-C6 alkynyl. In some embodiments, R 6 is unsubstituted C3-C 10 In some embodiments, R 6 is unsubstituted aryl. In some embodiments, R 6 is unsubstituted heterocyclyl. In some embodiments, R 6 is an unsubstituted heteroaryl.

[0193] In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is propyl. In some embodiments, R 6 is n-propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is butyl. In some embodiments, R 6 is n-butyl. In some embodiments, R 6 is isobutyl. In some embodiments, R 6 is sec-butyl. In some embodiments, R 6 is tert-butyl. In some embodiments, R 6 is pentyl. In some embodiments, R 6 is hexyl.

[0194] In some embodiments, R 6 is C1-C6 alkyl substituted with one or more halogens. In some embodiments, R 6is C1-C6 alkyl substituted with one or more F. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more Cl. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more Br. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more I. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more OH. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more NH2. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more C1-C6 alkyl. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 6 is one or more NRs 12 R 13 is C1-C6 alkyl substituted with

[0195] In some embodiments, R 6 is C alkenyl. In some embodiments, R 6 is C alkenyl. In some embodiments, R 6 is C4 alkenyl. In some embodiments, R 6 is C5 alkenyl. In some embodiments, R 6 is a C6 alkenyl.

[0196] In some embodiments, R 6 is a C-C alkenyl substituted with one or more halogens. In some embodiments, R 6 is a C2-C6 alkenyl substituted with one or more F. In some embodiments, R 6 is C-C alkenyl substituted with one or more Cl. In some embodiments, R 6is a C2-C6 alkenyl substituted with one or more Br. In some embodiments, R 6 is a C-C alkenyl substituted with one or more I. In some embodiments, R 6 is a C2-C6 alkenyl substituted with one or more OH. In some embodiments, R 6 is a C-C alkenyl substituted with one or more NH. In some embodiments, R 6 is a C2-C6 alkenyl substituted with one or more C1-C6 alkyl. In some embodiments, R 6 is a C2-C6 alkenyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 6 is one or more NRs 12 R 13 and C2-C6 alkenyl substituted with

[0197] In some embodiments, R 6 is C alkynyl. In some embodiments, R 6 is C alkynyl. In some embodiments, R 6 is C4 alkynyl. In some embodiments, R 6 is C5 alkynyl. In some embodiments, R 6 is a C6 alkynyl.

[0198] In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more halogens. In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more F. In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more Cl. In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more Br. In some embodiments, R6 is a C2-C6 alkynyl substituted with one or more I. In some embodiments, R 6is a C2-C6 alkynyl substituted with one or more OH. In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more NH2. In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more C1-C6 alkyl. In some embodiments, R 6 is a C2-C6 alkynyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 6 is one or more NRs 12 R 13 is a C2-C6 alkynyl substituted with

[0199] In some embodiments, R 6 is cycloisopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is cyclopentyl. In some embodiments, R 6 is cyclohexyl. In some embodiments, R 6 is cycloheptyl. In some embodiments, R 6 is cyclooctyl. In some embodiments, R 6 is cyclononyl. In some embodiments, R 6 is cyclodecyl.

[0200] In some embodiments, R 6 is a C3-C substituted with one or more halogens 10 In some embodiments, R 6 is C3-C substituted with one or more F 10 In some embodiments, R 6 is C3-C substituted with one or more Cl groups 10 In some embodiments, R 6 is C3-C substituted with one or more Br 10 In some embodiments, R 6is C3-C substituted with one or more I 10 In some embodiments, R 6 is a C3-C substituted with one or more OH 10 In some embodiments, R 6 is a C3-C substituted with one or more NH2 10 In some embodiments, R 6 is a C3-C substituted with one or more C1-C6 alkyl 10 In some embodiments, R 6 is a C3-C substituted with one or more C1-C6 alkoxy groups 10 In some embodiments, R 6 is one or more NRs 12 R 13 C3-C substituted with 10 It is cycloalkyl.

[0201] In some embodiments, R 6 is C6 aryl (e.g., phenyl).

[0202] In some embodiments, R 6 is aryl substituted with one or more halogens. In some embodiments, R 6 is aryl substituted with one or more F. In some embodiments, R 6 is aryl substituted with one or more Cl. In some embodiments, R 6 is aryl substituted with one or more Br. In some embodiments, R 6 is aryl substituted with one or more I. In some embodiments, R 6 is aryl substituted with one or more OH. In some embodiments, R 6 is aryl substituted with one or more NH. In some embodiments, R 6is aryl substituted with one or more C1-C6 alkyl. In some embodiments, R 6 is aryl substituted with one or more C1-C6 alkoxy. In some embodiments, R 6 is one or more NRs 12 R 13 is an aryl substituted with

[0203] In some embodiments, R 6 is a 3- to 8-membered heterocycle. In some embodiments, R 6 is a 3- to 10-membered heterocycle.

[0204] In some embodiments, R 6 is a monocyclic heterocycle. In some embodiments, R 6 is a polycyclic heterocycle.

[0205] In some embodiments, R 6 is a 3-membered heterocycle. In some embodiments, R 6 is a 4-membered heterocycle. In some embodiments, R 6 is a 5-membered heterocycle. In some embodiments, R 6 is a 6-membered heterocycle. In some embodiments, R 6 is a 7-membered heterocycle. In some embodiments, R 6 is an 8-membered heterocycle. In some embodiments, R 6 is a 9-membered heterocycle. In some embodiments, R 6 is a 10-membered heterocycle.

[0206] In some embodiments, R 6 is heterocyclyl substituted with one or more halogens. In some embodiments, R 6 is heterocyclyl substituted with one or more F. In some embodiments, R 6 is heterocyclyl substituted with one or more Cl. In some embodiments, R 6is heterocyclyl substituted with one or more Br. In some embodiments, R 6 is heterocyclyl substituted with one or more I. In some embodiments, R 6 is heterocyclyl substituted with one or more OH. In some embodiments, R 6 is heterocyclyl substituted with one or more NH. In some embodiments, R 6 is heterocyclyl substituted with one or more C1-C6 alkyl. In some embodiments, R 6 is heterocyclyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 6 is one or more NRs 12 R 13 and heterocyclyl substituted with

[0207] In some embodiments, R 6 is heteroaryl. In some embodiments, R 6 is a 5-6 membered heteroaryl. In some embodiments, R 6 is a 5- to 10-membered heteroaryl.

[0208] In some embodiments, R 6 is a heteroaryl containing 1, 2 or 3 heteroatoms.

[0209] In some embodiments, R 6 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0210] In some embodiments, R 6 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N and O.

[0211] In some embodiments, R 6 is a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R6 is a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 6 is a 7-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 6 is an 8-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 6 is a 9-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 6 is a 10-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S.

[0212] In some embodiments, R 6 is heteroaryl substituted with one or more halogens. In some embodiments, R 6 is heteroaryl substituted with one or more F. In some embodiments, R 6 is heteroaryl substituted with one or more Cl. In some embodiments, R 6 is heteroaryl substituted with one or more Br. In some embodiments, R 6 is heteroaryl substituted with one or more I. In some embodiments, R 6 is heteroaryl substituted with one or more OH. In some embodiments, R 6 is heteroaryl substituted with one or more NH. In some embodiments, R 6 is heteroaryl substituted with one or more C1-C6 alkyl. In some embodiments, R 6 is heteroaryl substituted with one or more C1-C6 alkoxy. In some embodiments, R 6 is one or more NRs 12 R 13 and heteroaryl substituted with

[0213] In some embodiments, R 7 is NH. In some embodiments, R 7 is NR 12 R 13 In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is C-C alkenyl. In some embodiments, R 7 is C2-C6 alkynyl. In some embodiments, R 7 is C3-C 10 In some embodiments, R 7 is aryl. In some embodiments, R 7 is heterocyclyl. In some embodiments, R 7 is heteroaryl.

[0214] In some embodiments, R 7 is NH2 or NR 12 R 13 In some embodiments, R 7 is C-C alkyl, C-C alkenyl, or C-C alkynyl. In some embodiments, R 7 is C3-C 10 It is cycloalkyl, aryl, heterocycle, or heteroaryl.

[0215] In some embodiments, R 7 is NH. In some embodiments, R 7 is NR 12 R 13 In some embodiments, R 7 is unsubstituted C1-C6 alkyl. In some embodiments, R 7 is unsubstituted C-C alkenyl. In some embodiments, R 7 is an unsubstituted C2-C6 alkynyl. In some embodiments, R 7 is unsubstituted C3-C 10 In some embodiments, R 7is unsubstituted aryl. In some embodiments, R 7 is unsubstituted heterocyclyl. In some embodiments, R 7 is an unsubstituted heteroaryl.

[0216] In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is propyl. In some embodiments, R 7 is n-propyl. In some embodiments, R 7 is isopropyl. In some embodiments, R 7 is butyl. In some embodiments, R 7 is n-butyl. In some embodiments, R 7 is isobutyl. In some embodiments, R 7 is sec-butyl. In some embodiments, R 7 is tert-butyl. In some embodiments, R 7 is pentyl. In some embodiments, R 7 is hexyl.

[0217] In some embodiments, R 7 is C1-C6 alkyl substituted with one or more halogens. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more F. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more Cl. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more Br. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more I. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more OH. In some embodiments, R 7is C1-C6 alkyl substituted with one or more NH2. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more C1-C6 alkyl. In some embodiments, R 7 is C1-C6 alkyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 7 is one or more NRs 12 R 13 is C1-C6 alkyl substituted with

[0218] In some embodiments, R 7 is C alkenyl. In some embodiments, R 7 is C alkenyl. In some embodiments, R 7 is C4 alkenyl. In some embodiments, R 7 is C5 alkenyl. In some embodiments, R 7 is a C6 alkenyl.

[0219] In some embodiments, R 7 is a C-C alkenyl substituted with one or more halogens. In some embodiments, R 7 is a C2-C6 alkenyl substituted with one or more F. In some embodiments, R 7 is a C-C alkenyl substituted with one or more Cl. In some embodiments, R 7 is a C2-C6 alkenyl substituted with one or more Br. In some embodiments, R 7 is a C-C alkenyl substituted with one or more I. In some embodiments, R 7 is a C2-C6 alkenyl substituted with one or more OH. In some embodiments, R 7 is a C-C alkenyl substituted with one or more NH. In some embodiments, R 7 is a C2-C6 alkenyl substituted with one or more C1-C6 alkyl. In some embodiments, R7 is a C2-C6 alkenyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 7 is one or more NRs 12 R 13 and C2-C6 alkenyl substituted with

[0220] In some embodiments, R 7 is C alkynyl. In some embodiments, R 7 is C alkynyl. In some embodiments, R 7 is C4 alkynyl. In some embodiments, R 7 is C5 alkynyl. In some embodiments, R 7 is a C6 alkynyl.

[0221] In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more halogens. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more F. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more Cl. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more Br. In some embodiments, R6 is a C2-C6 alkynyl substituted with one or more I. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more OH. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more NH2. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more C1-C6 alkyl. In some embodiments, R 7 is a C2-C6 alkynyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 7 is one or more NRs 12 R 13is a C2-C6 alkynyl substituted with

[0222] In some embodiments, R 7 is cycloisopropyl. In some embodiments, R 7 is cyclobutyl. In some embodiments, R 7 is cyclopentyl. In some embodiments, R 7 is cyclohexyl. In some embodiments, R 7 is cycloheptyl. In some embodiments, R 7 is cyclooctyl. In some embodiments, R 7 is cyclononyl. In some embodiments, R 7 is cyclodecyl.

[0223] In some embodiments, R 7 is a C3-C substituted with one or more halogens 10 In some embodiments, R 7 is C3-C substituted with one or more F 10 In some embodiments, R 7 is C3-C substituted with one or more Cl groups 10 In some embodiments, R 7 is C3-C substituted with one or more Br 10 In some embodiments, R 7 is C3-C substituted with one or more I 10 In some embodiments, R 7 is a C3-C substituted with one or more OH 10 In some embodiments, R 7 is a C3-C substituted with one or more NH2 10 In some embodiments, R 7 is a C3-C substituted with one or more C1-C6 alkyl 10 In some embodiments, R7 is a C3-C substituted with one or more C1-C6 alkoxy groups 10 In some embodiments, R 7 is one or more NRs 12 R 13 C3-C substituted with 10 It is cycloalkyl.

[0224] In some embodiments, R 7 is C6 aryl (e.g., phenyl).

[0225] In some embodiments, R 7 is aryl substituted with one or more halogens. In some embodiments, R 7 is aryl substituted with one or more F. In some embodiments, R 7 is aryl substituted with one or more Cl. In some embodiments, R 7 is aryl substituted with one or more Br. In some embodiments, R 7 is aryl substituted with one or more I. In some embodiments, R 7 is aryl substituted with one or more OH. In some embodiments, R 7 is aryl substituted with one or more NH. In some embodiments, R 7 is aryl substituted with one or more C1-C6 alkyl. In some embodiments, R 7 is aryl substituted with one or more C1-C6 alkoxy. In some embodiments, R 7 is one or more NRs 12 R 13 is an aryl substituted with

[0226] In some embodiments, R 7 is a 3- to 8-membered heterocycle. In some embodiments, R 7 is a 3- to 10-membered heterocycle.

[0227] In some embodiments, R 7 is monocyclic heterocyclyl. In some embodiments, R 7 is a polycyclic heterocyclyl.

[0228] In some embodiments, R 7 is a 3-membered heterocycle. In some embodiments, R 7 is a 4-membered heterocycle. In some embodiments, R 7 is a 5-membered heterocycle. In some embodiments, R 7 is a 6-membered heterocycle. In some embodiments, R 7 is a 7-membered heterocycle. In some embodiments, R 7 is an 8-membered heterocycle. In some embodiments, R 7 is a 9-membered heterocycle. In some embodiments, R 7 is a 10-membered heterocycle.

[0229] In some embodiments, R 7 is a heterocycle substituted with one or more halogens. In some embodiments, R 7 is a heterocycle substituted with one or more F. In some embodiments, R 7 is a heterocycle substituted with one or more Cl. In some embodiments, R 7 is a heterocycle substituted with one or more Br. In some embodiments, R 7 is a heterocycle substituted with one or more I. In some embodiments, R 7 is a heterocycle substituted with one or more OH. In some embodiments, R 7 is a heterocycle substituted with one or more NH. In some embodiments, R 7 is a heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 7 is a heterocycle substituted with one or more C1-C6 alkoxy. In some embodiments, R 7 is one or more NRs 12 R 13is a heterocycle substituted with

[0230] In some embodiments, R 7 is heteroaryl. In some embodiments, R 7 is a 5-6 membered heteroaryl. In some embodiments, R 7 is a 5- to 10-membered heteroaryl.

[0231] In some embodiments, R 7 is a heteroaryl containing 1, 2 or 3 heteroatoms.

[0232] In some embodiments, R 7 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0233] In some embodiments, R 7 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N and O.

[0234] In some embodiments, R 7 is a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 7 is a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 7 is a 7-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 7 is an 8-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 7 is a 9-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 7 is a 10-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S.

[0235] In some embodiments, R7 is heteroaryl substituted with one or more halogens. In some embodiments, R 7 is heteroaryl substituted with one or more F. In some embodiments, R 7 is heteroaryl substituted with one or more Cl. In some embodiments, R 7 is heteroaryl substituted with one or more Br. In some embodiments, R 7 is heteroaryl substituted with one or more I. In some embodiments, R 7 is heteroaryl substituted with one or more OH. In some embodiments, R 7 is heteroaryl substituted with one or more NH. In some embodiments, R 7 is heteroaryl substituted with one or more C1-C6 alkyl. In some embodiments, R 7 is heteroaryl substituted with one or more C1-C6 alkoxy. In some embodiments, R 7 is one or more NRs 12 R 13 and heteroaryl substituted with

[0236] In some embodiments, R 8 is halogen. In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is Br. In some embodiments, R 8 is I. In some embodiments, R 8 is oxo. In some embodiments, R 8 is CN. In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is C1-C6 alkoxy. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R8 is C1-C6 alkyl-NR 12 R 13 is.

[0237] In some embodiments, R 8 is halogen. In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is Br. In some embodiments, R 8 is I. In some embodiments, R 8 is oxo. In some embodiments, R 8 is CN. In some embodiments, R 8 is unsubstituted C1-C6 alkyl. In some embodiments, R 8 is unsubstituted C1-C6 alkoxy. In some embodiments, R 8 is unsubstituted C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 8 is unsubstituted C1-C6 alkyl-NR 12 R 13 is.

[0238] In some embodiments, R 8 is C1-C6 alkyl substituted with one or more halogens. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more F. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more Cl. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more Br. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more I. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more oxo. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more OH. In some embodiments, R8 is C1-C6 alkyl substituted with one or more NH2. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more C1-C6 alkyl. In some embodiments, R 8 is C1-C6 alkyl substituted with one or more C1-C6 alkoxy. In some embodiments, R 8 is one or more NRs 12 R 13 In some embodiments, R 8 is one or more C3-C 10 In some embodiments, R is C1-C6 alkyl substituted with cycloalkyl. 8 is C1-C6 alkyl substituted with one or more heterocycloalkyl.

[0239] In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more halogens. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more F. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more Cl. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more Br. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more I. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more oxo. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more OH. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more NH2. In some embodiments, R 8 is C1-C6 alkoxy substituted with one or more C1-C6 alkyl. In some embodiments, R 8is C1-C6 alkoxy substituted with one or more C1-C6 alkoxy. In some embodiments, R 8 is one or more NRs 12 R 13 In some embodiments, R 8 is one or more C3-C 10 In some embodiments, R is C1-C6 alkoxy substituted with cycloalkyl. 8 is C1-C6 alkoxy substituted with one or more heterocycloalkyl.

[0240] In some embodiments, R 8 is C-C alkyl-C-C alkoxy substituted with one or more halogens. In some embodiments, R 8 is C-C alkyl-C-C alkoxy substituted with one or more F. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more Cl. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more Br. In some embodiments, R 8 is C-C alkyl-C-C alkoxy substituted with one or more I. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more oxo. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more OH. In some embodiments, R 8 is C-C alkyl-C-C alkoxyNH. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more C1-C6 alkyl. In some embodiments, R 8is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more C1-C6 alkoxy. In some embodiments, R 8 is one or more NRs 12 R 13 In some embodiments, R 8 is one or more C3-C 10 In some embodiments, R is C-C alkyl-C-C alkoxy substituted with cycloalkyl. 8 is C1-C6 alkyl-C1-C6 alkoxy substituted with one or more heterocycloalkyl.

[0241] In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more halogens. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more F. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more Cl. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more Br. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more I. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more oxo. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more OH. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more NH2. In some embodiments, R8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more C1-C6 alkyls. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more C1-C6 alkoxy. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is one or more NR 12 R 13 In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is one or more C3-C 10 In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkyl is substituted with one or more heterocycloalkyl.

[0242] In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more halogens. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more F. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more Cl. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more Br. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more I. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more oxo. In some embodiments, R 8is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more OH. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more NH2. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more C1-C6 alkyl. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more C1-C6 alkoxy. In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is one or more NR 12 R 13 In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is one or more C3-C 10 In some embodiments, R 8 is C1-C6 alkyl-C1-C6 alkoxy, wherein the alkoxy is substituted with one or more heterocycloalkyl.

[0243] In some embodiments, R 8 is C1-C6 alkyl-NR substituted with one or more halogens 12 R 13 In some embodiments, R 8 is C1-C6 alkyl-NR substituted with one or more F 12 R 13 In some embodiments, R 8 is a C1-C6 alkyl-NR substituted with one or more Cl groups 12 R 13 In some embodiments, R 8 is a C1-C6 alkyl-NR substituted with one or more Br 12 R 13 In some embodiments, R8 is a C1-C6 alkyl-NR substituted with one or more I 12 R 13 In some embodiments, R 8 is a C1-C6 alkyl-NR substituted with one or more oxo groups 12 R 13 In some embodiments, R 8 is a C1-C6 alkyl-NR substituted with one or more OH groups 12 R 13 In some embodiments, R 8 is a C1-C6 alkyl-NR substituted with one or more NH2 12 R 13 In some embodiments, R 8 is C1-C6 alkyl-NR substituted with one or more C1-C6 alkyl groups 12 R 13 In some embodiments, R 8 is C1-C6 alkyl-NR substituted with one or more C1-C6 alkoxy 12 R 13 In some embodiments, R 8 is one or more NRs 12 R 13 C1-C6 alkyl-NR substituted with 12 R 13 In some embodiments, R 8 is one or more C3-C 10 Cycloalkyl-substituted C1-C6 alkyl-NR 12 R 13 In some embodiments, R 8 is a C1-C6 alkyl-NR substituted with one or more heterocycloalkyls 12 R 13 is.

[0244] In some embodiments, R 8 teeth [ka] In some embodiments, R8 teeth [ka] In some embodiments, R 8 teeth [ka] is.

[0245] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring. In some embodiments, R 6 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocyclic ring. In some embodiments, R 6 and R 8 together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocyclic ring.

[0246] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 5-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 6-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 7-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 8-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 9-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 10-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 11-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 12-membered heterocycle. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 13-membered heterocycle. In some embodiments, R 6and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 14-membered heterocycle.

[0247] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 6 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 5-membered heterocycle substituted with

[0248] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more I. In some embodiments, R6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 6-membered heterocycle substituted with

[0249] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more halogens. 6 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more OH. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more C1-C6 alkyl. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 6 and R 8are taken together with the molecule to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 7-membered heterocycle substituted with

[0250] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more NH2. 6 and R8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more C1-C6 alkyl. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form an 8-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms an 8-membered heterocycle substituted with

[0251] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 9-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 9-membered heterocycle substituted with

[0252] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more OH. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more C1-C6 alkyl. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 10-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8are taken together with the molecule to which they are attached and any intervening atoms to form a 10-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 10-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 10-membered heterocycle substituted with

[0253] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring substituted with one or more OH.6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring substituted with one or more C1-C6 alkyl. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form an 11-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form an 11-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms an 11-membered heterocycle substituted with

[0254] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring substituted with one or more OH. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring substituted with one or more C1-C6 alkyl. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 12-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 12-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 12-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms a 12-membered heterocycle substituted with

[0255] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocyclic ring substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocyclic ring substituted with one or more OH. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more NH2. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C1-C6 alkyl. 6 and R 8are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 13-membered heterocycle substituted with

[0256] In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more halogens. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more F. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more Cl. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more Br. In some embodiments, R 6 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more I. In some embodiments, R 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocyclic ring substituted with one or more OH. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more NH2. 6 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocyclic ring substituted with one or more C1-C6 alkyl. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 14-membered heterocycle substituted with one or more C1-C6 alkoxy. 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 14-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 6 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 14-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 6 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms a 14-membered heterocycle substituted with

[0257] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocyclic ring. In some embodiments, R7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocyclic ring. In some embodiments, R 7 and R 8 together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocyclic ring.

[0258] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 5-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 6-membered heterocycle. In some embodiments, R7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 7-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 8-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 9-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 10-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 11-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 12-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 13-membered heterocycle. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an unsubstituted 14-membered heterocycle.

[0259] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 5-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 5-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 5-membered heterocycle substituted with

[0260] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 7 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 6-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 6-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 6-membered heterocycle substituted with

[0261] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more I. In some embodiments, R7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more OH. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more C1-C6 alkyl. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 7-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 7-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 7-membered heterocycle substituted with

[0262] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more halogens. 7 and R 8taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more C1-C6 alkyl. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 8-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 7 and R 8are taken together with the molecule to which they are attached and any intervening atoms to form an 8-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms an 8-membered heterocycle substituted with

[0263] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocyclic ring substituted with one or more OH. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more NH2. 7 and R8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more C1-C6 alkyl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 9-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 9-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 9-membered heterocycle substituted with

[0264] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more OH. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 10-membered heterocycle substituted with one or more C1-C6 alkyl. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 10-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 10-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 10-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 10-membered heterocycle substituted with

[0265] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocyclic ring substituted with one or more OH. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more C1-C6 alkyl. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form an 11-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8taken together with the molecule to which they are attached and any intervening atoms, form an 11-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form an 11-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms an 11-membered heterocycle substituted with

[0266] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring substituted with one or more OH.7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 12-membered heterocyclic ring substituted with one or more C1-C6 alkyl. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 12-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 12-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 12-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms a 12-membered heterocycle substituted with

[0267] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocyclic ring substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocyclic ring substituted with one or more OH. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 13-membered heterocycle substituted with one or more NH2. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C1-C6 alkyl. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C-C alkyl-C-C alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 13-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 forming a 13-membered heterocycle substituted with

[0268] In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more halogens. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more F. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more Cl. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more Br. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more I. In some embodiments, R 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocyclic ring substituted with one or more OH. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocycle substituted with one or more NH2. 7 and R 8 taken together with the molecule to which they are attached and any intervening atoms, form a 14-membered heterocyclic ring substituted with one or more C1-C6 alkyl. 7 and R 8are taken together with the molecule to which they are attached and any intervening atoms to form a 14-membered heterocycle substituted with one or more C1-C6 alkoxy. 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 14-membered heterocycle substituted with one or more C1-C6 alkyl-C1-C6 alkoxy. In some embodiments, R 7 and R 8 are taken together with the molecule to which they are attached and any intervening atoms to form a 14-membered heterocycle substituted with one or more C-C alkyl-NHC-C alkyl. In some embodiments, R 7 and R 8 together with the molecules to which they are attached and any intervening atoms, form one or more NR 12 R 13 Forms a 14-membered heterocycle substituted with

[0269] In some embodiments, R 12 is H. In some embodiments, R 12 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy. In some embodiments, R 12 is C3-C 10 It is cycloalkyl, heterocycle, aryl, or heteroaryl.

[0270] In some embodiments, R 12 is C1-C6 alkyl.

[0271] In some embodiments, R 12 is methyl. In some embodiments, R 12 is ethyl. In some embodiments, R 12 is propyl. In some embodiments, R 12 is n-propyl. In some embodiments, R 12 is isopropyl. In some embodiments, R 12is butyl. In some embodiments, R 12 is n-butyl. In some embodiments, R 12 is isobutyl. In some embodiments, R 12 is sec-butyl. In some embodiments, R 12 is tert-butyl. In some embodiments, R 12 is pentyl. In some embodiments, R 12 is hexyl.

[0272] In some embodiments, R 12 is C1-C6 alkoxy.

[0273] In some embodiments, R 12 is methoxy. In some embodiments, R 12 is ethoxy. In some embodiments, R 12 is propoxy. In some embodiments, R 12 is n-propoxy. In some embodiments, R 12 is isopropoxy. In some embodiments, R 12 is butoxy. In some embodiments, R 12 is n-butoxy. In some embodiments, R 12 is isobutoxy. In some embodiments, R 12 is sec-butoxy. In some embodiments, R 12 is tert-butoxy. In some embodiments, R 12 is pentoxy. In some embodiments, R 12 is hexoxy.

[0274] In some embodiments, R 12 is C3-C 10 It is cycloalkyl.

[0275] In some embodiments, R 12 is cycloisopropyl. In some embodiments, R 12is cyclobutyl. In some embodiments, R 12 is cyclopentyl. In some embodiments, R 12 is cyclohexyl. In some embodiments, R 12 is cycloheptyl. In some embodiments, R 12 is cyclooctyl. In some embodiments, R 12 is cyclononyl. In some embodiments, R 12 is cyclodecyl.

[0276] In some embodiments, R 12 is C2-C6 alkenyl.

[0277] In some embodiments, R 12 is C alkenyl. In some embodiments, R 12 is C alkenyl. In some embodiments, R 12 is C4 alkenyl. In some embodiments, R 12 is C5 alkenyl. In some embodiments, R 12 is a C6 alkenyl.

[0278] In some embodiments, R 12 is C2-C6 alkynyl.

[0279] In some embodiments, R 12 is C alkynyl. In some embodiments, R 12 is C alkynyl. In some embodiments, R 12 is C4 alkynyl. In some embodiments, R 12 is C5 alkynyl. In some embodiments, R 12 is a C6 alkynyl.

[0280] In some embodiments, R 12 is heterocyclyl.

[0281] In some embodiments, R 12is a 3- to 8-membered heterocyclyl. In some embodiments, R 12 is a 3- to 10-membered heterocyclyl.

[0282] In some embodiments, R 12 is monocyclic heterocyclyl. In some embodiments, R 12 is a polycyclic heterocyclyl.

[0283] In some embodiments, R 12 is a 3-membered heterocyclyl. In some embodiments, R 12 is a 4-membered heterocyclyl. In some embodiments, R 12 is a 5-membered heterocyclyl. In some embodiments, R 12 is a 6-membered heterocyclyl. In some embodiments, R 12 is a 7-membered heterocyclyl. In some embodiments, R 12 is an 8-membered heterocyclyl. In some embodiments, R 12 is a 9-membered heterocyclyl. In some embodiments, R 12 is a 10-membered heterocyclyl.

[0284] In some embodiments, R 12 is aryl. In some embodiments, R 12 is C6 aryl (e.g., phenyl).

[0285] In some embodiments, R 12 is heteroaryl.

[0286] In some embodiments, R 12 is heteroaryl. In some embodiments, R 12 is a 5-6 membered heteroaryl. In some embodiments, R 12 is a 5- to 10-membered heteroaryl.

[0287] In some embodiments, R 12 is a heteroaryl containing 1, 2 or 3 heteroatoms.

[0288] In some embodiments, R 12 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0289] In some embodiments, R 12 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N and O.

[0290] In some embodiments, R 12 is a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 12 is a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 12 is a 7-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 12 is an 8-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 12 is a 9-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 12 is a 10-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S.

[0291] In some embodiments, R 13 is H. In some embodiments, R 13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy. In some embodiments, R 13 is C3-C 10 It is cycloalkyl, heterocycle, aryl, or heteroaryl.

[0292] In some embodiments, R 13 is C1-C6 alkyl.

[0293] In some embodiments, R 13 is methyl. In some embodiments, R 13 is ethyl. In some embodiments, R 13 is propyl. In some embodiments, R 13 is n-propyl. In some embodiments, R 13 is isopropyl. In some embodiments, R 13 is butyl. In some embodiments, R 13 is n-butyl. In some embodiments, R 13 is isobutyl. In some embodiments, R 13 is sec-butyl. In some embodiments, R 13 is tert-butyl. In some embodiments, R 13 is pentyl. In some embodiments, R 13 is hexyl.

[0294] In some embodiments, R 13 is C1-C6 alkoxy.

[0295] In some embodiments, R 13 is methoxy. In some embodiments, R 13 is ethoxy. In some embodiments, R 13 is propoxy. In some embodiments, R 13 is n-propoxy. In some embodiments, R 13 is isopropoxy. In some embodiments, R 13 is butoxy. In some embodiments, R 13 is n-butoxy. In some embodiments, R 13 is isobutoxy. In some embodiments, R 13 is sec-butoxy. In some embodiments, R 13 is tert-butoxy. In some embodiments, R 13 is pentoxy. In some embodiments, R 13is hexoxy.

[0296] In some embodiments, R 13 is C3-C 10 It is cycloalkyl.

[0297] In some embodiments, R 13 is cycloisopropyl. In some embodiments, R 13 is cyclobutyl. In some embodiments, R 13 is cyclopentyl. In some embodiments, R 13 is cyclohexyl. In some embodiments, R 13 is cycloheptyl. In some embodiments, R 13 is cyclooctyl. In some embodiments, R 13 is cyclononyl. In some embodiments, R 13 is cyclodecyl.

[0298] In some embodiments, R 13 is C2-C6 alkenyl.

[0299] In some embodiments, R 13 is C alkenyl. In some embodiments, R 13 is C alkenyl. In some embodiments, R 13 is C4 alkenyl. In some embodiments, R 13 is C5 alkenyl. In some embodiments, R 13 is a C6 alkenyl.

[0300] In some embodiments, R 13 is C2-C6 alkynyl.

[0301] In some embodiments, R 13 is C alkynyl. In some embodiments, R 13 is C alkynyl. In some embodiments, R 13 is C4 alkynyl. In some embodiments, R13 is C5 alkynyl. In some embodiments, R 13 is a C6 alkynyl.

[0302] In some embodiments, R 13 is heterocyclyl.

[0303] In some embodiments, R 13 is a 3- to 8-membered heterocycle. In some embodiments, R 13 is a 3- to 10-membered heterocycle.

[0304] In some embodiments, R 13 is a monocyclic heterocycle. In some embodiments, R 13 is a polycyclic heterocycle.

[0305] In some embodiments, R 13 is a 3-membered heterocycle. In some embodiments, R 13 is a 4-membered heterocycle. In some embodiments, R 13 is a 5-membered heterocycle. In some embodiments, R 13 is a 6-membered heterocycle. In some embodiments, R 13 is a 7-membered heterocycle. In some embodiments, R 13 is an 8-membered heterocycle. In some embodiments, R 13 is a 9-membered heterocycle. In some embodiments, R 13 is a 10-membered heterocycle.

[0306] In some embodiments, R 13 is aryl. In some embodiments, R 13 is C6 aryl (e.g., phenyl).

[0307] In some embodiments, R 13 is heteroaryl.

[0308] In some embodiments, R 13 is heteroaryl. In some embodiments, R 13is a 5-6 membered heteroaryl. In some embodiments, R 13 is a 5- to 10-membered heteroaryl.

[0309] In some embodiments, R 13 is a heteroaryl containing 1, 2 or 3 heteroatoms.

[0310] In some embodiments, R 13 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0311] In some embodiments, R 13 is heteroaryl containing 1, 2 or 3 heteroatoms selected from N and O.

[0312] In some embodiments, R 13 is a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 13 is a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 13 is a 7-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 13 is an 8-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 13 is a 9-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, R 13 is a 10-membered heteroaryl containing 1 to 4 heteroatoms selected from O, N, and S.

[0313] In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0314] In some embodiments, p is 0. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0315] In some embodiments, q is 0. In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2.

[0316] In some embodiments, s is 0. In some embodiments, s is 1 or 2. In some embodiments, s is 1. In some embodiments, s is 2.

[0317] In some embodiments, the compound is a compound of formula (IA), (IB), (ID), (IE), (IF), or (IG): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0318] In some embodiments, the compound is a compound of formula (IAI), (IA-II), (IA-III), (IA-IV), (IAV), or (IA-VI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Ring E is selected from halogen, OH, NH, C-C alkyl, C-C alkoxy, and NR 12 R 13 and all other variables are as defined herein.

[0319] In some embodiments, Ring E is aryl. In some embodiments, Ring E is heteroaryl. In some embodiments, Ring E is unsubstituted aryl. In some embodiments, Ring E is unsubstituted heteroaryl.

[0320] In some embodiments, ring E is C6 aryl (eg, phenyl).

[0321] In some embodiments, ring E is heteroaryl. In some embodiments, ring E is a 5-6 membered heteroaryl. In some embodiments, ring E is a 5-10 membered heteroaryl.

[0322] In some embodiments, Ring E is a heteroaryl containing 1, 2, or 3 heteroatoms.

[0323] In some embodiments, ring E is heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0324] In some embodiments, ring E is heteroaryl containing 1, 2, or 3 heteroatoms selected from N and O.

[0325] In some embodiments, ring E is a 5-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, ring E is a 6-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, ring E is a 7-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, ring E is an 8-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, ring E is a 9-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S. In some embodiments, ring E is a 10-membered heteroaryl containing 1-4 heteroatoms selected from O, N, and S.

[0326] In some embodiments, ring E is a heteroaryl containing one heteroatom selected from N and O. In some embodiments, ring E is a heteroaryl containing two heteroatoms selected from N and O. In some embodiments, ring E is a heteroaryl containing three heteroatoms selected from N and O.

[0327] In some embodiments, Ring E is a monocyclic heteroaryl. In some embodiments, Ring E is a bicyclic heteroaryl.

[0328] In some embodiments, ring E is:

[0329] [ka] .

[0330] In some embodiments, ring E is [ka] is.

[0331] In some embodiments, ring E is [ka] is.

[0332] In some embodiments, ring E is [ka] is.

[0333] In some embodiments, the compound is a compound of formula (IAI). In some embodiments, the compound is a compound of formula (IA-II). In some embodiments, the compound is a compound of formula (IA-III). In some embodiments, the compound is a compound of formula (IA-IV). In some embodiments, the compound is a compound of formula (IAV). In some embodiments, the compound is a compound of formula (IA-VI).

[0334] In some embodiments, the compound is a compound of formula (I-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein W is independently, at each occurrence, -CH2-, -(CH2)2-, or -(CH2)3-.

[0335] In various embodiments, the inhibitor of menin-MLL interaction is a compound having a structure represented by formula (I-1-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0336] In various embodiments, the compound according to formula (I-1-A) is a 4-(3,9-diazaspiro[5.5]undecan-3-yl)-substituted quinazoline. In specific embodiments of these quinazolines, L 1 is H or a sulfonamide spaced from the 3,9-diazaspiro[5.5]undecane moiety by a tether containing an aryl or carbocyclic ring as a spacer. In these and other embodiments, p is 2 and one R 1 is a tethered trifluoromethyl group, and the other R 1 is an amino group or a substituted amino group. In other examples, p=0, and therefore R1 is null.

[0337] In various embodiments, the compound according to formula (I-1-A) is a 4-(2,7-diazaspiro[3.5]nonan-2-yl)-substituted quinazoline. In specific embodiments of these quinazolines, L 1 is H. In these and other embodiments, p is 1 and R 1 is a tethered aryl group, such as a phenyl or pyridomyl group, tethered to the quinazoline core structure, for example at the 6-position, by a chain of 1 to 4 carbons in length, which is saturated or contains an alkene or alkyne functionality within the carbon chain.

[0338] In some embodiments, the compound is a compound of formula (I-1-A-1), (I-1-A-2), (I-1-A-3), or (IA-VII): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein ring G is selected from the group consisting of halogen, OH, NH, C-C alkyl, C-C alkoxy, NR 12 R 13 and all other variables are as defined herein.

[0339] In some embodiments, ring G is a 5-8 membered heterocycle. In some embodiments, ring G is a 5-6 membered heterocycle.

[0340] In some embodiments, ring G is a 5-8 membered heterocycle containing 1, 2, or 3 heteroatoms.

[0341] In some embodiments, ring G is a 5-8 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0342] In some embodiments, ring G is a 5-8 membered heterocycle containing 1, 2, or 3 heteroatoms selected from N and O.

[0343] In some embodiments, ring G is a 5-membered heterocycle containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, ring G is a 6-membered heterocycle containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, ring G is a 7-membered heterocycle containing 1 to 4 heteroatoms selected from O, N, and S. In some embodiments, ring G is an 8-membered heterocycle containing 1 to 4 heteroatoms selected from O, N, and S.

[0344] In some embodiments, ring G is a 5-8 membered heterocycle containing one heteroatom selected from N and O. In some embodiments, ring G is a 5-8 membered heterocycle containing two heteroatoms selected from N and O. In some embodiments, ring G is a 5-8 membered heterocycle containing three heteroatoms selected from N and O.

[0345] In some embodiments, the compound is a compound of formula (I-1-A-1). In some embodiments, the compound is a compound of formula (I-1-A-2). In some embodiments, the compound is a compound of formula (I-1-A-3). In some embodiments, the compound is a compound of formula (IA-VII).

[0346] In some embodiments, the compound is a compound of formula (I-1-A-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0347] In some embodiments, the compound is a compound of formula (I-1-A-1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0348] In some embodiments, the compound is a compound of formula (I-1-A-1-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0349] In some embodiments, the compound is a compound of formula (I-1-A-1-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0350] In some embodiments, the compound is a compound of formula (I-1-A-1-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0351] In some embodiments, the compound is a compound of formula (I-1-A-1-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0352] In some embodiments, the compound is a compound of formula (I-1-A-1-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0353] In some embodiments, the compound is a compound of formula (I-1-A-1-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0354] In some embodiments, the compound is a compound of formula (I-1-A-1-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0355] In some embodiments, the compound is a compound of formula (I-1-A-1-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0356] In some embodiments, the compound is a compound of formula (I-1-A-1-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0357] In some embodiments, the compound is a compound of formula (I-1-A-1-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0358] In some embodiments, the compound is a compound of formula (I-1-A-1-12): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0359] In some embodiments, the compound is a compound of formula (I-1-A-1-13): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0360] In some embodiments, the compound is a compound of formula (I-1-A-1-14): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0361] In some embodiments, the compound is a compound of formula (I-1-A-1-15): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0362] In some embodiments, the compound is a compound of formula (I-1-A-1-16): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0363] In some embodiments, the compound is a compound of formula (I-1-A-1-17): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0364] In some embodiments, the compound is a compound of formula (I-1-B-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0365] In some embodiments, the compound is a compound of formula (I-1-B-1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0366] In some embodiments, the compound is a compound of formula (I-1-B-1-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0367] In some embodiments, the compound is a compound of formula (I-1-B-1-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0368] In some embodiments, the compound is a compound of formula (I-1-D-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0369] In some embodiments, the compound is a compound of formula (I-1-D-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0370] In some embodiments, the compound is a compound of formula (I-1-E-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0371] In some embodiments, the compound is a compound of formula (I-1-E-1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0372] In some embodiments, the compound is a compound of formula (I-1-F-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0373] In some embodiments, the compound is a compound of formula (I-1-F-1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0374] In some embodiments, the compound is a compound of formula (I-1-G-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0375] In some embodiments, the compound is a compound of formula (I-1-G-1-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0376] In some embodiments, the compound is a compound of formula (I-1-A-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0377] In some embodiments, the compound is a compound of formula (I-1-A-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0378] In some embodiments, the compound is a compound of formula (I-1-A-2-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0379] In some embodiments, the compound is a compound of formula (I-1-A-2-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0380] In some embodiments, the compound is a compound of formula (I-1-A-2-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0381] In some embodiments, the compound is a compound of formula (I-1-B-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0382] In some embodiments, the compound is a compound of formula (I-1-D-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0383] In some embodiments, the compound is a compound of formula (I-1-D-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0384] In some embodiments, the compound is a compound of formula (I-1-E-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0385] In some embodiments, the compound is a compound of formula (I-1-E-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0386] In some embodiments, the compound is a compound of formula (I-1-F-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0387] In some embodiments, the compound is a compound of formula (I-1-F-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0388] In some embodiments, the compound is a compound of formula (I-1-G-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0389] In some embodiments, the compound is a compound of formula (I-1-G-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0390] In some embodiments, the compound is a compound of formula (I-1-A-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0391] In some embodiments, the compound is a compound of formula (I-1-A-3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0392] In some embodiments, the compound is a compound of formula (I-1-A-3-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0393] In some embodiments, the compound is a compound of formula (I-1-A-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0394] In some embodiments, the compound is a compound of formula (I-1-A-4-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0395] In some embodiments, the compound is a compound of formula (I-1-A-4-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0396] In some embodiments, the compound is a compound of formula (I-1-A-4-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0397] In some embodiments, the compound is a compound of formula (I-1-A-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0398] In some embodiments, the compound is a compound of formula (I-1-A-5-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0399] In some embodiments, the compound is a compound of formula (I-1-A-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0400] In some embodiments, the compound is a compound of formula (I-1-A-6-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0401] In some embodiments, the compound is a compound of formula (I-2-I), (I-2-II), (I-2-III), or (I-2-IV): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all variables are as defined herein.

[0402] In some embodiments, the compound is a compound of Formula (I-2-I). In some embodiments, the compound is a compound of Formula (I-2-II). In some embodiments, the compound is a compound of Formula (I-2-III). In some embodiments, the compound is a compound of Formula (I-2-IV).

[0403] In some embodiments, the compound is a compound of formula (I-2-AI), (I-2-A-II), (I-2-A-III), or (I-2-A-IV): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all variables are as defined herein.

[0404] In some embodiments, the compound is a compound of formula (I-2-BI), (I-2-B-II), (I-2-B-III), or (I-2-B-IV): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein all variables are as defined herein.

[0405] In some embodiments, the compound is selected from the compounds set forth in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0406] In some embodiments, the compound is selected from the compounds set forth in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0407] In some embodiments, the compound is selected from the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0408] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0409] In some embodiments, the compound is selected from the compounds set forth in Table 1.

[0410] JPEG2024545511000102.jpg242170JPEG2024545511000103.jpg242170JPEG2024545511000104.jpg235170JPEG20245455110 00105.jpg248170JPEG2024545511000106.jpg235170JPEG2024545511000107.jpg247170JPEG2024545511000108.jpg178170

[0411] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

[0412] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 1.

[0413] In some embodiments, the compound is the sodium or potassium salt of any one of the compounds listed in Table 1.

[0414] In some embodiments, the compound is the sodium salt of any one of the compounds listed in Table 1.

[0415] In some embodiments, the compound is the potassium salt of any one of the compounds listed in Table 1.

[0416] 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.

[0417] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0418] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0419] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0420] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0421] 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 performing the procedures disclosed in the schemes and / or examples described herein by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0422] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0423] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0424] As used herein, the term "isotopic derivative" 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 with or labeled with one or more atoms selected from S and S). 2 H).

[0425] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0426] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0427] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0428] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 1.

[0429] 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%.

[0430] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation in 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 between the deuterium abundance and the natural abundance of deuterium.

[0431] 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.

[0432] Compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof containing the above deuterium atom(s) are within the scope of the present disclosure. 2 H) may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0433] In some embodiments, the compound is 18 F-labeled compound.

[0434] 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.

[0435] 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.

[0436] 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 are generally prepared using S-labeled compounds instead 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 / or 36 It can be prepared by using an S-labeled reagent and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0437] The above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof containing one or more S atom(s) are within the scope of the present disclosure.18 F, 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.

[0438] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that the group encompasses the broadest definition occurring first, as well as each and every specific definition of that group.

[0439] 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 daltons, for example, less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. More conveniently, the molecular weight is less than 600 daltons, for example, 550 daltons or less.

[0440] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure, which are sufficiently basic, for example, 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 the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0441] It will be understood that the compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include all isomeric forms, stereoisomers, mixtures of stereoisomers, and polymorphs of the compounds.

[0442] As used herein, the term "isomer" 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."

[0443] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0444] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog. (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).

[0445] As used herein, the term "geometric isomer" refers to diastereomers whose existence results from 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 that the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0446] It should be understood that the compounds of the present disclosure can be represented as different chiral or geometric isomers. 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 it should be understood that the name of the compound does not exclude any isomeric form, and not all isomers may have the same level of activity.

[0447] It should 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 may have the same level of activity.

[0448] 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 owe their existence to restricted rotation caused by the hindrance of rotation of large groups around a central bond. 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.

[0449] 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 tautomeric sets 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 are interconvertible by tautomerism is called tautomerism. Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous electron and hydrogen atom shift occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) form, such as that exhibited by glucose.

[0450] It should be understood that the compounds of the present disclosure can be represented as different tautomeric forms. When a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and it should also be understood that the naming of a compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[0451] 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 non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be 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, referred to as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0452] The compounds of the present disclosure may have one or more asymmetric centers. Therefore, such compounds can be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and their racemic 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 ed., J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E- 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.

[0453] The present disclosure also includes compounds of the present disclosure as defined herein that contain one or more isotopic substitutions.

[0454] It should be understood that the compounds of any formula described herein include the compounds themselves, as well as their salts and solvates, if applicable.Salts can be formed, for example, 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, trifluoroacetic acid, glutamate, glucuronic acid, glutaric acid, malate, maleate, succinate, fumarate, tartaric acid, tosylate, salicylate, lactic acid, naphthalenesulfonate, and acetate (e.g., trifluoroacetic acid).

[0455] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate). 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.

[0456] It is understood that compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0457] As used herein, the term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent.Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate.A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance, where the water retains its molecular state as HO.

[0458] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to the reference compound.

[0459] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0460] As used herein, the term "bioisostere" 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 create a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be physicochemical or topologically based. 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.

[0461] It should also be understood that any particular compound of any one of the formulas disclosed herein can exist in solvated form as well as unsolvated form, such as hydrated form.Suitable pharmaceutically acceptable solvates are, for example, hydrates 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.

[0462] 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 powder X-ray 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 determined by Karl Fischer analysis.

[0463] Compounds of any one of the formulas disclosed herein can exist in several different tautomeric forms, and a reference to a compound of formula (I) or (II) 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 shown, 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 / acylnitro. [ka]

[0464] Any compound of any one of the formulas disclosed herein containing an amine functional group can also form an N-oxide. Reference herein 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 the nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed 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. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn.Comm. 1977, 7, 509-514), which involves reacting an amine compound with meta-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0465] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is decomposed in the human or animal body to release the compound of the present disclosure.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.Prodrugs can be formed when the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached.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 in the ester or amide group.

[0466] Therefore, the present disclosure includes any one compound of the formula disclosed herein as defined herein above when it is made available by organic synthesis and when it is made available in the human or animal body by cleavage of its prodrug.Therefore, the present disclosure includes any one compound of the formula disclosed herein that is produced by organic synthesis means, and also includes compounds that are produced in the human or animal body by metabolism of precursor compounds, that is, any one compound of the formula disclosed herein can be a synthetically produced compound or a metabolically produced compound.

[0467] Suitable pharmaceutically acceptable prodrugs of compounds of any one of the formulae disclosed herein are those that, based on sound medical judgment, 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 literature: 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," 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. al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Vol. 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0468] Suitable pharmaceutically acceptable prodrugs of the compounds of any one of the formulas disclosed herein having a hydroxy group are, for example, their in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of the compounds of any one of the formulas disclosed herein containing a hydroxy group 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 the hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C1-C2 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 and alkoxycarbonyl groups. Examples of ring substituents on the 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.

[0469] 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, etc. 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 or esters such as glycine.

[0470] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Included are amides formed with alkanoyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0471] The in vivo effect of any one compound of the formula disclosed herein can be partially exerted by one or more metabolites formed in the human or animal body after administration of any one compound of the formula disclosed herein.As mentioned hereinabove, the in vivo effect of any one compound of the formula disclosed herein can also be exerted by the metabolism of precursor compound (prodrug). Compound synthesis method

[0472] The compounds of the invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes shown below.

[0473] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as illustrated in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis, using methods readily apparent to those skilled in the art. The presence or absence of a stereocenter in a compound of formula (I) can be recognized by one of ordinary skill in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis), 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 resolution of the final product or any convenient intermediate. Resolution 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 E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0474] 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

[0475] The compounds of the present invention can be prepared by several methods well known to those skilled in the art of organic synthesis.For example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the field of synthetic organic chemistry, or variations thereof recognized by those skilled in the art.Suitable methods include, but are not limited to, the methods described below.The compounds of the present invention can be synthesized according to the steps outlined in General Procedure A or B, which includes different orders for assembling intermediates or compounds.Starting materials are commercially available or are prepared by known procedures reported in the literature, or as shown below. General Procedure A

[0476] In general, compounds of formula (I) can be prepared using the reductive amination reaction of a carbonyl compound (A) with an amine (B) in the presence of a suitable reducing agent ([H]): AC(O)H + B-NH2 + [H] → compound of formula (I)

[0477] In a more particular embodiment, compounds of formula (I) can be obtained according to the scheme presented below. [ka]

[0478] A specific, non-limiting example of this procedure can be illustrated by the reaction of the preparation of compound 7 (Example 7): [ka]

[0479] Reagents (A) and (B) can be commercially available compounds themselves or synthetic products from commercially available reagents. In the case of compounds (A) and (B), the preparation can use one-step or multi-step synthetic procedures (including, but not limited to, the procedures described herein in the preparation part). General Procedure B

[0480] In general, compounds of formula (I) can be prepared using reactive displacement of a halogen in a halogen derivative (A) with an amine (B) in the presence of a base (Base): A-Hal + B-NH2 + base → compound of formula (I) + base: HCl

[0481] In a more particular embodiment, compounds of formula (I) can be obtained according to the scheme presented below. [ka]

[0482] A specific, non-limiting example of this procedure can be illustrated by the reaction of the preparation of compound 75 (Example 16): [ka]

[0483] Reagents (A) and (B) can be commercially available compounds themselves or synthetic products from commercially available reagents. In the case of compounds (A) and (B), the preparation can use one-step or multi-step synthetic procedures (including, but not limited to, the procedures described herein in the preparation part).

[0484] It should be clear to those skilled in the art that any of the compounds of formula (I) obtained according to procedure A or B above may be subject to further transformations and modifications leading to other compounds of formula (I). Biological assays

[0485] Once compounds designed, selected, and / or optimized by the above methods are produced, 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, the assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0486] Furthermore, high-throughput screening can be used to speed up the analysis using such assays.As a result, it may be possible to quickly screen the activity of the molecules described herein using techniques known in the art.The general methodology for carrying out high-throughput screening is 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 techniques, including but not limited to those described below.

[0487] 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

[0488] In some aspects, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure as active ingredients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0489] 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.

[0490] The compounds of the present disclosure may 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 may 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.

[0491] The formulation of the present disclosure can be in the form of an aqueous solution containing an aqueous vehicle.The aqueous vehicle component can include 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 / suspending agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[0492] Any suitable solubility enhancer can be used, including, for example, cyclodextrins such as 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.

[0493] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0494] Any suitable preservative can be used, including, for example, 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.

[0495] In some embodiments, preservatives include, for example, 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 quaternary ammonium salts such as butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0496] The aqueous vehicle may also contain an isotonicity agent to adjust the tonicity (osmolality). The isotonicity agent may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the isotonicity agent is selected from the group consisting of glycols (e.g., propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0497] 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 (e.g., 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 (Carbopol-Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, Carbopol 974P, etc.), and mixtures thereof.

[0498] 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 may not be necessary to use both an acid and a base; depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0499] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or salts thereof, including disodium tetraborate), citrate buffers (e.g., citric acid or salts thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0500] 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.

[0501] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, and the compound in the fluid carrier is orally applied, swallowed, expectorated, or swallowed.Pharmaceutically compatible binding agents and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch, lactose, a disintegrating agent such as alginic acid, Primogel, corn starch, etc.; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavoring.

[0502] 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 above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0503] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional pharmaceutically active agents.

[0504] Compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (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).

[0505] The compositions of the present disclosure may be obtained by conventional procedures 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.

[0506] 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 reduce the symptoms associated with the MLL-associated conditions referred to herein.

[0507] 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 reduce the symptoms associated with the MLL-associated conditions referred to herein.

[0508] The size of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary according to 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

[0509] 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.

[0510] 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.

[0511] 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.

[0512] In some embodiments, the disease or disorder is associated with MLL. In some embodiments, the disease or disorder is a disease or disorder in which menin-MLL binding is implicated.

[0513] The compounds of the present invention are inhibitors of the interaction between menin and MLL or MLL fusion proteins. In some embodiments, the present invention 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 invention. The contacting can be performed in vitro or in vivo. In some embodiments, the compounds of the present invention can bind to menin, thereby preventing MLL binding to menin. In some embodiments, the present invention provides methods for inhibiting the activity of menin by contacting menin with a compound of the present invention in the presence of an MLL or MLL fusion protein. In further embodiments, the present invention provides methods for inhibiting the binding of MLL or MLL fusion proteins to menin, comprising contacting menin with a compound of the present invention in the presence of an MLL or MLL fusion protein.

[0514] The compounds of the present invention 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 invention include cancer, such as leukemia, and other diseases or disorders mediated by menin-MLL interaction or menin-MLL fusion protein interaction, such as diabetes.

[0515] In some embodiments, 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. 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.

[0516] In some embodiments, the disease or disorder is cancer.

[0517] In some embodiments, the cancer is selected from hematological 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), colorectal cancer, cervical cancer, gastrointestinal cancer (e.g., colorectal 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 cardiac cancer, sarcoma (such as angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, including bronchogenic carcinoma (such as squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung carcinoma, small cell lung carcinoma, bronchial adenoma / carcinoid, and pleural pulmonary blastoma; gastrointestinal cancers, including, for example, cancer of the esophagus (such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cancer of the stomach (such as carcinoma, lymphoma, and leiomyosarcoma), cancer of the pancreas (such as tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and lipoma), cancer of the small intestine (such as adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), cancer of the large intestine or colon cancers of the liver (such as adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma), and other cancers of the gastrointestinal tract (such as anal cancer, anorectal cancer, appendix cancer, anal canal cancer, tongue cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); cancers of the genitourinary tract, including, for example, kidney cancer (adenocarcinoma, Wilm's tumor (nephroblastoma)), lymphoma and leukemia, cancers of the bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, cancer of the prostate (such as adenocarcinoma and sarcoma); cancer of the testis (such as seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma), and transitional cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter and other urinary system, urethral carcinoma, and bladder cancer; liver cancer, including liver cancer (such as hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma;Bone cancers, including, for example, osteogenic sarcoma (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, chondrofibroma, osteoid osteoma, and giant cell tumor; cancers of the nervous system, including, for example, cancers of the skull (such as osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans); cancers of the meninges (such as meningioma, meningeal sarcoma, and gliomatosis). Cancers of the brain (such as astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors); cancers of the spinal cord (such as neurofibroma, meningioma, glioma, and sarcoma), other cancers of the nervous system (e.g., brain stem glioma, diffuse intrinsic cavernous glioma (DIPG)), brain tumors, central nervous system cancers, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and and hypothalamic glioma, nervous system lymphoma, supraventricular primitive neuroectodermal tumor, pineoblastoma and supraventricular primitive neuroectodermal tumor, etc.; gynecological cancers, such as cancer of the uterus (such as endometrial carcinoma), cancer of the cervix (such as cervical carcinoma and cervical predysplastic neoplasia), cancer of the ovary (ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-Tehkar cell tumor, Sertoli-Leydig cell tumor, dysblastoma, and malignant teratoma), cancer of the vulva (squamous cell carcinoma, epithelial carcinoma, cancer of the vagina (such as clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (such as carcinoma); other reproductive system cancers, including, for example, endometrial cancer, endometrial cancer, 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, extragonadal germ cell tumor, uterine cancer, endometrial cancer, and uterine sarcoma;For example, cancers of the lymphatic and hematological systems, including cancers of the blood (such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia), as well as cancers of the lymphatic and hematological systems, such as Other cancers of the lymphatic or hematologic systems, including childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasms / multiple myeloma, myelodysplasia, myelodysplastic syndromes, cutaneous T-cell lymphoma, lymphoid neoplasms, AIDS-related lymphoma, thymoma, thymic carcinoma and thymic carcinoma, mycosis fungoides, and Sézary syndrome; Skin cancers, including lipomas, hemangiomas, dermatofibromas, keloids, psoriasis, Merkel cell carcinoma, Merkel cell skin carcinoma, melanoma, and carcinoid tumors; adrenal cancers, including neuroblastoma; endocrine system-related cancers, including adrenocortical carcinoma, multiple endocrine neoplasia (including multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid carcinoma, pituitary tumors, pheochromocytoma, islet cell pancreatic cancer, and islet cell tumors. connective tissue cancers (such as bone cancer, bone and joint cancer, osteosarcoma, and malignant fibrous histiocytoma); cancers associated with the head, neck, and oral cavity (such as head and neck cancer, paranasal sinus and nasal cancer, metastatic cervical squamous cell carcinoma, oral cancer, throat cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cancer, oropharynx cancer, and salivary gland cancer); and cancers associated with the eye (such as eye cancer and intraocular melanoma). In some embodiments, the cancer is Ewing's sarcoma;

[0518] 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 invention 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) (chronic lymphoblastic leukemia), These include: chronic myelogenous leukemia (CML) (also called chronic myeloid leukemia), therapy-related leukemia, myelodysplastic syndromes (MDS), myeloproliferative disorders (MPDs) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasms (MPNs), plasma cell neoplasms, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasms, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma mycosis, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningeal inflammation, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Waldenstrom's macroglobulinemia.

[0519] In some embodiments, diseases and conditions treatable with the compounds of the present invention 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 the compounds of the present invention include hyperglycemia. In some embodiments, hyperglycemia is associated with diabetes, such as type 2 diabetes. In some embodiments, compounds of the present invention are used to treat loss of response to other antidiabetic agents and / or reduced beta cell function in a patient or subject. In some embodiments, compounds of the present invention are used to restore response to other antidiabetic agents, 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 invention are used to reduce insulin resistance, reduce the risk of diabetes, or reduce statin-induced increases in blood glucose in subjects taking statins. In some embodiments, compounds of the present invention are used to treat diabetes in subjects taking statins or prevent diabetes in subjects taking statins. Methods of the present invention include reducing, reducing, inhibiting, suppressing, 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.

[0520] 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.

[0521] 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.

[0522] 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).

[0523] 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 a disease or disorder disclosed herein.

[0524] 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.

[0525] 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.

[0526] 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.

[0527] 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).

[0528] 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.

[0529] 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.

[0530] 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.

[0531] 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.

[0532] 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, comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0533] In some embodiments, the menin / MLL interaction inhibitor is a compound of the present disclosure.

[0534] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models according to standard practices for elucidating the same as described in the art and as found in current general knowledge.

[0535] The present disclosure also provides a method of treating a disease or disorder involving the interaction of menin and MLL in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0536] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human. Route of administration

[0537] The compounds of the present disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0538] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., including patches, bandages, etc.); transmucosal (e.g., including patches, bandages, etc.); intranasal (e.g., by nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., through the mouth or nose, by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly. [Example]

[0539] Abbreviations used in the examples below and elsewhere in this specification are as follows: JPEG2024545511000114.jpg253169JPEG2024545511000115.jpg73170(Example) General Synthetic Procedures and Examples for the Preparation of Compounds. Building Block Synthesis Synthesis of 4-chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7) [ka]

[0540] 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, followed by portionwise addition of aqueous potassium sulfate 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).

[0541] 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 minutes 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 hours (TLC control). The mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was then concentrated, and the residue was purified by silica gel column chromatography (dichloromethane) to give the product (P2) as a white solid (16 g, 99% yield). 1H 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).

[0542] 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 Celite pad. 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, yield 59%). 1 H NMR(400 MHz,DMSO-d6),δ:10.10(s,1H),8.20(t,J=20.8 Hz,1H),7.92(s,1H),7.50(d,J=23.8 Hz,1H),3.86(s,3H),3.74-3.48(m,2H),1.48(s,9H).

[0543] 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 hours (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).

[0544] Preparation 5. 2-Amino-5-(2,2,2-trifluoroethyl)benzoic acid (P5) [ka] A solution of lithium hydroxide (2 g, 83 mmol) in water (35 ml) was added to a solution of methyl 2-amino-5-(2,2,2-trifluoroethyl)benzoate (P4, 4.6 g, 17.6 mmol) in methanol (100 ml). 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 off, washed with water (15 ml), and dried to give the 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).

[0545] 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, then at 165° C. for 40 minutes. The reaction mixture was cooled, and 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%). 1 H 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).

[0546] Preparation 7. 4-Chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7) [ka] POCl3 (35 ml) was added to 6-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one (P6, 2.52 g, 11 mmol), and the reaction mixture was stirred and refluxed for 1 hour. The solution was cooled and poured into an ice-cold aqueous solution of sodium bicarbonate. The mixture was stirred for 30 minutes and then extracted with dichloromethane (2 x 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 (400MHz, CDCl3), δ:9.12-9.07(m,1H),8.25-8.22(m,1H),8.12(d,J=8.3Hz,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]

[0547] 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 a solution of 4-chloro-6-(2,2,2-trifluoroethyl)quinazoline (P7, 3 g, 12.2 mmol) in dichloroethane (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 as a white solid (5.1 g, 96%). 1 H NMR(400MHz,DMSO-d6)δ8.47-8.43(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).

[0548] 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 in vacuo 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.1 H NMR(400MHz,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-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)phenyl]amine (P11) [ka]

[0549] Preparation 10. 4-[7-(4-nitrobenzyl)-2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P10) [ka] A mixture of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9, 194 mg, 0.55 mmol), 4-nitrobenzaldehyde (165 mg, 0.8 mmol), and sodium triacetoxyborohydride (170 mg, 0.8 mmol) in dichloromethane (2 ml) was stirred at room temperature for 5 hours (LCMS control). After the reaction was complete, an aqueous solution of sodium bicarbonate was added, and the mixture was stirred for an additional 30 minutes. The mixture was then extracted with DCM (20 ml). The solvent was evaporated and the residue was purified by silica column chromatography (ethyl acetate-methanol 95:5) to give 4-[7-(4-nitrobenzyl)-2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P10, 170 mg, 65%).

[0550] 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 a solution of 4-[7-(4-nitrobenzyl)-2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P10, 170 mg, 0.36 mmol) in THF (3 ml) was added acetic acid (220 mg, 3.6 mmol) and Zn dust (400 mg, 7.2 mmol). The mixture was stirred at room temperature for 18 hours (LCMS control). After the reaction was complete, the mixture was filtered from Zn, concentrated, washed with an aqueous solution of sodium bicarbonate, and extracted with DCM (2 x 20 ml). The organic extract was evaporated to dryness to give product P11 (159 mg, 100%). LCMS (ESI) [MH] + :442. Synthesis of 4-[7-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-2,7-diazaspiro[3.5]non-2-yl]-6-(2,2,2-trifluoroethyl)quinazoline (P36) [ka]

[0551] Preparation 12. 6-(2,2,2-trifluoroethyl)-4-{7-[(2-trityl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]-2,7-diazaspiro[3.5]non-2-yl}quinazoline (P12) [ka] Sodium triacetoxyborohydride (227 mg, 1.07 mmol) was added to a mixture of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9, 60 mg, 0.16 mmol) and 2-trityl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde P87 (97 mg, 0.24 mmol) in DCM (5 ml), and the reaction mixture was stirred at room temperature for 24 hours (LCMS control). An aqueous solution of sodium bicarbonate was then added with vigorous stirring. The mixture was stirred for 30 minutes, the phases were separated, and the aqueous phase was extracted with DCM (100 ml). The combined DCM solution was concentrated, and the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:2) to give the product (P12, 47 mg, 39%). LCMS [MH] + :725.

[0552] Preparation 13. 4-[7-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-2,7-diazaspiro[3.5]non-2-yl]-6-(2,2,2-trifluoroethyl)quinazoline (P13) [ka] 6-(2,2,2-Trifluoroethyl)-4-{7-[(2-trityl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]-2,7-diazaspiro[3.5]non-2-yl}quinazoline (P12, 47 mg, 0.62 mmol) was added to a solution of HCl in dioxane (3 M, 1 ml). The reaction mixture was stirred at room temperature for 3 hours (LCMS control), then evaporated to dryness under reduced pressure and washed with hexane to give product P13 (31 mg, 97%). LCMS (ESI) [MH] + :482. Synthesis of 4-[7-(2,3-dihydro-1H-isoindol-5-ylmethyl)-2,7-diazaspiro[3.5]non-2-yl]-6-(2,2,2-trifluoroethyl)quinazoline (P15) [ka]

[0553] Preparation 14. tert-Butyl 5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1,3-dihydro-2H-isoindole-2-carboxylate (P14) [ka] To a mixture of tert-butyl 5-formyl-1,3-dihydro-2H-isoindole-2-carboxylate (P88, 110 mg, 0.44 mmol) and 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P9, 166 mg, 0.44 mmol) in DCM (5 ml) was added sodium triacetoxyborohydride (227 mg, 1.07 mmol). The mixture was stirred at room temperature for 24 hours (LCMS control). An aqueous solution of sodium bicarbonate was then added with vigorous stirring. The mixture was stirred for 30 minutes, the phases were separated, and the aqueous phase was extracted with DCM (100 ml). The combined DCM solution was concentrated, and the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:2) to give product P14 (30.8 mg, 12%). LCMS(ESI)[MH] + :568.

[0554] Preparation 15. 4-[7-(2,3-Dihydro-1H-isoindol-5-ylmethyl)-2,7-diazaspiro[3.5]non-2-yl]-6-(2,2,2-trifluoroethyl)quinazoline (P15) [ka] To a solution of HCl / dioxane (3M, 1 ml) was added tert-butyl 5-({2-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-7-yl}methyl)-1,3-dihydro-2H-isoindole-2-carboxylate (P14, 30.8 mg, 0.054 mmol) in portions. The reaction mixture was stirred at room temperature for 3 hours (LCMS control) and then evaporated to dryness in vacuo to give the product (P15, 28 mg, 100%). LCMS (ESI) [MH] + :468. Synthesis of 4-(2,7-diazaspiro[3.5]non-7-yl)-6-(2,2,2-trifluoroethyl)quinazoline (P28) [ka]

[0555] 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 the reaction was complete, the solvent was evaporated and the residue was purified by column chromatography on silica using ethyl acetate-methanol (10:1) to give 5.1 g of product P27 as a white solid. LCMS (ESI) [MH] + :437.

[0556] 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]

[0557] 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 using ethyl acetate-methanol (10:1) to give the product P29 as a white solid (5.1 g, 92%). LCMS (ESI) [MH] + :465.

[0558] 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]

[0559] 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 bisulfate 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 (2.76 g, 91%). 1H NMR (400MHz, 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).

[0560] 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 aqueous LiOH (1.72 g, 71.7 mmol) and the reaction mixture was refluxed for 1 h, then evaporated under reduced pressure, dissolved in water and adjusted to pH 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 (400MHz, DMSO-d6), δ:13.30(s,1H),8.25(d,J=2.5Hz,1H),8.09(d,J=2.5Hz,1H),7.38(s,1H).

[0561] 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 break up 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 (400MHz, DMSO-d6), δ:12.69(s,1H),9.03(d,J=2.6Hz,1H),8.60(d,J=2.6Hz,1H),8.35(s,1H).

[0562] Preparation 34. tert-Butyl-2-(6-bromopyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (P34) [ka] 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) were dissolved 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 afford the title compound (P34) as a white solid (150 mg, 44%). 1 H NMR(400MHz,DMSO-d6),δ:9.03(d,J=2.4Hz,1H),8.59(s,1H),8.46(d,J=2.5Hz,1H),3.3 5(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).

[0563] 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.

[0564] 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 an argon-filled mixture of dioxane (6 mL) and water (2 mL) was added a solution of OsO (17 mg, 0.06 mmol) in t-BuOH (1 mL). The reaction mixture was stirred at room temperature for 20 h. 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(400MHz,CDCl3),δ:10.19(s,1H),9.46(d,J=2.2Hz,1H),8.83(s,1H),8.65(d,J=2.2Hz,1H),4. 36(br.s,2H),3.17(d,J=3.4Hz,2H),1.89(t,J=5.4Hz,4H),1.72(s,2H),1.62(s,2H),1.49(s,9H).

[0565] 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.

[0566] 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 h. 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 (400MHz, CDCl3), δ:8.95(s,1H),8.78(s,1H),8.12(s,1H),4.29(s,4H),3.55(d,J=10.4Hz,2H),3.47(s,4H),1.94-1.84(m,4H),1.48(s,9H).

[0567] 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) in DCM (1 ml) and TFA (3 ml) was stirred at room temperature for 1 hour. 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%). 1H NMR(400MHz,CDCl3),δ:8.94(d,J=1.8Hz,1H),8.77(s,1H),8.14-8.08(m,1H),4.2 7(s,4H),3.58-3.49(m,2H),3.17(d,J=3.0Hz,1H),2.89(s,4H),1.93-1.86(m,4H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)cinnoline (P49) [ka]

[0568] 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 US 2015 / 259331, 2015, A1) (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 silica column chromatography using ethyl acetate-methanol (10:1) to give the title compound P45 (1.3 g, 47%) as a white solid. LCMS (ESI) [MH] + :434.

[0569] 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[l,l'-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 worked up 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.

[0570] 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), and sodium periodate (354 mg, 1.65 mmol) in tert-BuOH (0.5 mL). The reaction mixture was stirred at room temperature for 24 hours. 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 (145 mg, 65%) as a brown solid. LCMS (ESI) [MH] + :383.

[0571] 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-phosphatidylcinnolin-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 hours (TLC control). The reaction mixture was then 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 Togni reagent (144 mg, 0.456 mmol) and TFA (43 mg, 0.38 mmol) were added. The resulting mixture was stirred at 50 °C for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 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(400MHz,CDCl3),δ:8.35(s,1H),8.29(d,J=5.2Hz,1H),7.80(s,1H),7.62(d,J =9.4Hz,1H),4.29-4.17(m,4H),3.60-3.43(m,6H),1.92-1.85(m,4H),1.49(s,9H).

[0572] 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 x 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(400MHz,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]

[0573] 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, and the solution was 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 (555 mg, 50%) as an orange solid. 1H NMR (400MHz, CDCl3), δ:8.06(dd,J=4.0,1.4Hz,1H),7.22(dd,J=8.4,4.0Hz,1H),7.05(dd,J=8.4,1.4Hz,1H),5.73(br.s,2H),3.97(s,3H).

[0574] 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 stirred at room temperature for 4 h, after which the solution was diluted with NaSO. 3(水溶液) The organic layer was collected, washed with brine, and extracted with MgSO. 4(s) The residue was purified by flash column chromatography (Et0Ac:n-hexane=1:3) to give P51 (5.56 g, 73%) as an orange solid. 1 H NMR (400MHz, CDCl3), δ:7.34(d,J=8.6Hz,1H),6.94(d,J=8.6Hz,1H),5.82(br.s,2H),3.95(s,3H).

[0575] Preparation 52. Methyl 3-amino-6-vinylpicolinate (P52) [ka] To a stirred solution of P51 (500 mg, 2.16 mmol, 1.0 equiv.) in n-butanol (10 mL) was added potassium polyvinyltrifluoroborate (435 mg, 3.25 mmol, 1.5 equiv.) and trimethylamine (1.51 mL, 10.8 mmol, 5.0 equiv.) at room temperature. After degassing the solution with argon, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex was added. The reaction mixture was then stirred at 80 °C for 16 h, cooled to room temperature, and filtered through a Celite pad. The solution was treated with water and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO(s), 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(400MHz,CDCl3),δ:7.47(d,J=8.8Hz,1H),7.04(d,J=8.8Hz,1H),6.81(dd,J=17.6,10.8Hz,1H),5. 86(dd,J=17.6,0.8Hz,1H),5.79(br.s,2H),5.36(dd,J=10.8,0.8Hz,1H),3.97(s,3H);LCMS(ESI)[MH] + :179.1.

[0576] 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) were 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 in vacuo. The residue was purified by flash column chromatography (EtOAc:n-hexane = 1:3) to give P53 (432 mg, 88%) as a white solid. 1H NMR(400MHz,CDCl3),δ:7.54(m,2H),6.91(dd,J=17.6,11.2Hz,1H),6.22(d,J= 17.6Hz,1H),5.60(d,J=11.2Hz,1H),3.94(s,3H),1.38(s,18H);LCMS(ESI)[MH] + :379.2.

[0577] 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) was added 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.) 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 cooled to 5°C. The resulting mixture was ... 4(s) The residue was purified by flash column chromatography (EtOAc:dichloromethane=1:4) to give P54 (402 mg, 93%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ10.15(s,1H),8.13(d,J=8.0Hz,1H),7.77(dd,J=8.0Hz,1H),4.00(s,3H),1.39(s,18H).

[0578] Preparation 55. Methyl (E)-3-(di-tert-butoxycarbonylamino)-6-(hydrazinelidenemethyl)-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.

[0579] 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 dried over MgSO 4(s) The residue was purified by flash column chromatography (Et0Ac:n-hexane=1:2) to give P56 (258 mg, crude) as a yellow solid. 1 H NMR(400MHz,CDCl3),δ:7.60(d,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),3.95(s,3H),2.80(q,J=10.4Hz,2H),1.38(s,18H);LRMS(ESI)[MH] + :435.1.

[0580] 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 H NMR(400MHz,CDCl3),δ:7.28(d,J=8.6Hz,1H),7.07(d,J=8.6Hz,1H),3.97(s,3H),3.57(q,J=10.8Hz,2H);LCMS(ESI)[MH] + :235.1.

[0581] Preparation 117. 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% aqueous ammonia (50 mL) was stirred at room temperature for 16 h. The solution was diluted with water and extracted with EtOAc. The organic l...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof, During the ceremony, X １ is N; each X １ ´ is CH ２ and N are independently selected; X ２ , X ３ , X ４ , X ５ , and X ６ each from is independently selected from CH or N; And X ２ , X ３ , X ４ , X ５ , and X ６ is N; X ７ is N; Each R １ is halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, heterocyclyl, aryl, heteroaryl, C １ -C ６ Alkyl-Aryl, C １ -C ６ Alkyl-Heteroaryl, C ２ -C ６ Alkenyl-aryl, C ２ -C ６ Alkenyl-heteroaryl, C ２ -C ６ Alkynyl-aryl, C ２ -C ６ Alkynyl-heteroaryl, and NR １２ R １３ wherein said alkyl, alkoxy, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, or heteroaryl is independently selected from halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １２ R １３ , C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ optionally substituted with one or more substituents independently selected from alkynyl, heterocyclyl, aryl, heteroaryl; R ２ and R ３ are each independently H or C １ -C ６ alkyl; or R ２ and R ３ together with the atom to which they are attached and any intervening atoms form a 3- to 8-membered heterocycle, said heterocycle being free of halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and NR １２ R １３ and optionally substituted with one or more substituents independently selected from: R ４ , R ４ ', and R ５ are each independently H and C １ -C ６ alkyl; or R ４ and R ５ together with the atom to which they are attached and any intervening atoms form a 3- to 8-membered heterocycle or heteroaryl, said heterocycle and heteroaryl being free of halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and NR １２ R １３ or R ４ ' and R ５ together with the atom to which they are attached and any intervening atoms form a 3- to 8-membered heterocycle or heteroaryl, said heterocycle and heteroaryl being free of halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and NR １２ R １３ and optionally substituted with one or more substituents independently selected from: In the formula, at least (a) R ２ and R ３ together with the atom to which they are attached and any intervening atoms, form said 3- to 8-membered heterocyclic ring; or (b) R ４ and R ５ together with the atom to which they are attached and any intervening atoms, form said 3- to 8-membered heterocycle or heteroaryl; or (c) R ４ ' and R ５ together with the atom to which they are attached and any intervening atoms, form said 3- to 8-membered heterocycle or heteroaryl; L １ is H or 【Chemistry 2】 and During the ceremony, R' and R" are both H; Ring A is an aryl or C ３ -C １４ cycloalkyl; L ２ is halogen, C １ -C ６ Alkyl, NR １２ R １３ , -N(R ６ ) S (O) ２ R ７ , -N(R ６ ) CH ２ R ７ , -N(R ６ ) C(O)R ７ , -C(O)NR ６ R ７ , -S(O) ２ N.R. ６ R ７ wherein the alkyl is independently selected from halogen, oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １２ R １３ optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocyclyl; R ６ is H, C １ -C ６ alkyl; R ７ is N.R. １２ R １３ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １０ cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, -S(O) ２ R ７ , N(R ６ ) S (O) ２ R ７ , and N.R. １２ R １３ and optionally substituted with one or more substituents independently selected from: Each R ８ is halogen, OH, oxo, CN, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NR １２ R １３ , -NR １２ R １３ wherein the alkyl or alkoxy is independently selected from halogen, oxo, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １２ R １３ optionally substituted with one or more substituents independently selected from cycloalkyl and heterocyclyl; or L ２ and R ８ together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered cycloalkyl, a 5- to 14-membered heterocycle, or a 5- to 6-membered heteroaryl, wherein said cycloalkyl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NHC １ -C ６ Alkyl, and NR １２ R １３ or Each R １２ and R １３ are independently H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, -S(O) ２ R ７ , C １ -C ６ acyl, heterocyclyl, aryl, or heteroaryl; Or R １２ and R １３ together with the atoms to which they are attached and any intervening atoms, represent -S(O) ２ R ７ forming a 5-14 membered heterocycle optionally substituted with one or more substituents independently selected from m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1 and 2; s is an integer selected from 0, 1 and 2; v is 1; w is an integer selected from 0 and 1; R ４ is part of an aromatic ring, then w is 0; During the ceremony, 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 spirocyclic), or 11-14 membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is 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.

2. The compound of claim 1, which is a compound of formula (IA), (IB), (ID), (IE), (IF), or (IG): 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

3. The compound of claim 1, which is a compound of formula (I-A-I), (I-A-II), (I-A-III), (I-A-IV), (I-A-V), or (I-A-VI): 【Chemistry 6】 【Chemistry 7】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein Ring E is halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and NR １２ R １３ A compound which is an aryl or heteroaryl optionally substituted with one or more substituents independently selected from:

4. The compound according to claim 1, which is a compound of formula (I-1) 【Chemistry 8】 or a pharma- ceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein W is independently, at each occurrence, -CH ２ -, -(CH ２ ) ２ - or - (CH ２ ) ３ A compound which is -.

5. The compound according to claim 4, which is a compound of formula (I-1-A): 【Chemistry 9】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

6. The compound of claim 1, which is a compound of formula (I-1-A-1), (I-1-A-2), (I-1-A-3), or (I-A-VII): 【Chemistry 10】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein ring G is halogen, OH, NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １２ R １３ A compound which is a 3-8 membered heterocycle optionally substituted with one or more substituents independently selected from:

7. The compound of claim 1, which is a compound of formula (I-2-I), (I-2-II), (I-2-III), or (I-2-IV): 【Chemistry 11】 【Chemistry 12】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

8. The compound of claim 1, which is a compound of formula (I-2-A-I), (I-2-A-II), (I-2-A-III), or (I-2-A-IV): 【Chemistry 13】 【Chemistry 14】 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

9. A, 【Chemistry 15】 2. The compound of claim 1 , selected from:

10. L ２ But N(R ６ ) S (O) ２ R ７ 2. The compound of claim 1,

11. L ２ but, 【Chemistry 16】 2. The compound of claim 1,

12. L ２ But S(O) ２ N.R. ６ R ７ 2. The compound of claim 1 ,

13. L ２ but, 【Chemistry 17】 2. The compound of claim 1,

14. A compound selected from the following: or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

15. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and a pharma- ceutically acceptable carrier.

16. 16. The pharmaceutical composition of claim 15, further comprising one or more additional pharma- ceutical active agents.

17. 17. 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 15.

18. 17. 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 15.

19. 18. The method of claim 17, wherein said contacting is in vitro or in vivo.

20. A method for treating or preventing a disease or disorder associated with inhibition of the interaction between menin and MLL, comprising administering to a subject in need thereof a compound of claim 1 or a pharmaceutical composition of claim 15.

21. 21. The method of claim 20, 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.

22. 22. The method of claim 21, wherein the leukemia is selected from the group consisting of AML, ALL, mixed lineage leukemia, and leukemia with partial tandem duplication of MLL.

23. 21. The method of claim 20, wherein the subject is a mammal.

24. 24. The method of claim 23, wherein the subject is a human.

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