Imidazopyrimidines as EED inhibitors and their uses.

Abstract

This disclosure is based on the R 1 , R 2 , R 3 , and R 4 The present invention provides compounds represented by formula (I), and salts and solvates thereof, wherein: R is as defined herein. The compounds of formula (I) are EED inhibitors. EED inhibitors are useful in the treatment of cancer and other diseases. JPEG2022541436000215.jpg35103

Description

[Technical Field]

[0001] The present disclosure provides embryonic ectoderm development (EED) inhibitors, synthetic intermediates used to prepare EED inhibitors, and methods of treating conditions and diseases, e.g., cancer, in which inhibiting EED proteins provides a benefit. [Background technology]

[0002] Polycomb group (PcG) proteins are chromatin-modifying enzymes that are dysregulated in many human cancers. Polycomb repressive complex 2 (PRC2), which includes SUZ12 (suppressor of zeste 12), EED, and the catalytic subunit EZH2 (enhancer of zeste homolog 2), represses genes by methylating core histone H3 lysine 27 (H3K27me3) at and around the promoter regions of target genes. PRC2 is a key component of the cellular machinery involved in the epigenetic regulation of gene transcription and plays important functions in development, tissue differentiation, and regeneration. See, for example, Moritz and Trievel, J. Biol. Chem. 293(36):13805-13814 (2018); Fiskus et al., Mol Cancer Ther 5(12):3096-3014 (2006).

[0003] PRC2 requires at least EED and SUZ12 for its methyltransferase activity.EED, SUZ12 and EZH2 are overexpressed in many cancers, including but not limited to breast cancer, prostate cancer and hepatocellular carcinoma.There is a need in the art for a small molecule that inhibits the activity of EED for the treatment of cancer and other diseases. Summary of the Invention

[0004] In one aspect, the present disclosure provides compounds represented by any one of the following formulas: I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, as well as pharmaceutically acceptable salts and solvates thereof, such as hydrates, collectively referred to as "compounds of the present disclosure." The compounds of the present disclosure are EED inhibitors and / or synthetic intermediates that can be used to prepare EED inhibitors. Thus, certain compounds of the present disclosure are useful for treating or preventing diseases or conditions, such as cancer, in which inhibition of EED proteins provides benefits.

[0005] In another aspect, the present disclosure provides a method for treating or preventing a condition or disease by administering a therapeutically effective amount of a compound of the present disclosure to a subject, e.g., a human, in need thereof. Diseases or conditions of interest that are treatable or preventable by inhibiting EED are, for example, cancer, chronic autoimmune diseases, inflammatory conditions, proliferative diseases, sepsis, or viral infections. A method for preventing the proliferation of undesirable proliferative cells, such as cancer, in a subject is also provided, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject at risk of developing a condition characterized by undesirable proliferative cells. In some embodiments, the compound of the present disclosure can reduce the proliferation of undesirable cells by inducing apoptosis in those cells. In some embodiments, the compound of the present disclosure is administered in combination with any therapeutic agent.

[0006] In another embodiment, the present disclosure provides a method of inhibiting EED in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0007] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier.

[0008] In another aspect, the present disclosure provides a composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for use in treating or preventing a disease or condition, e.g., cancer, in which inhibition of EED provides a benefit.

[0009] In another aspect, the present disclosure provides a composition comprising (a) a compound of the present disclosure, (b) a second therapeutically active agent, and (c) optionally an excipient and / or a pharmaceutically acceptable carrier.

[0010] In another aspect, the disclosure provides a compound of the disclosure for use in treating or preventing a disease or condition of interest, for example, cancer.

[0011] In another aspect, the disclosure provides the use of a compound of the disclosure for the manufacture of a medicament for treating a disease or condition of interest, for example, cancer.

[0012] In another aspect, the disclosure provides a kit comprising a packaged composition comprising a compound of the disclosure and, optionally, any therapeutic agent useful in treating the disease or condition of interest, and a package insert containing instructions for use in treating the disease or condition, e.g., cancer.

[0013] In another aspect, the present disclosure provides methods of preparing the disclosed compounds and disclosed intermediates.

[0014] Additional embodiments and advantages of the disclosure will be set forth in part in the description which follows, and may be learned from the description, or may be learned by the practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0015] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a line graph showing the antitumor efficacy of representative compounds of the present disclosure in a KARPAS422 tumor model in mice. [Figure 2] 1 is a line graph showing weight changes in tumor-bearing mice treated with representative compounds of the disclosure in a KARPAS422 tumor model in mice. DETAILED DESCRIPTION OF THE INVENTION

[0017] I. Compounds of the Present Disclosure The compounds of the present disclosure are EED inhibitors and / or synthetic intermediates that can be used to prepare EED inhibitors.

[0018] In one embodiment, the compound of the present disclosure is a compound of formula I,

[0019] [ka]

[0020] During the ceremony, R 1 is an aralkyl, R 2 is selected from the group consisting of hydrogen and C1-C4 alkyl; R 3 and R 4 together with the carbon atoms to which they are attached form a radical of formula IA, IB, or IC,

[0021] [ka]

[0022] X is -C(R 5a )(R 5b )—, —C(═O)—, and —S(═O)—; R 5a and R 5bare independently selected from the group consisting of hydrogen and C1-C4 alkyl; Y is -C(R 6a )(R 6b )-, -S-, -O-, and -N(R 7 )-, X and Y together form a 5-membered heteroarylenyl; Z is -C(R 6c )(R 6d ) m - and R 6a and R 6b are independently selected from the group consisting of hydrogen and C1-C4 alkyl; Each R 6c and R 6d are independently selected from the group consisting of hydrogen and C1-C4 alkyl; m is 0, 1, or 2; R 7 is selected from the group consisting of hydrogen, C-C alkyl, C-C haloalkyl, optionally substituted C-C cycloalkyl, optionally substituted C-C heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R 8a , R 8b , and R 8c are independently hydrogen, halo, C1-C4 alkyl, C 1- selected from the group consisting of C4 haloalkyl, C1-C4 alkoxy, carboxamido, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-8 membered heterocyclo, (heterocyclo)C1-C4 alkyl, and alkylsulfonyl;

[0023] [ka]

[0024] is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl;

[0025] [ka]

[0026] is an optionally substituted fused 3- to 8-membered cycloalkyl or an optionally substituted fused 4- to 8-membered heterocyclo;

[0027] [ka]

[0028] is an optionally substituted fused 4- to 8-membered heterocyclo;

[0029] [ka]

[0030] The bond designated by R in Formula I 3 and the bond designated by "*" is R 4 Binding at position, or R 3 But R 3a and R 4 But R 4a and R 3a is selected from the group consisting of optionally substituted aryl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 4- to 8-membered heterocyclo; R 4a is hydrogen, halo, C1-C4 haloalkyl, -S(=O)2R 9 , -P(=O)(R 10a )(R 10b ), -C(=O)OR 11a , -C(=O)NR 11b R 11c , and -S(=O)(=NR 13a )R 13b is selected from the group consisting of R 9 is selected from the group consisting of C1-C4 alkyl and C3-C6 cycloalkyl; R10a and R 10b are independently C1-C4 alkyl; R 11a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 11b and R 11c are independently selected from the group consisting of hydrogen and C1-C4 alkyl; or R 11b and R 11c together with the nitrogen atom to which they are attached form a 4- to 6-membered optionally substituted heterocycle; R 13a is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and hydroxyalkyl; R 13b is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; or R 13a and R 13b together form a 5- to 7-membered heterocycle, [ka] is a single bond or a double bond, or a pharmaceutically acceptable salt or solvate thereof.

[0031] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein: X is -C(R 5a )(R 5b )—, —C(═O)—, and —S(═O)—; Y is -C(R 6a )(R 6b )-, -S-, -O-, and -N(R 7 )-, R 8a , R 8b , and R 8c are independently hydrogen, halo, C1-C4 alkyl, C 1-A compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of C4 haloalkyl, C1-C4 alkoxy, and alkylsulfonyl.

[0032] In another embodiment, the compounds of the present disclosure are compounds of formula I, wherein R 3 and R 4 are taken together with the carbon atom to which they are attached to form a radical of formula IA, IB, or IC, or a pharmaceutically acceptable salt or solvate thereof.

[0033] In another embodiment, the compound of the present disclosure is a compound of formula II,

[0034] [ka]

[0035] In the formula, R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, Z,

[0036] [ka]

[0037] , and

[0038] [ka]

[0039] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0040] In another embodiment, the compound of the present disclosure is a compound of formula III,

[0041] [ka]

[0042] In the formula, L is -C(R 8b )= and -N=, R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0043] In another embodiment, the compound of the present disclosure is a compound of formula IV:

[0044] [ka]

[0045] In the formula, L is -C(R 8b )= and -N=, R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0046] In another embodiment, the compound of the present disclosure is a compound of formula V:

[0047] [ka]

[0048] In the formula, L is -C(R 8b )= and -N=, R 1 , R 2 , R 8a , R 8b , R 8c, X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0049] In another embodiment, the compound of the present disclosure is a compound of formula VI,

[0050] [ka]

[0051] In the formula, L is -C(R 8b )= and -N=, R 1 , R 2 , R 8a , R 8b , R 8c , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0052] In another embodiment, the compound of the present disclosure is a compound of any one of formulas III-VI, or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 8b )=.

[0053] In another embodiment, the compound of the present disclosure is a compound of any one of formulas III-VI, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -N=.

[0054] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-VI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a , R 8b , and R 8c is independently selected from the group consisting of hydrogen, C-C alkyl, C-C haloalkyl, and C-C cycloalkyl. 8a is selected from the group consisting of -CHF2, -CF3, -CH3, -CD3, and cyclopropyl; R 8b and R8c is hydrogen. In another embodiment, R 8a is selected from the group consisting of -CF3 or -CH3, and R 8c is hydrogen.

[0055] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-VI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a is selected from the group consisting of C1-C4 alkyl, 4-8 membered heterocyclo, and (heterocyclo)C1-C4 alkyl; R 8b and R 8c is hydrogen. In another embodiment, R 8a is C1-C4 alkyl. In another embodiment, R 8a is a 4-8 membered heterocyclo. 8a is (heterocyclo)C1-C4 alkyl. In another embodiment, R 8a teeth,

[0056] [ka]

[0057] is selected from the group consisting of:

[0058] In another embodiment, the compound of the present disclosure is a compound of formula VII:

[0059] [ka]

[0060] During the ceremony, L 1 -S-, -O-, and -N(R 8a )-, L 2 But -C(R 8b )= and -N=; L 3 But -C(R 8c)= and -N=; R 8a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8b is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 8c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 1 , R 2 , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0061] In another embodiment, the compound of the present disclosure is a compound of formula VIII: [ka] During the ceremony, L 1 -S-, -O-, and -N(R 8a )-, L 2 But -C(R 8b )= and -N=; L 3 But -C(R 8c )= and -N=; R 8a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8b is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 8c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 1 , R 2 , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0062] In another embodiment, the compound of the present disclosure is a compound of formula IX,

[0063] [ka]

[0064] During the ceremony, L 1 -S-, -O-, and -N(R 8a )-, R 8a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 8b is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 8c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 1 , R 2 , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0065] In another embodiment, the compound of the present disclosure is a compound of formula X,

[0066] [ka]

[0067] In the formula, R 1 , R 2 , X, Y, Z,

[0068] [ka]

[0069] , and

[0070] [ka]

[0071] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0072] In another embodiment, the compound of the present disclosure is a compound of formula XI,

[0073] [ka]

[0074] During the ceremony, R 8d , R 8e , and R 8f is independently selected from the group consisting of hydrogen, halo, and C1-C4 alkyl; n is 1, 2, or 3; R 1 , R 2 , X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0075] In another embodiment, the compound of the present disclosure is a compound of formula XI-A,

[0076] [ka]

[0077] In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , n, X, Y, and Z are as defined in relation to formula XI, or a pharmaceutically acceptable salt or solvate thereof.

[0078] In another embodiment, the compound of the present disclosure is a compound of formula XI-B,

[0079] [ka]

[0080] In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , n, X, Y, and Z are as defined in relation to formula XI, or a pharmaceutically acceptable salt or solvate thereof.

[0081] In another embodiment, the compound of the present disclosure is a compound of formula XII:

[0082] [ka]

[0083] During the ceremony, L 4 -S-, -O-, and -N(R 8g )-, R 8g is selected from the group consisting of hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 4-8 membered heterocyclo; o is 0, 1, 2, or 3; p is 0, 1, 2, or 3; the sum of o and p is 1, 2, 3, 4, or 5; R 1 , R 2 X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0084] In another embodiment, the compound of the present disclosure is a compound of formula XII-A:

[0085] [ka]

[0086] In the formula, R 1 , R 2 , L 4 , o, p, X, Y, and Z are as defined in relation to formula XII, or a pharmaceutically acceptable salt or solvate thereof.

[0087] In another embodiment, the compound of the present disclosure is a compound of formula XII-B:

[0088] [ka]

[0089] In the formula, R 1 , R 2 , L 4 , o, p, X, Y, and Z are as defined in relation to formula XII, or a pharmaceutically acceptable salt or solvate thereof.

[0090] In another embodiment, the compound of the present disclosure is a compound of formula XIII:

[0091] [ka]

[0092] In the formula, R 1 , R 2 , X, Y, Z, and

[0093] [ka]

[0094] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0095] In another embodiment, the compound of the present disclosure is a compound of formula XIII-A,

[0096] [ka]

[0097] In the formula, R 1 , R 2 , X, Y, Z, and

[0098] [ka]

[0099] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0100] In another embodiment, the compound of the present disclosure is a compound of formula XIII-B,

[0101] [ka] In the formula, R 1 , R 2 , X, Y, Z, and [ka] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0102] In another embodiment, the compound of the present disclosure is a compound of formula XIV: [ka] During the ceremony, R 8d , R 8e , and R 8f are independently selected from the group consisting of hydrogen and C1-C4 alkyl; q is 1, 2, or 3; R 1 , R 2, X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0103] In another embodiment, the compound of the present disclosure is a compound of formula XIV-A, [ka] In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , q, X, Y, and Z are as defined in relation to formula XIV, or a pharmaceutically acceptable salt or solvate thereof.

[0104] In another embodiment, the compound of the present disclosure is a compound of formula XIV-B, [ka] In the formula, R 1 , R 2 , R 8d , R 8e , R 8f , q, X, Y, and Z are as defined in relation to formula XIV, or a pharmaceutically acceptable salt or solvate thereof.

[0105] In another embodiment, the compound of the present disclosure is a compound of formula XV: [ka] During the ceremony, L 5 -S-, -O-, and -N(R 8h )-, R 8h is hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4-8 membered heterocyclo, -C(=O)R 14a , and -S(=O)2R 14b is selected from the group consisting of R 14a and R 14b is independently selected from the group consisting of C1-C6 alkyl and optionally substituted C3-C8 cycloalkyl; r is 1, 2, or 3; s is 1, 2, or 3; R 1 , R 2 and X, Y, and Z are as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0106] In another embodiment, the compound of the present disclosure is a compound of formula XV-A, [ka] In the formula, R 1 , R 2 , L 5 , r, s, X, Y, and Z are as defined in relation to formula XV, or a pharmaceutically acceptable salt or solvate thereof.

[0107] In another embodiment, the compound of the present disclosure is a compound of formula XV-B, [ka] In the formula, R 1 , R 2 , L 5 , r, s, X, Y, and Z are as defined in relation to formula XV, or a pharmaceutically acceptable salt or solvate thereof.

[0108] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein Z is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[0109] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[0110] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X is -C(=O)-, or a pharmaceutically acceptable salt or solvate thereof.

[0111] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X is -S(=O)2-, or a pharmaceutically acceptable salt or solvate thereof.

[0112] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein Y is -O-, or a pharmaceutically acceptable salt or solvate thereof.

[0113] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein Y is —N(R 7)-, or a pharmaceutically acceptable salt or solvate thereof. 7 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and optionally substituted C3-C8 cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0114] In another embodiment, a compound of the present disclosure is a compound of any one of Formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, where Z is —CH—, X is —C(═O)—, and Y is —N(R 7 )-, or a pharmaceutically acceptable salt or solvate thereof. 7 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, and optionally substituted C3-C8 cycloalkyl. 7 is C1-C4 alkyl. In another embodiment, R 7 is selected from the group consisting of methyl, ethyl, propyl, or isopropyl.

[0115] In another embodiment, the compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, or a pharmaceutically acceptable salt or solvate thereof, wherein X and Y together form an optionally substituted fused 5- or 6-membered heteroaryl. In another embodiment, X and Y together form a 5-membered heteroaryl enyl.

[0116] In another embodiment, a compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X and Y together form a 5-membered heteroaryl enyl of formula ID; [ka] X 1 But, =CR 15a - and =N-; Y 1 -O-, -S-, and -NR 15c - selected from the group consisting of Z 1 But, =CR 15b - and =N-; R 15a and R 15b are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl; R 15c is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; [ka] is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the bond designated

[0117] In another embodiment, a compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X and Y together form a 5-membered heteroaryl enyl of formula IE; [ka] X 2 But, =CR 16a- and =N-; Y 2 But, =CR 16b - and =N-; Z 2 But, =CR 16b - and =N-; R 16a , R 16b , and R 16c are independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; [ka] is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the bond designated

[0118] In another embodiment, a compound of the present disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, wherein X and Y together represent: [ka] forming a 5-membered heteroaryl enyl selected from the group consisting of [ka] is a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the bond designated

[0119] In another embodiment, the compound of the present disclosure is a compound of formula XVI: [ka] In the formula, R 1 , R 2 , R 3a , and R 4ais as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0120] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is optionally substituted phenyl.

[0121] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is an optionally substituted 5-membered heteroaryl.

[0122] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is an optionally substituted 6-membered heteroaryl. In another embodiment, R 3a is selected from the group consisting of: [ka]

[0123] In another embodiment, the compound of the present disclosure is a compound of formula XVI, wherein R 3a is selected from the group consisting of: [ka]

[0124] In another embodiment, the compound of the present disclosure is a compound of formula XVI, wherein R 3a is selected from the group consisting of: [ka]

[0125] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is an optionally substituted 4- to 6-membered heterocyclo.

[0126] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is C1-C4 haloalkyl.

[0127] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is -S(=O)2R 9 is.

[0128] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is -P(=O)(R 10a )(R 10b )

[0129] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is -C(=O)OR 11a In another embodiment, R 11a is hydrogen.

[0130] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is -C(=O)NR 11b R 11c is.

[0131] In another embodiment, the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is -S(=O)(=NR 13a )R 13b In another embodiment, R 13a is selected from the group consisting of hydrogen and C1-C4 alkyl, and R 13bis C1-C4 alkyl. In another embodiment, R 13a and R 13b together form a 6-membered heterocycle, for example: [ka]

[0132] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 2 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0133] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 But R 1 -1, [ka] R 12a , R 12b , and R 12c are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; W is selected from the group consisting of -CH2- and -C(=O)-; t is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

[0134] In another embodiment, a compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is R 1 -1 and R 12a is fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro. 12a is fluoro and R 12b and R 12c is hydrogen.

[0135] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 But R 1 -2, [ka] R 12a , R 12b , and R 12c are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; t is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

[0136] In another embodiment, a compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is R 1 -2 and R 12a is fluoro and R 12band R 12c is independently selected from the group consisting of hydrogen and fluoro. 12a is fluoro and R 12b and R 12c is hydrogen.

[0137] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 But R 1 -3, [ka] R 12a , R 12b , and R 12c are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, or a pharmaceutically acceptable salt or solvate thereof.

[0138] In another embodiment, a compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is R 1 -3 and R 12a is fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro. 12a is fluoro and R 12b and R 12c is hydrogen.

[0139] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein: R 1 But R 1 -4, [ka] R 12a , R 12b , and R 12c are each independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, or a pharmaceutically acceptable salt or solvate thereof.

[0140] In another embodiment, a compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is R 1 -4 and R 12a is fluoro and R 12b and R 12c is independently selected from the group consisting of hydrogen and fluoro. 12a is fluoro and R 12b and R 12c is hydrogen.

[0141] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is selected from the group consisting of: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0142] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is selected from the group consisting of: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0143] In another embodiment, the compound of the disclosure is a compound of any one of formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, XV-B, or XVI, wherein R 1 is selected from the group consisting of: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0144] In another embodiment, the compound of the present disclosure is any one or more of the compounds listed in Table 1, or a pharmaceutically acceptable salt or solvate thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

[0145] In another embodiment, the compound of the present disclosure is 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, and a compound of formula I selected from the group consisting of 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide; or a pharmaceutically acceptable salt or solvate thereof.

[0146] The present disclosure encompasses the preparation and use of salts of the disclosed compounds. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of the disclosed compound. The salt of the disclosed compound can be prepared during the final isolation and purification of the compound, or separately by reacting the compound with a suitable acid. The disclosed compound's pharmaceutically acceptable salt can be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Non-limiting examples of salts of compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate The salts include mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate. Additionally, available amino groups present in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfate; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.In light of the above, any reference to a compound of the present disclosure appearing herein is intended to include the compound of the present disclosure, as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0147] The present disclosure encompasses the preparation and use of solvates of the disclosed compounds. Solvates typically do not significantly alter the physiological activity or toxicity of the compound and therefore may function as pharmacological equivalents. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of a disclosed compound with solvent molecules, such as a disolvate, monosolvate, or hemisolvate, in which the ratio of solvent molecules to the disclosed compound is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate may be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. The compounds of the present disclosure can exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and the present disclosure is intended to include both solvated and unsolvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can typically function as pharmacological equivalents. The preparation of solvates is known in the art. For example, see M. Caira et al., J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. The preparation of similar solvates, hemisolvates, hydrates, and the like is described by EC van Tonder et al., AAPS Pharm.Sci.Tech., 5(1):Article 12 (2004), and ALBingham et al., Chem.Commun. 603-604 (2001). A typical, non-limiting method for preparing a solvate involves dissolving a compound of the present disclosure in a desired solvent (organic, water, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals and isolating the crystals by known methods, for example, filtration.Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in crystals of the solvate.

[0148] II. Intermediates of the Disclosure The present disclosure also provides synthetic intermediates, collectively referred to as "intermediates of the present disclosure," that can be used to prepare compounds of the present disclosure.

[0149] In one embodiment, the intermediate of the present disclosure is a compound of formula I: R 3 But R 3a and R 4 But R 4a and R 3a is selected from the group consisting of substituted aryl, substituted 5- to 10-membered heteroaryl, and substituted 4- to 8-membered heterocyclo; at least one of the aryl, 5- to 10-membered heteroaryl, or 4- to 8-membered heterocyclo substituents is amino, hydroxyalkyl, or (amino)alkyl; R 4a Halo or -C(=O)OR 11a or a pharmaceutically acceptable salt or solvate thereof.

[0150] In one embodiment, the intermediate of the present disclosure is a compound of formula XVII: [ka] During the ceremony, [ka] is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, and R 1 , R 2 , R 7 , R 8a , R 8b , R 8c , and [ka] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0151] In another embodiment, the intermediate of the present disclosure is a compound of formula XVIII: [ka] During the ceremony, [ka] is an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 4- to 8-membered heterocyclo; R 1 , R 2 , R 7 , and [ka] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0152] In another embodiment, the intermediate of the present disclosure is a compound of formula XIX: [ka] During the ceremony, [ka] is an optionally substituted 4- to 8-membered heterocyclo; R 1 , R 2 , and R 7 is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0153] In one embodiment, the intermediate of the present disclosure is a compound of formula XX: [ka] During the ceremony, [ka] is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, and R 1 , R 2 , R 8a , R 8b , R 8c , and [ka] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0154] In another embodiment, the intermediate of the present disclosure is a compound of formula XXI: [ka] During the ceremony, [ka] is an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 4- to 8-membered heterocyclo; R 1 , R 2 , and [ka] is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0155] In another embodiment, the intermediate of the present disclosure is a compound of formula XXII: [ka] During the ceremony, [ka] is an optionally substituted 4- to 8-membered heterocyclo; R 1 and R 2is as defined in relation to formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0156] Exemplary intermediates of the present disclosure include, but are not limited to, E12-8 and E12-9 of Example 1, E16-1 and E-16-2 of Example 2, E3-1 of Example 3, E36-6 and E36-7 of Example 4, E10-8 of Example 5, E95-3 of Example 6, E-2211.2 and E-2211.3 of Example 26, E-2189.1 and E-2189.2 of Example 27, and E-2206.2 and E-2206.3 of Example 28.

[0157] III. Methods of Preparing the Compounds and Intermediates of the Disclosure The present disclosure also provides methods for preparing the compounds of the present disclosure and / or the intermediates of the present disclosure.

[0158] Exemplary methods for preparing compounds of the present disclosure and / or intermediates of the present disclosure are provided in Examples 1-6 and 17.

[0159] IV. Methods of Treating Diseases with Compounds of the Disclosure The compounds of the present disclosure inhibit EED and are therefore useful in the treatment or prevention of various diseases and conditions. In particular, the compounds of the present disclosure are useful in methods for treating or preventing diseases or conditions for which inhibition of EED provides benefit. Foremost among these diseases and conditions are cancers and proliferative diseases. In one embodiment, such cancers are referred to as "EED-mediated cancers." EED-mediated cancers are known in the art. The therapeutic method of the present disclosure includes administering a therapeutically effective amount of a compound of the present disclosure to a subject, e.g., a human, in need thereof. The method of the present disclosure also encompasses optionally administering to the subject any therapeutic agent in addition to the compound of the present disclosure. The optional therapeutic agent is selected from drugs known to be useful in treating the disease or condition afflicting the subject in a subject in need of treatment, such as chemotherapeutic agents and / or radiation known to be useful in treating certain cancers.

[0160] In one embodiment, the present disclosure relates to a method of treating an individual suffering from a disease or condition in which inhibition of EED provides a benefit, the method comprising administering a therapeutically effective amount of a compound of the present disclosure.

[0161] Because the compounds of the present disclosure are inhibitors of EED proteins, some diseases and conditions mediated by EED can be treated by using these compounds. Thus, the present disclosure is generally directed to a method for treating a condition or disorder responsive to EED inhibition in a subject, e.g., a human subject, suffering from or at risk of suffering from the condition or disorder, the method comprising administering an effective amount of one or more compounds of the present disclosure to the subject.

[0162] In another embodiment, the present disclosure is directed to a method of inhibiting EED in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one compound of the present disclosure.

[0163] The method of the present disclosure can be achieved by administering the compound of the present disclosure as a neat compound or as a pharmaceutical composition. The administration of the pharmaceutical composition or neat compound of the compound of the present disclosure can be carried out during or after the onset of the disease or condition of interest. Typically, the pharmaceutical composition is sterile and does not contain toxic, carcinogenic, or mutagenic compounds that cause adverse reactions when administered. Kits containing the compound of the present disclosure and, optionally, any therapeutic agent, packaged separately or together, as well as package inserts with instructions for using these active agents, are further provided.

[0164] In one embodiment, the compound of the present disclosure is administered in combination with any therapeutic agent useful for treating diseases or conditions that benefit from the inhibition of EED protein.The any therapeutic agent is different from the compound of the present disclosure.The compound of the present disclosure and any therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.In addition, the compound of the present disclosure and any therapeutic agent can be administered from a single composition or two separate compositions.

[0165] Any therapeutic agent is administered in an amount that provides the desired therapeutic effect. Effective dosage ranges for each therapeutic agent are known in the art, and any therapeutic agent is administered within such established ranges to individuals in need thereof.

[0166] The compound of the present disclosure and any therapeutic agent can be administered together as a single unit dose or separately as multiple unit doses, with the compound of the present disclosure being administered before any therapeutic agent, or vice versa. One or more doses of the compound of the present disclosure and / or one or more doses of any therapeutic agent can be administered. Thus, the compound of the present disclosure can be used in combination with one or more therapeutic agents, for example, but not limited to, anticancer agents.

[0167] Diseases and conditions treatable by the methods of the present disclosure include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections. In one embodiment, a human subject is treated with a compound of the present disclosure or a pharmaceutical composition comprising a compound of the present disclosure, wherein the compound is administered in an amount sufficient to inhibit EED protein in the subject.

[0168] In another embodiment, the present disclosure provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. Without being limited to a particular mechanism of action, in some embodiments, the compound of the present disclosure treats cancer by inhibiting EED. Examples of treatable cancers include, but are not limited to, any one or more of the cancers in Table 3. [Table 2-1] [Table 2-2]

[0169] In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, those listed in Table 4. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. [Table 3]

[0170] In another embodiment, the cancer is a leukemia, e.g., a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the cancer is NUT midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0171] In another embodiment, the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0172] In another embodiment, the present disclosure provides a method of treating benign proliferative diseases such as, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumor, prolactinoma, pseudotumor cerebri, seborrheic keratosis, gastric polyps, thyroid nodules, cystic tumors of the pancreas, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.

[0173] The compounds of the present disclosure can also treat infectious and non-infectious inflammatory events, as well as autoimmune and other inflammatory diseases, in mammals, particularly humans, in need of such treatment by administering an effective amount of the compounds. Examples of autoimmune and inflammatory diseases, disorders, and syndromes that can be treated using the compounds and methods described herein include pelvic inflammatory disease, urethritis, sun dermatitis, and the like. sunburn), sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpa These include Schuur's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, type 1 diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0174] In another embodiment, the present disclosure provides a method for treating systemic inflammatory response syndrome, such as LPS-induced endotoxic shock and / or bacterial-induced sepsis, by administering to a mammal, particularly a human, in need of such treatment an effective amount of a compound of the present disclosure.

[0175] In another embodiment, the present disclosure provides a method for treating viral infections and diseases.The example of viral infections and diseases that can be treated using compounds and methods described herein includes but is not limited to episomal DNA viruses, including human papillomavirus, herpesvirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus and hepatitis C virus.

[0176] In another embodiment, the present disclosure provides methods of modulating protein methylation, gene expression, cell proliferation, cell differentiation, and / or apoptosis in vivo in the provided diseases, particularly cancer, inflammatory diseases, and / or viral diseases, by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure.

[0177] In another embodiment, the present disclosure provides methods of modulating endogenous or heterologous promoter activity by contacting a cell with a compound of the present disclosure.

[0178] In the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure, typically formulated according to pharmaceutical practice, is administered to a human in need thereof. Whether such treatment is indicated depends on the individual case and is subject to a medical evaluation (diagnosis) that takes into account the signs, symptoms, and / or dysfunctions present, the risk of developing the particular signs, symptoms, and / or dysfunctions, and other factors.

[0179] The compounds of the present disclosure can be administered by any suitable route, for example, oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal, or intrathecal via lumbar puncture, transurethral, ​​nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at a specific site) administration. Parenteral administration can be accomplished using a needle and syringe or using high pressure techniques.

[0180] Pharmaceutical compositions include those in which the compound of the present disclosure is administered in an amount effective to achieve its intended purpose.The exact formulation, route of administration and dosage will be determined by an individual physician in consideration of the diagnosed condition or disease.Dosage and administration interval can be individually adjusted to provide a level of the compound of the present disclosure sufficient to maintain therapeutic effect.

[0181] The toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined, for example, by standard pharmaceutical procedures in cell cultures or experimental animals to determine the maximum tolerated dose (MTD) of the compound, which is defined as the highest dose that does not cause toxicity in animals.The dose ratio between the maximum tolerated dose and therapeutic effect (e.g., tumor growth inhibition) is the therapeutic index.Dosage can vary within this range depending on the dosage form used and the route of administration utilized.Determining a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0182] The therapeutically effective amount of the compound of the present disclosure required for use in treatment varies depending on the nature of the condition being treated, the desired duration of activity, and the age and condition of the patient, and is ultimately determined by the attending physician.Dosage and interval can be individually adjusted to provide a plasma level of the compound of the present disclosure sufficient to maintain the desired therapeutic effect.The desired dose is administered as a single dose or as subdoses at appropriate intervals, for example, 1, 2, 3, or 4 or more times per day.Multiple doses are often desired or required.For example, the compound of the present disclosure can be administered at four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qdx5); one dose per week for three weeks (qwk3); five daily doses, two days off, and five more daily doses (5 / 2 / 5), or any other dosage regimen determined to be appropriate for the situation.

[0183] The compounds of the present disclosure used in the methods of the present disclosure can be administered in amounts of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, the compounds of the present disclosure can be administered in amounts of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams per dose (including all doses from 0.005 to 500 milligrams).

[0184] The dosage of a composition comprising a compound of the present disclosure or a composition comprising a compound of the present disclosure can be about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of the composition can be any dosage, including, but not limited to, about 1 μg / kg. The dosage of the composition can be, but is not limited to, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 3 μg / kg, or about 4 μg / kg. 25μg / kg, about 350μg / kg, about 375μg / kg, about 400μg / kg, about 425μg / kg, about 450μg / kg, about 475μg / kg, about 500μg / kg, about 525μg / kg, approximately 550μg / kg, approximately 575μg / kg, approximately 600μg / kg, approximately 625μg / kg, approximately 650μg / kg, approximately 675μg / kg, approximately 700μg / kg, Approximately 725μg / kg, approximately 750μg / kg, approximately 775μg / kg, approximately 800μg / kg, approximately 825μg / kg, approximately 850μg / kg, approximately 875μg / kg, approximately 900μg / k g, approximately 925μg / kg, approximately 950μg / kg, approximately 975μg / kg, approximately 1mg / kg, approximately 5mg / kg, approximately 10mg / kg, approximately 15mg / kg, approximately 20mg / kg, approximately 25m The dosage may be any dosage, including about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, or more. The dosages above are exemplary of the average case, but there may be individual cases where higher or lower dosages are merited, and these cases are within the scope of the present disclosure. In practice, a physician will determine the actual dosage regimen most suitable for an individual subject, which may vary depending on the age, weight, and response of the particular subject.

[0185] The compounds of the present disclosure are typically administered in admixture with a pharmaceutical carrier to obtain a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in conventional manner using one or more physiologically acceptable carriers, including excipients and / or adjuvants that facilitate processing of the compounds of the present disclosure.

[0186] These pharmaceutical compositions can be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Suitable formulations depend on the chosen route of administration. When a therapeutically effective amount of a compound of the present disclosure is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition may further contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules, and powders contain about 0.01% to about 95%, preferably about 1% to about 50%, of a compound of the present disclosure. When administered in liquid form, a liquid carrier such as water, petroleum, or animal or vegetable oil can be added. Liquid forms of the composition may further contain saline, dextrose or other saccharide solution, or glycol. When administered in liquid form, the composition contains about 0.1% to about 90%, preferably about 1% to about 50%, by weight of a compound of the present disclosure.

[0187] When a therapeutically effective amount of the compound of the present disclosure is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. It is within the skill of the art to prepare such a parenterally acceptable solution, taking into consideration pH, isotonicity, stability, etc. A composition suitable for intravenous, cutaneous or subcutaneous injection typically contains an isotonic vehicle.

[0188] The compounds of the present disclosure can be easily combined with pharmaceutically acceptable carriers that are well known in the art.Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.For oral ingestion by the subject to be treated, such carriers allow the active agent to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc.Pharmaceutical preparations for oral use can be obtained by adding the compounds of the present disclosure to solid excipients, optionally grinding the resulting mixture, and if desired, adding suitable auxiliary agents, and then processing the granular mixture to obtain tablets or dragee cores.Suitable excipients include, for example, fillers and cellulose preparations.If desired, disintegrants can be added.

[0189] The compounds of the present disclosure can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be provided in a unit dosage form with preservatives added, for example, in ampoules or multi-dose containers.The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents.

[0190] Pharmaceutical compositions for parenteral administration include aqueous solutions of active agents in water-soluble form.In addition, the suspension of the compounds of the present disclosure can be prepared as suitable oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension.Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions.Alternatively, the composition can be in powder form, which can be reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0191] The compound of the present disclosure can also be formulated into rectal compositions, such as suppositories or retention enemas containing conventional suppository bases.In addition to the formulations described above, the compound of the present disclosure can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compound of the present disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as emulsions in acceptable oils) or ion exchange resins.

[0192] In particular, the compounds of the present disclosure can be administered orally, bucally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules, either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavorings or colorings.Such liquid preparations can be prepared using pharmaceutically acceptable additives such as suspending agents.The compounds of the present disclosure can also be parenterally injected, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.For parenteral administration, the compounds of the present disclosure are typically used in the form of a sterile aqueous solution, which may contain other substances, such as salts or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood.

[0193] V. Any Therapeutic Agent In some of the therapeutic methods and uses of the present disclosure, the compound of the present disclosure is administered to a subject with a disease, disorder, or condition, such as cancer, as a single agent. In other of the therapeutic methods and uses of the present disclosure, the compound of the present disclosure is administered to a subject with a disease, disorder, or condition, such as cancer, in combination with one or more optional therapeutic agents. In one embodiment, the compound of the present disclosure is administered in combination with one optional therapeutic agent. In another embodiment, the compound of the present disclosure is administered in combination with two optional therapeutic agents. In another embodiment, the compound of the present disclosure is administered in combination with three optional therapeutic agents. The optional therapeutic agents useful for treating cancer patients include those known in the art as well as those that will be developed in the future.

[0194] Any therapeutic agent is administered in an amount that provides their desired therapeutic effect. Effective dosage ranges for each therapeutic agent are known in the art, and any therapeutic agent is administered within such established ranges to individuals in need thereof.

[0195] The compound of the present disclosure and any therapeutic agent(s) can be administered together as a single unit dose or separately as multiple unit doses, in any order, for example, with the compound of the present disclosure administered before any therapeutic agent(s), or vice versa. One or more doses of the compound of the present disclosure and any therapeutic agent(s) can be administered to the subject.

[0196] In one embodiment, the optional therapeutic agent is an immune checkpoint inhibitor. Immune checkpoint inhibitors are therapeutics that block immune system inhibitor checkpoints. Immune checkpoints can be stimulatory or inhibitory. Blocking inhibitory immune checkpoints activates immune system function and can be used in cancer immunotherapy. Pardoll, Nature Reviews, Cancer 12:252-64 (2012). When tumor cells bind to specific T cell receptors, they turn off activated T cells. Immune checkpoint inhibitors prevent tumor cells from binding to T cells, leaving them activated. In effect, the coordinated action of cellular and soluble components combats pathogens and damage caused by cancer. Modulation of an immune system pathway can include altering the expression or functional activity of at least one component of the pathway to modulate the immune system response. US2015 / 0250853. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, CD47 inhibitors, and B7-H1 inhibitors. Thus, in one embodiment, the immune checkpoint inhibitor is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, and CD47 inhibitors.

[0197] In another embodiment, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T cell co-inhibitory receptor that plays a crucial role in the ability of tumor cells to evade the host's immune system. Blocking the interaction between PD-1 and its ligand, PD-L1, enhances immune function and mediates anti-tumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Specific anti-PD-1 antibodies include, but are not limited to, nivolumab, pembrolizumab, STI-A1014, pidiluzumab, and cemiplimab-rwlc. For a general discussion of the availability, production methods, mechanism of action, and clinical studies of anti-PD-1 antibodies, see US2013 / 0309250, US6,808,710, US7,595,048, US8,008,449, US8,728,474, US8,779,105, US8,952,136, US8,900,587, US9,073,994, US9,084,776, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0198] In another embodiment, the immune checkpoint inhibitor is a PD-L1 (also known as B7-H1 or CD274) inhibitor. Examples of PD-L1 inhibitors include antibodies that specifically bind to PD-L1. Specific anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559. For a general discussion of availability, production methods, mechanism of action, and clinical studies, see US8,217,149, US2014 / 0341917, US2013 / 0071403, WO2015 / 036499, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0199] In another embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor. CTLA-4, also known as cytotoxic T-lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 is characterized as a "brake" that binds to costimulatory molecules on antigen-presenting cells, preventing their interaction with CD28 on T cells and generating a clear inhibitory signal that suppresses T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Specific anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. For a general discussion of availability, manufacturing methods, mechanism of action, and clinical studies, see US 6,984,720, US 6,207,156, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0200] In another embodiment, the immune checkpoint inhibitor is a LAG3 inhibitor. LAG3, lymphocyte activation gene 3, is a negative co-stimulatory receptor that regulates T cell homeostasis, proliferation, and activation. Furthermore, LAG3 has been reported to be involved in the suppressive function of regulatory T cells (Tregs). Most LAG3 molecules are retained in cells near microtubule-organizing centers and are induced only after antigen-specific T cell activation. US2014 / 0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Specific anti-LAG3 antibodies include, but are not limited to, GSK2831781. For a general discussion of availability, production methods, mechanism of action, and research, see US2011 / 0150892, US2014 / 0093511, US2015 / 0259420, and Huang et al., Immunity 21:503-13 (2004).

[0201] In another embodiment, the immune checkpoint inhibitor is a TIM3 inhibitor. TIM3, T-cell immunoglobulin and mucin domain 3, is a T H 1 and T C1 The TIM3 pathway is an immune checkpoint receptor that functions to limit the duration and magnitude of T cell responses. The TIM3 pathway inhibits dysfunctional CD8 T cells, two reported immune cell populations that constitute immunosuppression in tumor tissue. + Because it is expressed in T cells and Tregs, it is considered a target for anti-cancer immunotherapy. Anderson, Cancer Immunology Research 2:393-98(2014). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. For a general discussion of the availability, production methods, mechanism of action, and research of TIM3 inhibitors, see US2015 / 0225457, US2013 / 0022623, US8,522,156, Ngiow et al., Cancer Res 71:6567-71(2011), Ngiow, et al., Cancer Res 71:3540-51(2011), and Anderson, Cancer Immunology Res 2:393-98(2014).

[0202] In another embodiment, the immune checkpoint inhibitor is a CD47 inhibitor. See Unanue, ER, PNAS 110:10886-87 (2013).

[0203] The term "antibody" is intended to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. In another embodiment, "antibody" is intended to include soluble receptors that do not have the Fc portion of an antibody. In one embodiment, the antibody is a recombinantly engineered humanized monoclonal antibody and fragments thereof.

[0204] Another class of immune checkpoint inhibitors includes polypeptides that bind to and block the PD-1 receptor on T cells without inducing inhibitor signaling. Such peptides include B7-DC, B7-H1, B7-1, and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Patent No. 8,114,845.

[0205] Another class of immune checkpoint inhibitors includes compounds having a peptide moiety that inhibits PD-1 signaling. Examples of such compounds are disclosed in U.S. Patent No. 8,907,053 and have the following structure: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least five amino acids useful as a therapeutic agent capable of inhibiting the PD-1 signaling pathway.

[0206] Another class of immune checkpoint inhibitors includes inhibitors of certain metabolic enzymes, such as indoleamine 2,3-dioxygenase (IDO), which is expressed by infiltrating myeloid and tumor cells, and isocitrate dehydrogenase (IDH), which is mutated in leukemia cells. Mutant IDH enzymes result in elevated levels of 2-hydroxyglutarate (2-HG), which inhibits myeloid differentiation. (Stein et al., Blood 130:722-31 (2017); Wouters, Blood 130:693-94 (2017)). Specific mutant IDH blockers include, but are not limited to, ivosidenib and enasidenib mesylate. (Dalle and DiNardo, Ther Adv Hematol 9(7):163-73 (2018); Nassereddine et al., Onco Targets Ther 12:303-08 (2018)). The IDO enzyme inhibits immune responses by depleting T cells of amino acids required for their anabolic function or by synthesizing specific natural ligands for cytosolic receptors that can alter lymphocyte function. (Pardoll, Nature Reviews, Cancer 12:252-64 (2012); Lob, Cancer Immunol Immunother 58:153-57 (2009)). Specific IDO blockers include, but are not limited to, levo-1-methyltryptophan (L-1MT) and 1-methyl-tryptophan (1MT). (Qian et al., Cancer Res 69:5498-504 (2009) and Lob et al., Cancer Immunol Immunother 58:153-7 (2009)).

[0207] In one embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559, or MED14736.

[0208] In another embodiment, any therapeutic agent is an epigenetic drug.As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets epigenetic regulators.Examples of epigenetic regulators include histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase.Histone deacetylase inhibitors include, but are not limited to, vorinostat and panobinostat lactate.

[0209] In another embodiment, any therapeutic agent is a chemotherapeutic agent or other anti-proliferative agent that can be administered in combination with the compounds of the present disclosure to treat cancer. Examples of conventional therapies and anti-cancer agents that can be used in combination with the compounds of the present disclosure include surgery, radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, tumor necrosis factors (TNF)), hyperthermia and cryotherapy, any adverse effect-reducing agents (e.g., antiemetics), and any other approved biological or chemotherapy treatment regimens, such as those that use drugs to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Chemotherapy can be administered orally, by injection or infusion, or through the skin, depending on the type and stage of the cancer being treated.

[0210] Non-limiting exemplary anti-proliferative compounds include aromatase inhibitors, antiestrogens, antiandrogens, gonadorelin agonists, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule activators, alkylating agents (e.g., temozolomide), retinoids, carotenoids or tocopherols, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antimetabolites, platin compounds, methionine aminopeptidase inhibitors, bisphosphonates, anti-proliferative antibodies, heparanase inhibitors, Ras oncogenic isoform inhibitors, telomerase inhibitors, proteasome inhibitors, compounds used in the treatment of hematopoietic tumors, Flt-3 inhibitors, Hsp90 inhibitors, kinesin spindle protein inhibitors, MEK inhibitors, anti-tumor antibiotics, nitrosoureas, compounds that target / reduce protein or lipid kinase activity, compounds that target / reduce protein / lipid phosphatase activity, or any additional anti-angiogenic compounds.

[0211] Non-limiting exemplary aromatase inhibitors include steroids such as atamestane, exemestane, and formestane, and non-steroids such as aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole.

[0212] Non-limiting examples of antiestrogens include tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Antiandrogens include, but are not limited to, bicalutamide and apalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

[0213] Exemplary topoisomerase I inhibitors include topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones such as mitoxantrone and lozoxantrone; and podophyllotoxins such as etoposide and teniposide.

[0214] Microtubule active agents include microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubulin polymerization inhibitors (including, but not limited to, taxanes such as paclitaxel and docetaxel), discodermolide, colchicine, and epothilones, and their derivatives.

[0215] Exemplary, non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, trabectedin, and nitrosoureas, such as carmustine and lomustine.

[0216] Exemplary, non-limiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY12-9566, TAA211, MMI270B, and AAJ996.

[0217] Exemplary, non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and have proliferative activity, such as sirolimus, everolimus, CCI-779, and ABT578.

[0218] Exemplary, non-limiting antimetabolites include DNA demethylating compounds such as 5-fluorouracil (5-FU), capecitabine, gemcitabine, 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed.

[0219] Exemplary, non-limiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.

[0220] Exemplary, non-limiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.

[0221] Exemplary, non-limiting bisphosphonates include etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

[0222] Exemplary, non-limiting heparanase inhibitors include compounds that target, reduce, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.

[0223] Non-limiting exemplary compounds that target, reduce, or inhibit the oncogenic activity of Ras include farnesyltransferase inhibitors such as L-744832, DK8G557, tipifarnib, and lonafarnib.

[0224] Exemplary, non-limiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, including compounds that inhibit the telomerase receptor, such as telomestatin.

[0225] Exemplary, non-limiting proteasome inhibitors include compounds that target, reduce, or inhibit the activity of the proteasome, including, but not limited to, bortezomib. In some embodiments, the proteasome inhibitor is carfilzomib or ixazomib.

[0226] Non-limiting exemplary FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R), include gilteritinib, interferon, I-β-D-arabinofuransylcytosine (ara-c), and bisulfan, and ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase, include alectinib, brigatinib, and lorlatinib.

[0227] Exemplary, non-limiting Flt-3 inhibitors include PKC412, midostaurin, staurosporine derivatives, SU11248, MLN518, and gilteritinib.

[0228] Exemplary, non-limiting HSP90 inhibitors include compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, or compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[0229] Non-limiting exemplary protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors include: a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFRs), such as imatinib, SUL01, SU6668, and compounds that target, reduce or inhibit the activity of PDGFRs, including olaratumab and N-phenyl-2-pyrimidine-amine derivatives, such as GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs), such as erdafitinib and lenvatinib; c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as brigatinib; d) compounds that target, reduce or inhibit the activity of vascular endothelial growth factor receptors (VEGFRs), such as lenvatinib; e) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family; or ephrin B4 inhibitors such as larotrectinib, f) compounds that target, reduce or inhibit the activity of the Axl receptor tyrosine kinase family, g) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase, such as alectinib, h) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib, i) c-Kit receptor tyrosine kinase, such as imatinib j) compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., Bcr-Abl kinase), and mutants, such as N-phenyl-2-pyrimidine-amine derivatives, imatinib or nilotinib, PD180970, AG957, NSC680410, PD173955, or dasatinib; k) compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., Bcr-Abl kinase), and mutants, such as midostaurin, U.S. Pat. No. 5,093,compounds that target, reduce, or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK, FAK, PDK1, and PKB / Akt family members, and / or members of the cyclin-dependent kinase family (CDK), such as the staurosporine derivatives disclosed in US Pat. No. 3,330 (further exemplary compounds include UCN-01, safingol, BAY43-9006, Bryomycin, and the like); statin 1, perifosine; ilmofosine; RO318220 and RO320432; GO6976; Isis3521; LY333531 / LY379196; isoquinoline compounds; farnesyltransferase inhibitors; PD184352 or QAN697, or AT7519; abemaciclib; binimetinib; cobimetinib; encorafenib; neratinib; palbociclib; ribociclib), l) acalabrutinib, imatinib mesylate, or thiamin monophosphate Protein-like compounds such as tyrphostins, e.g., tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin). Compounds that target, decrease, or inhibit the activity of tyrosine kinases, m) brigatinib, CP358774, ZD1839, ZM105180; trastuzumab, cetuximab, gefitinib, erlotinib, osimertinib, dacomitinib, necitumumab, neratinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3, and 7H-pyrrolo-[2,These include compounds that target, reduce, or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as 3-d]pyrimidine derivatives; n) compounds that target, reduce, or inhibit the activity of phosphatidylinositol 3-kinase (PI3K), such as alpelisib, copanlisib, and duvelisib; and o) compounds that target, reduce, or inhibit the activity of the c-Met receptor.

[0230] Exemplary compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[0231] Additional anti-angiogenic compounds include compounds that have another mechanism for activity unrelated to the inhibition of protein or lipid kinases, such as thalidomide and TNP-470.

[0232] One or more of additional non-limiting exemplary chemotherapeutic compounds can be used in combination with the compounds of the present disclosure, including Avastin, Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum, PKC412, 6-mercaptopurine (6-MP), Fludarabine phosphate, Octreotide, SOM230, FTY720, 6-Thioguanine, Cladribine, 6-Mercaptopurine, Pentostatin, Hydroxyurea , 2-hydroxy-1H-isoindole-1,3-dione derivatives, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, angiostatin, endostatin, anthranilic acid amide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macgon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 These include IgGI antibodies, RPI4610, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloids, hormonal compounds and / or antagonists, biological response modifiers such as lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA, and siRNA.

[0233] Any suitable therapeutic agent, for example, an anti-cancer agent, is contemplated for use in the methods of treatment provided herein. Indeed, the methods provided herein include, but are not limited to, agents that induce apoptosis; polynucleotides (e.g., antisense, ribozymes, siRNA); polypeptides (e.g., enzymes and antibodies); biomimetics (e.g., gossypol or BH3 mimetics); agents that bind (e.g., oligomerize or complex) with Bcl-2 family proteins such as Bax; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated to anticancer drugs, toxins, defensins), toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN-α) and interleukins (e.g., IL-2)); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans retinoic acid); gene therapy reagents (e.g., antisense therapy reagents and nucleotides); tumor vaccines; angiogenesis inhibitors; proteosome inhibitors; NF-KB modulators; anti-CDK compounds; HDAC inhibitors, and the like. Many other examples of any therapeutic agent, such as chemotherapeutic compounds and anti-cancer therapies, suitable for co-administration with the disclosed compounds will be known to those of skill in the art.

[0234] In certain embodiments, the anticancer drug comprises an agent that induces or stimulates apoptosis. Agents that induce or stimulate apoptosis include agents that interact with or modify DNA, for example, by intercalating, cross-linking, alkylating, or otherwise damaging or chemically modifying DNA. Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, UV), tumor necrosis factor (TNF)-related factors (e.g., antibodies against TNF family receptor proteins, TNF family ligands, TRAIL, TRAIL-R1, or TRAIL-R2), and kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitors).Additional anticancer agents include vascular growth factor receptor (VGFR) kinase inhibitors, fibroblast growth factor receptor (FGFR) kinase inhibitors, platelet-derived growth factor receptor (PDGFR) kinase inhibitors, and Bcr-Abl kinase inhibitors (such as GLEEVEC); antisense molecules; antibodies (e.g., Herceptin, Rituxan, Zevalin, Bexal, and Avastin); antiestrogens (e.g., raloxifene and tamoxifen); antiandrogens (e.g., flutamide, apalutamide, bicalutamide, finasteride, aminoglutethimide, ketoconazole, and corticosteroids); BCL-2 inhibitors (e.g., venetoclax); cyclooxygenase-2 (COX-2) inhibitors (e.g., celecoxib, meloxicam, NS-398, and nonsteroidal anti-inflammatory drugs (NSAIDs)); anti-inflammatory drugs (e.g., , butazolidine, decadron, deltasone, dexamethasone, dexamethasone intensol, dexon, hexadrol, hydroxychloroquine, methycortene, oladexon, olasone, oxyphenbutazone, pediapred, phenylbutazone, plaquenil, prednisolone, prednisone, prelon, and tandearyl); and cancer chemotherapy drugs (e.g., irinotecan (camptosar), CPT-11, fludarabine (Fludara), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, gemcitabine, bortezomib, gefitinib, bevacizumab, taxotere, or taxol); cell signaling molecules; ceramides and cytokines; and staurosporine.

[0235] In still other embodiments, the methods of treatment provided herein comprise administering to a subject having cancer (cancer patient) a therapeutically effective amount of a compound of the present disclosure, an immune checkpoint inhibitor, and at least one additional optional therapeutic agent, such as an anti-hyperproliferative or anti-tumor agent selected from alkylating agents, antimetabolites, and natural products (e.g., compounds derived from herbs and other plants and / or animals).

[0236] Alkylating agents suitable for use in the present methods include, but are not limited to, 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin); and chlorambucil), 2) ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), 3) alkylsulfonates (e.g., busulfan), 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl-CCNU); and streptozotocin (streptozotocin)), 5) triazenes (e.g., dacarbazine (DTIC; dimethyltriazenoimide-azolecarboxamide)).

[0237] In some embodiments, antimetabolites suitable for use in the present methods include, but are not limited to, 1) folic acid analogs (e.g., methotrexate (amethopterin)), 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil; 5-FU), floxuridine (fluorodeoxyuridine), and cytarabine (cytosine arabinoside)), 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; TG), and pentostatin (2'-deoxycoformycin)).

[0238] In yet another embodiment, chemotherapeutic agents suitable for use in the methods of the present disclosure include, but are not limited to, 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine), 2) epipodophyllotoxins (e.g., etoposide and teniposide), 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)), 4) enzymes (e.g., L-asparaginase), 5) biological response modifiers (e.g., interferon-alpha), 6) platinum coordination complexes (e.g., cisplatin (cis-DDP) and carboplatin), 7) anthracenediones (e.g., mitoxantrone), 8) substituted ureas (e.g., , hydroxyurea), 9) methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine; MIH)), 10) adrenocortical suppressants (e.g., mitotane (o,p'-DDD) and aminoglutethimide), 11) adrenocorticosteroids (e.g., prednisone), 12) progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate), 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol), 14) antiestrogens (e.g., tamoxifen), 15) androgens (e.g., testosterone propionate and fluoxymesterone), 16) antiandrogens (e.g., flutamide), and 17) gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0239] Oncolytic agents routinely used in the context of cancer treatment find use in the therapeutic methods of the present disclosure. For example, the U.S. Food and Drug Administration (FDA) maintains a formulary of oncolytic agents approved for use in the United States. FDA's international counterparts maintain similar formularies. Those skilled in the art will understand that the required "product labeling" for all chemotherapeutics approved in the United States describes the approved indications, administration information, toxicity data, etc., of exemplary agents.

[0240] Anti-cancer agents further include compounds that have been identified to have anti-cancer activity. Examples include, but are not limited to, 3-AP, 12-O-tetradecanoylphorbol-13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG20, AE-941, AG-013736, AGRO100, alanosine, AMG706, antibody G250, antineoplastic agent, AP23573, apaziquone, APC8 015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, BMS247550, bortezomib, bryostatin-1, buserelin, calaspargase pegol-mknl, calcitriol, CCI-779, CDB-2914, cefixime, cetuximab, CG0 070, cilengitide, clofarabine, combretastatin A4 phosphate, CP-675,206, CP-724,714, CpG7909, curcumin, daratumumab, decitabine, DENSPM, dinutuximab, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eflornithine, EKB-569, elotzu Zumab, enzastaurin, erlotinib, exisulind, fenretinide, flavopiridol, fludarabine, flutamide, fotemustine, FR901228, G17DT, galiximab, gefitinib, genistein, glasdegib, glufosfamide, GTI-2040, histrelin, HKI-272, homoharringtonine, HSPPC-96, hu14.18-interleukin-2 fusion protein, HuMax-CD4, iloprost, imiquimod, infliximab, inotuzumab ozogamicin, interleukin-12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, lonafarnib, luniliximab, lutetium Lu177 dotatate, mafosfamide, MDX-010, MLN2704, mogamulizumab-kpkc, monoclonal antibody 3F8, monoclonal antibody J591, motexafine, moxetumomab-pasudotox-tdfk, MS-275, MV A-MUC1-IL2, nilutamide, niraparib, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS-9, O6-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, paraplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, polatuzumab vedotin-piiq, PS-341, PSC833, PXD101, pyrazoloacridine, R115777, RAD001, ranpirnase, rebeccamycin analog, rhu angiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, rucaparib, S-1, S-8184, satraplatin, SB-, 15992, SGN-0010, SGN-40, sonidegib, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, tagraxofusp-erzs, talabostat, talampanel, talazoparib, tariquidar, temsirolimus, TGFα-PE 38 immunotoxins, thalidomide, thymalfasin, tipifarnib, tirapazamine, TLK286, trabectedin, trifluridine and tipiracil hydrochloride, trimetrexate glucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839, ZD6474, zileuton, and zosuquidar trihydrochloride.

[0241] In one embodiment, the optional therapeutic agent comprises one of the anti-cancer agents or combinations of anti-cancer agents listed in Table 5. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0242] The present disclosure provides the following specific embodiments in connection with treating a disease in a subject.

[0243] Embodiment I. A method of treating a subject comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject, wherein the subject has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

[0244] Embodiment II. The method embodiment I, wherein the subject has cancer.

[0245] Embodiment III. The method of embodiment II, wherein the cancer is any one or more of the cancers in Table 3.

[0246] Embodiment IV. The method of embodiment II, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0247] Embodiment V. The method of embodiment II, wherein the cancer is any one or more of the cancers in Table 4.

[0248] Embodiment VI. The method of any one of Embodiments I-V, further comprising administering a therapeutically effective amount of any therapeutic agent useful in treating the disease or condition, e.g., an immune checkpoint inhibitor or other anti-cancer agent.

[0249] Embodiment VII. The method of any one of Embodiments I-VI, wherein the compound of the present disclosure is a compound of any one of Formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, or a pharmaceutically acceptable salt or solvate thereof.

[0250] Embodiment VIII. The method of any one of Embodiments I-VI, wherein the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof.

[0251] Embodiment IX. A pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

[0252] Embodiment X. The pharmaceutical composition of embodiment IX for use in treating cancer.

[0253] Embodiment XI. The pharmaceutical composition of embodiment X, wherein the cancer is any one or more of the cancers in Table 3.

[0254] Embodiment XII. The pharmaceutical composition of embodiment X, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0255] Embodiment XIII. The pharmaceutical composition of embodiment X, wherein the cancer is any one or more of the cancers in Table 4.

[0256] Embodiment XIV. The pharmaceutical composition of any one of Embodiments IX-XIII, wherein the compound of the present disclosure is a compound of any one of Formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, or a pharmaceutically acceptable salt or solvate thereof.

[0257] Embodiment XV. The pharmaceutical composition of any one of Embodiments IX-XIII, wherein the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof.

[0258] Embodiment XVI. A compound of the present disclosure for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disease, sepsis, or a viral infection.

[0259] Embodiment XVII. The compound of embodiment XVI for use in treating cancer.

[0260] Embodiment XVIII. The compound of embodiment XVII, wherein the cancer is any one or more of the cancers in Table 3.

[0261] Embodiment XIX. The compound of embodiment XVII, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0262] Embodiment XX. The compound of embodiment XVII, wherein the cancer is any one or more of the cancers in Table 4.

[0263] Embodiment XXI. The compound of any one of Embodiments XVI-XX, wherein the compound of the present disclosure is a compound of any one of Formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, or a pharmaceutically acceptable salt or solvate thereof.

[0264] Embodiment XXII. The compound of any one of Embodiments XVI-XX, wherein the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof.

[0265] Embodiment XXIII. Use of a compound of the present disclosure for the manufacture of a medicament for the treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disease, sepsis, or a viral infection.

[0266] Embodiment XXIV. The use of embodiment XXIII for the treatment of cancer.

[0267] Embodiment XXV. The use of embodiment XXIV, wherein the cancer is any one or more of the cancers in Table 3.

[0268] Embodiment XXVI. The use of embodiment XXIII, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colon cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0269] Embodiment XXVII. The use of embodiment XXIV, wherein the cancer is any one or more of the cancers in Table 4.

[0270] Embodiment XXVIII. The use of any one of Embodiments XXIII-XXVII, wherein the compound of the present disclosure is a compound of any one of Formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, or a pharmaceutically acceptable salt or solvate thereof.

[0271] Embodiment XXIX. The use of any one of Embodiments XXIII-XXVII, wherein the compound of the present disclosure is a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof.

[0272] Embodiment XXX. A method of inhibiting EED protein in a cell of a subject in need thereof, comprising administering to the subject a compound of any one of Formulas I-XI, XI-A, XI-B, XII, XII-A, XII-B, XIII, XIII-A, XIII-B, XIV, XIV-A, XIV-B, XV, XV-A, or XV-B, or a pharmaceutically acceptable salt or solvate thereof.

[0273] Embodiment XXXI. A method of inhibiting EED protein in cells of a subject in need thereof, comprising administering to the subject a compound of formula XVI, or a pharmaceutically acceptable salt or solvate thereof.

[0274] V. Kits of the Present Disclosure In another embodiment, the present disclosure provides kits comprising a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a manner that facilitates their use to practice a method of the present disclosure. In one embodiment, the kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container, such as a sealed bottle or vessel, having a label affixed to the container or included in the kit that describes the use of the compound or composition to practice a method of the present disclosure, e.g., the method of any one of Embodiments I-VI. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration.

[0275] VI.Definition The term "disease or condition that EED inhibition provides benefits" and the like refer to diseases or conditions in which EED is important or necessary for, for example, the onset, progression, or development of the disease or condition, or diseases or conditions that are known to be treated by EED inhibitors.Examples of such conditions include, but are not limited to, cancer, chronic autoimmune disease, inflammatory disease, proliferative disease, sepsis, and viral infection.Those skilled in the art can easily determine whether a compound treats the disease or condition mediated by EED inhibitors for any specific cell type, for example, by conveniently using assays that can be used to evaluate the activity of a specific compound.See, for example, Yue and Turkson, Expert Opinion Invest Drugs 18:45-56(2009).

[0276] The term "EED" refers to embryonic ectoderm development protein. See Moritz and Trievel, J. Biol. Chem. 293(36):13805-13814 (2018).

[0277] The term "any therapeutic agent" refers to a therapeutic agent that is known to treat the disease or condition of interest, other than the compounds of the present disclosure. For example, if cancer is the disease or condition of interest, the any therapeutic agent can be, for example, a known chemotherapeutic agent such as taxol or radiation.

[0278] The term "disease" or "condition" refers to a disorder and / or abnormality that is typically considered to be a pathological state or function and may manifest itself in the form of specific signs, symptoms, and / or dysfunction. The compounds of the present disclosure are EED inhibitors and can be used to treat or prevent diseases and conditions in which inhibition of EED provides a benefit.

[0279] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or alleviating a disease or condition and / or its associated symptoms. Although not exclusive, treatment of a disease or condition does not require that the disease, condition, or its associated symptoms be completely eliminated. The term "treat" and cognate terms contemplate administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. Treatment can be indicated symptomatically, for example, to suppress symptoms. It can be short-term, directed over the medium term, or can be long-term treatment, for example, in the context of maintenance therapy.

[0280] As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease or condition and / or its associated symptoms, or a method of barring a subject from contracting a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its associated symptoms, and reducing a subject's risk of contracting a disease. The terms "prevent," "preventing," and "prevention" can include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition reoccurring or a disease or condition that has already been controlled in a subject who is at risk or susceptible to, but who does not have, a disease or condition reoccurring or a recurrence of the disease or condition.

[0281] As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of active ingredient(s) sufficient, when administered by the methods of the present disclosure, to effectively deliver the active ingredient(s) to a subject in need of treatment to treat the condition or disease of interest. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (i.e., inhibit or stop to some extent) unwanted cell proliferation, decrease cancer cell number, decrease tumor size, inhibit (i.e., inhibit or stop to some extent) cancer cell invasion into peripheral organs, inhibit (i.e., inhibit or stop to some extent) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that the administered compound or composition prevents growth and / or kills existing cancer cells, the compound or composition may be cytostatic and / or cytotoxic.

[0282] The term "container" means any receptacle and closure suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0283] The term "package insert" means the information that accompanies a drug product that provides instructions on how to administer the product, along with safety and effectiveness data necessary for physicians, pharmacists, and subjects to make informed decisions about the product's use. Package inserts are generally considered the drug's "label."

[0284] "Co-administration," "administered in combination," "co-administration," and similar phrases mean that two or more agents are administered to a subject being treated at the same time. "Concurrently" means that each agent is administered either simultaneously or sequentially in any order at different times. However, if not administered simultaneously, it means that they are administered to a subject in a sequence and sufficiently close in time to provide the desired therapeutic effect, and can act in concert. For example, a compound of the present disclosure can be administered simultaneously as any therapeutic agent or sequentially in any order at different times. The compound of the present disclosure and any therapeutic agent can be administered separately in any suitable form and by any suitable route. If the compound of the present disclosure and any therapeutic agent are not administered simultaneously, it is understood that the compound of the present disclosure and the second therapeutic agent can be administered to a subject in need thereof in any order. For example, a compound of the disclosure can be administered to a subject in need thereof prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of any therapeutic therapy (e.g., radiation therapy). In various embodiments, the compounds of the disclosure and any therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1-2 hours apart, 2-3 hours apart, 3-4 hours apart, 4-5 hours apart, 5-6 hours apart, 6-7 hours apart, 7-8 hours apart, 8-9 hours apart, 9-10 hours apart, 10-11 hours apart, 11-12 hours apart, 24 hours or less apart, or 48 hours or less apart. In one embodiment, the components of the combination therapy are administered from about 1 minute to about 24 hours apart.

[0285] The use of the terms "a," "an," "the," and similar referents in the context of describing this disclosure (particularly in the context of the claims) is intended to encompass both the singular and the plural unless otherwise indicated. The recitation of ranges of values ​​herein is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually listed herein. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended to better explain the disclosure and does not limit the scope of the disclosure unless otherwise asserted. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[0286] The term "halo" as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I.

[0287] The term "nitro" as used herein by itself or as part of another group refers to -NO2.

[0288] The term "cyano" as used herein by itself or as part of another group refers to --CN.

[0289] The term "hydroxy" as used herein by itself or as part of another group refers to --OH.

[0290] The term "alkyl" as used herein by itself or as part of another group refers to an alkyl group having 1 to 12 carbon atoms, i.e., C1-C 12 Alkyl refers to a straight or branched chain aliphatic hydrocarbon containing a specified number of carbon atoms, e.g., C1 alkyl such as methyl, C2 alkyl such as ethyl, etc. In one embodiment, alkyl is a C1-C 10In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C 12 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. In another embodiment, one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms, i.e., the alkyl group is isotopically labeled with deuterium. A non-limiting exemplary deuterated alkyl group is -CD3.

[0291] The term “optionally substituted alkyl,” as used herein by itself or as part of another group, refers to an alkyl group that is unsubstituted or substituted with one, two, or three substituents, each of which is independently selected from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl, carboxyalkyl, —N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , or -S(=O)2R 58 where: R 56a is hydrogen or alkyl, R 56b is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C-C10 aryl, or optionally substituted heteroaryl; R 56c is hydrogen or alkyl, R 56d is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C-C 10 aryl, or optionally substituted heteroaryl; R 56e is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C-C 10 aryl, or optionally substituted heteroaryl; R 57 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl; R 58is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl. Non-limiting exemplary optionally substituted alkyl groups include -CH(COMe)CHCOMe and -CH(CH)CHN(H)C(=O)O(CH).

[0292] The term "alkenyl," as used herein by itself or as part of another group, refers to an alkyl group containing one, two, or three carbon-carbon double bonds. In one embodiment, an alkenyl group is a C2-C6 alkenyl group. In another embodiment, an alkenyl group is a C2-C4 alkenyl group. In another embodiment, an alkenyl group has one carbon-double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0293] The term "optionally substituted alkenyl," as used herein by itself or as part of another group, refers to an alkenyl group that is unsubstituted or substituted with one, two, or three substituents, each of which is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting exemplary optionally substituted alkenyl groups include -CH=CHPh.

[0294] The term "alkynyl," as used herein by itself or as part of another group, refers to an alkyl group containing one, two, or three carbon-carbon triple bonds. In one embodiment, an alkynyl is a C2-C6 alkynyl. In another embodiment, an alkynyl is a C2-C4 alkynyl. In another embodiment, an alkynyl has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0295] The term "optionally substituted alkynyl," as used herein by itself or as part of another group, refers to an alkynyl group that is unsubstituted or substituted with one, two, or three substituents, each of which is independently halo, nitro, cyano, hydroxy, amino, e.g., alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting exemplary optionally substituted alkynyl groups include -C≡CPh and -CH(Ph)C≡CH.

[0296] The term "haloalkyl," as used herein by itself or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with 1, 2, or 3 fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted with 1, 2, or 3 fluorine atoms. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0297] The terms "hydroxyalkyl" or "(hydroxy)alkyl," as used herein by themselves or as part of another group, refer to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting exemplary (hydroxyl)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

[0298] The term "alkoxy," as used herein by itself or as part of another group, refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C1-C6 alkyl, and the resulting alkoxy is thus referred to as a "C1-C6 alkoxy." In another embodiment, the alkyl is a C1-C4 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0299] The term "haloalkoxy," as used herein by itself or as part of another group, refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6 haloalkyl. In another embodiment, the haloalkyl group is a C1-C4 haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0300] The term "alkylthio," as used herein by itself or as part of another group, refers to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkylthio groups include -SCH3 and -SCH2CH3.

[0301] The terms "alkoxyalkyl" or "(alkoxy)alkyl," as used herein by themselves or as part of another group, refer to an alkyl group substituted with an alkoxy group. In one embodiment, the alkoxy is a C1-C6 alkoxy. In another embodiment, the alkoxy is a C1-C4 alkoxy. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0302] The term "heteroalkyl," as used herein by itself or as part of another group, refers to an unsubstituted straight- or branched-chain aliphatic hydrocarbon containing 3 to 12 chain atoms, i.e., 3 to 20-membered heteroalkyl, or the specified number of chain atoms, in which at least one -CH- is replaced with at least one of -O-, -N(H)-, -N(C-C alkyl)-, or -S-. The -O-, -N(H)-, -N(C-C alkyl)-, or -S- groups may be independently located at any interior position of the aliphatic hydrocarbon chain, so long as each -O-, -N(H)-, -N(C-C alkyl)-, and -S- group is separated by at least two -CH- groups. In one embodiment, one -CH- group is replaced with one -O- group. In another embodiment, two -CH- groups are replaced with two -O- groups. In another embodiment, three -CH- groups are replaced with three -O- groups. In another embodiment, four -CH- groups are replaced with four -O- groups. Non-limiting exemplary heteroalkyl groups include -CHOCH, -CHOCHCHCH, -CHCHCHOCH, -CHCHOCHCHOCHCH, -CHCHOCHCHOCHCH, -CHCHOCHCHOCHCHOCHCH.

[0303] The term "cycloalkyl" when used by itself or as part of another group refers to cycloalkyl groups of 3 to 12 carbon atoms, i.e., C, which are saturated and partially unsaturated, e.g., containing one or two double bonds. 3-12 Cycloalkyl refers to a monocyclic, bicyclic, or tricyclic aliphatic hydrocarbon containing a specified number of carbons, e.g., C cycloalkyl such as cyclopropyl, cycloalkyl such as cyclobutyl, etc. In one embodiment, a cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, a cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, a cycloalkyl group is C 3-8 In another embodiment, cycloalkyl is C 3-6In another embodiment, the cycloalkyl is a C5 cycloalkyl, i.e., cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C6 cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C 3-12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0304] The term "optionally substituted cycloalkyl," as used herein by itself or as part of another group, refers to a cycloalkyl group that is unsubstituted or substituted with 1, 2, or 3 substituents, each of which is independently halo, nitro, cyano, hydroxy, amino (e.g., -NH, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkyl, Thio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 and R 56a , R56b , R 56c , R 56d , R 56e , R 57 , and R 58 is as defined in connection with the term "optionally substituted alkyl" and R 59 is (hydroxy)alkyl or (amino)alkyl. The term optionally substituted cycloalkyl also includes cycloalkyl groups having an optionally substituted aryl or an optionally substituted heteroaryl group fused thereto, such as: [ka]

[0305] Non-limiting exemplary optionally substituted cycloalkyl groups include: [ka]

[0306] The term "heterocyclo" as used herein by itself or as part of another group refers to monocyclic, bicyclic, or tricyclic groups, including saturated and partially unsaturated, e.g., 3-14 membered heterocyclos containing 3 to 14 ring members, i.e., 1, 2, 3, or 4 heteroatoms, containing one or two double bonds. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom can be independently oxidized to a sulfoxide, i.e., S(=O), or a sulfone, i.e., S(=O)2.

[0307] The term heterocyclo includes groups in which one or more -CH2- groups are replaced by one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one.

[0308] The term heterocyclo includes groups having an optionally substituted aryl or an optionally substituted heteroaryl group fused thereto, such as indoline, indolin-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0309] In one embodiment, a heterocyclo group is a 4-8 membered ring containing one ring and one or two oxygen atoms, e.g., tetrahydrofuran or tetrahydrofuran, or one or two nitrogen atoms, e.g., pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, e.g., morpholine, and optionally, one -CH2- group is replaced with one -C(=O)- group, e.g., pyrrolidin-2-one or piperazin-2-one. In another embodiment, a heterocyclo group is a 5-8 membered ring containing one ring and one or two nitrogen atoms, and optionally, one -CH2- group is replaced with one -C(=O)- group, e.g., pyrrolidin-2-one or piperazin-2-one. 2- In another embodiment, the heterocyclo group is a 5- or 6-membered ring containing one ring and one or two nitrogen atoms, and optionally one -CH 2- In one embodiment, the heterocyclo group is an 8- to 12-membered ring containing two rings and one or two nitrogen atoms. The heterocyclo can be attached to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include: [ka]

[0310] The term "optionally substituted heterocyclo" as used herein alone or as part of another group refers to a heterocyclo group that is unsubstituted or substituted with 1 to 4 substituents, each of which is independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 and R 59 is as defined in connection with the term "optionally substituted cycloalkyl." Substitution can occur at any available carbon or nitrogen atom of the heterocyclo group. Non-limiting exemplary optionally substituted heterocyclo groups include: [ka]

[0311] The term "aryl" as used herein by itself or as part of another group refers to an aromatic ring system having 6 to 14 carbon atoms, i.e., C6-C 14"aryl" refers to aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0312] The term "optionally substituted aryl," as used herein by itself or as part of another group, refers to an aryl that is unsubstituted or substituted with 1 to 5 substituents, each independently selected from halo, nitro, cyano, hydroxy, amino (e.g., -NH, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 and R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , and R 59is as defined in connection with the term "optionally substituted cycloalkyl."

[0313] In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-limiting exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclo groups. Non-limiting examples include 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and 2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl.

[0314] The term "heteroaryl," as used herein by itself or as part of another group, refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members, i.e., 5- to 14-membered heteroaryls containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, a heteroaryl has three heteroatoms. In another embodiment, a heteroaryl has two heteroatoms. In another embodiment, a heteroaryl has one heteroatom. In another embodiment, a heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, a heteroaryl has five ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, a heteroaryl has six ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl.In one embodiment, heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyridin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyridin-5 ...5-yl), pyrimidinyl (e.g., pyridin-5-yl, pyridin-3-yl, and pyridin-5-yl), pyrimidinyl (e.g., pyridin-5-yl, pyridin For example, selected from pyrimidin-2-yl, pyrimidin-4-yl, and pyridin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazole (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0315] The term “optionally substituted heteroaryl,” as used herein by itself or as part of another group, refers to a heteroaryl that is unsubstituted or substituted with 1 to 4 substituents, the substituents being independently selected from halo, nitro, cyano, hydroxy, amino (e.g., —NH, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 and R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , and R 59 is as defined in connection with the term "optionally substituted cycloalkyl."

[0316] In one embodiment, the optionally substituted heteroaryl has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

[0317] The term "5-membered heteroarylenyl," as used herein by itself or as part of another group, refers to a divalent form of an optionally substituted 5-membered heteroaryl group. In one embodiment, the heteroarylenyl is a substituted 5-membered heteroarylenyl. In one embodiment, the heteroarylenyl is an unsubstituted 5-membered heteroarylenyl. Non-limiting exemplary 5-membered heteroarylenyls include: [ka]

[0318] The term "aryloxy" as used herein by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0319] The term "heteroaryloxy" as used herein by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is pyridyl-O-.

[0320] The term "aralkyloxy" as used herein by itself or as part of another group refers to an aralkyl attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCHO-.

[0321] The term "(cyano)alkyl," as used herein by itself or as part of another group, refers to an alkyl substituted with one, two, or three cyano groups. In one embodiment, the alkyl is substituted with one cyano group. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0322] The term "(cycloalkyl)alkyl," as used herein by itself or as part of another group, refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group(s) is an optionally substituted C3-C6 cycloalkyl. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl)alkyl groups include the following: [ka]

[0323] The term "sulfonamide" as used herein by itself or as part of another group refers to a group of the formula -SONR 50a R 50b where R 50a and R 50b are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl, or R 50a and R 50b taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary sulfonamide groups include -SONH, -SON(H)CH, and -SON(H)Ph.

[0324] The term "carboxamide" as used herein by itself or as part of another group refers to a group of formula -C(=O)NR 50c R 50d where R 50c and R 50dare each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl, or R 50c and R 50d taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary carboxamide groups include -C(=O)NH, -C(=O)(H)CH, and -C(=O)N(CH).

[0325] The term "alkylcarbonyl," as used herein by itself or as part of another group, refers to a carbonyl group substituted with an alkyl group, i.e., -C(=O)-. In one embodiment, the alkyl is a C1-C4 alkyl. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0326] The term "arylcarbonyl," as used herein by itself or as part of another group, refers to a carbonyl group substituted with an optionally substituted aryl group, i.e., -C(=O)-. A non-limiting exemplary arylcarbonyl group is -COPh.

[0327] The term "alkylsulfonyl," as used herein by itself or as part of another group, refers to a sulfonyl group substituted with an alkyl group, i.e., -SO2-. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.

[0328] The term "arylsulfonyl," as used herein by itself or as part of another group, refers to a sulfonyl group substituted with an optionally substituted aryl group, i.e., -SO2-. A non-limiting exemplary arylsulfonyl group is -SO2Ph.

[0329] The term "mercaptoalkyl" as used herein by itself or as part of another group refers to an alkyl substituted with an --SH group.

[0330] The term "carboxy" when used by itself or as part of another group refers to a radical of the formula -C(=O)OH.

[0331] The term "ureido" as used herein by itself or as part of another group refers to a group of the formula -NR 51a -C(=O)-NR 51b R 51c where R 51a is hydrogen or alkyl, and R 51b and R 51c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl, or R 51b and R 51c taken together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary ureido groups include -NH-C(C=O)-NH and -NH-C(C=O)-NHCH.

[0332] The term "guanidino" as used herein by itself or as part of another group refers to a group of the formula -NR 52a -C(=NR 53 )-NR 52b R 52c where R 52a is hydrogen or alkyl, and R 52b and R 53c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl, or R 52b and R 52c together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclo group, and R 53is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include -NH-C(C=NH)-NH 2、 -NH-C(C=NCN)-NH 2、 and -NH-C(C=NH)-NHCH3.

[0333] The term "(heterocyclo)alkyl," as used herein by itself or as part of another group, refers to an alkyl substituted with one, two, or three heterocyclo groups. In one embodiment, the alkyl is substituted with one optionally substituted 5-8 membered heterocyclo group. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. The heterocyclo group can be attached to the alkyl group via a carbon atom or a nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include: [ka]

[0334] The term "carbamate" as used herein by itself or as part of another group refers to a group of the formula -NR 54a -C(=O)-OR 54b where R 54a is hydrogen or alkyl, and R 54b is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting exemplary carbamate group is -NH-(C=O)-OtBu.

[0335] The term "(heteroaryl)alkyl," as used herein by itself or as part of another group, refers to an alkyl substituted with one or two optionally substituted heteroaryl groups. In one embodiment, an alkyl group is substituted with one optionally substituted 5-14 membered heteroaryl group. In another embodiment, an alkyl group is substituted with two optionally substituted 5-14 membered heteroaryl groups. In another embodiment, an alkyl group is substituted with one optionally substituted 5-9 membered heteroaryl group. In another embodiment, an alkyl group is substituted with two optionally substituted 5-9 membered heteroaryl groups. In another embodiment, an alkyl group is substituted with one optionally substituted 5-6 membered heteroaryl group. In another embodiment, an alkyl group is substituted with two optionally substituted 5-6 membered heteroaryl groups. In one embodiment, an alkyl group is C1-C6 alkyl. In another embodiment, an alkyl group is C1-C4 alkyl. In another embodiment, an alkyl group is C1 or C2 alkyl. Non-limiting exemplary (heteroaryl)alkyl groups include: [ka]

[0336] The terms "aralkyl" or "(aryl)alkyl," as used herein by themselves or as part of another group, refer to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or an optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0337] The term "amide" as used herein by itself or as part of another group refers to a group of the formula -C(=O)NR 60a R 60b refers to the radical of R 60a and R 60b are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl; or R 60a and R 60b taken together with the nitrogen to which they are attached form a 4-8 membered optionally substituted heterocyclo group. 60a and R 60b are each independently hydrogen or C1-C6 alkyl.

[0338] The term "amino" when used by itself or as part of another group has the formula -NR55a R 55b refers to the radical of R 55a and R 55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl.

[0339] In one embodiment, amino is —NH 2 .

[0340] In another embodiment, amino is an "alkylamino," i.e., an amino group, R 55a is C 1-6 alkyl, and R 55b is hydrogen. In one embodiment, R 55a is C1-C4 alkyl. Non-limiting examples of alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0341] In another embodiment, amino is a "dialkylamino," i.e., an amino group, R 55a and R 55b are each independently, C 1-6 In one embodiment, R 55a and R 55b is each independently C1-C4 alkyl. Non-limiting examples of dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0342] In another embodiment, amino is a "hydroxyalkylamino," i.e., an amino group, R 55a is (hydroxyl)alkyl and R 55b is hydrogen or C1-C4 alkyl.

[0343] In another embodiment, amino is a "cycloalkylamino," i.e., an amino group, R 55a is an optionally substituted cycloalkyl, and R 55b is hydrogen or C1-C4 alkyl.

[0344] In another embodiment, amino is an "aralkylamino," i.e., an amino group, and R 55a is aralkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary aralkyl groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0345] In another embodiment, amino is a "(cycloalkyl)alkylamino", i.e., an amino group, R 55a is (cycloalkyl)alkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary (cycloalkyl)alkylamino groups include: [ka]

[0346] In another embodiment, amino is a "(heterocyclo)alkylamino", i.e., an amino group, R 55a is (heterocyclo)alkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary (heterocyclo)alkylamino groups include: [ka]

[0347] The term "(amino)alkyl," as used herein by itself or as part of another group, refers to an alkyl substituted with an amino group. In one embodiment, the amino group is -NH. In one embodiment, the amino group is alkylamino. In another embodiment, the amino group is dialkylamino. In another embodiment, the alkyl is C-C alkyl. In another embodiment, the alkyl is C-C alkyl. Non-limiting exemplary (amino)alkyl groups include -CHNH, CHCHN(H)CH, -CHCHN(CH), CHN(H)cyclopropyl, -CHN(H)cyclobutyl, and -CHN(H)cyclohexyl, as well as -CHCHCHN(H)CHPh and -CHCHCHN(H)CH(4-CF-Ph).

[0348] The present disclosure encompasses any of the compounds of the present disclosure that are isotopically labeled (i.e., radiolabeled) by having one or more atoms replaced with an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H (or deuterium (D)), 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl, e.g. 3 H, 11 C, and 14These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as C. In one embodiment, compounds are provided in which substantially all of the atoms at positions in the compounds of the present disclosure are replaced with atoms having different atomic masses or mass numbers. In another embodiment, compounds are provided in which substantially all of the atoms at positions in the compounds of the present disclosure are replaced with deuterium atoms, for example, all hydrogen atoms in a -CH group are replaced with deuterium atoms to obtain a -CD group. In another embodiment, compounds are provided in which some of the atoms at positions in the compounds of the present disclosure are replaced, i.e., the compounds of the present disclosure are enriched at certain positions with atoms having different atomic masses or mass numbers. In another embodiment, compounds are provided in which none of the atoms in the compounds of the present disclosure are replaced with atoms having different atomic masses or mass numbers. Isotopically labeled disclosed compounds can be prepared by methods known in the art.

[0349] The compounds of the present disclosure may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomers. The present disclosure encompasses the use of all such possible forms, as well as racemic and resolved forms, and mixtures thereof. Individual enantiomers can be separated in light of the present disclosure according to methods known in the art. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, they are intended to include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.

[0350] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. Stereoisomers include enantiomers and isomers of compounds with two or more chiral centers that are not mirror images of one another (diastereomers).

[0351] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are bonded.

[0352] The terms "enantiomer" and "enantiomeric" refer to a molecule that is not superimposable on its mirror image and is therefore optically active; an enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

[0353] The term "racemic" refers to a mixture of equal parts of enantiomers, which mixture is optically inactive. In one embodiment, the compounds of the present disclosure are racemic.

[0354] The term "absolute configuration" refers to the arrangement in space of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0355] Stereochemical terminology and conventions used herein, unless otherwise indicated, are intended to be consistent with those described in Pure & Appl. Chem 68:2193 (1996).

[0356] The term "enantiomeric excess" or "ee" refers to a measure of how much of one enantiomer is present relative to the other. For a mixture of R and S enantiomers, percent enantiomeric excess is defined as |RS| * 100, where R and S are the mole or weight fractions of each of the enantiomers in the mixture such that R + S = 1. With an understanding of the optical rotation of a chiral substance, percent enantiomeric excess can be calculated as ([α] obs / [α] max )*100, where [α] obs is the optical rotation of the mixture of enantiomers, [α] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry. [Example]

[0357] As used herein, the term "about" includes ±10% of the recited number. Thus, "about 10" means 9 to 11. Example 1 Synthesis of 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3H,5H-4-oxa-2,6,11,12a-tetraazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. 12) [ka]

[0358] A solution of ethyl 2-(diphenylmethyleneamino)acetate (18.4 g, 69 mmol) in DMSO (50 ml) was added dropwise to a suspension of NaH (60%) (5.0 g, 125.5 mmol) in 70 ml of anhydrous DMSO at 0 °C. The reaction mixture immediately turned orange. After 5 min, ethyl 2-((diphenylmethylene)amino)acetate (15 g, 62.7 mmol) in 50 ml of DMSO was added dropwise. The mixture was stirred at room temperature for 2 h. After that, the reaction mixture was quenched by carefully adding aqueous NH4Cl solution. The mixture was then extracted with ethyl acetate, washed with brine, dried, concentrated, and used crude in the next step. LC-MS: [M+H]+ = 470.01.

[0359] To a solution of compound E12-2 (crude, 5.0 g, 10.6 mmol) in THF (50 ml) was added 10 ml of 3N HCl in water at 0 °C. The mixture was stirred at room temperature for 1 h, and the reaction mixture was concentrated and subsequently basified to pH 8-9 with aqueous Na2CO3. The mixture was extracted with DCM and washed with brine. Concentration under reduced pressure followed by purification by flash chromatography (0-100% EtOAc / hexane) afforded the desired compound E12-3 in 80% overall yield. LC-MS: [M+H]+ = 305.95.

[0360] A mixture of HCOOH (4 ml) and AcO (4 ml) was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and added to a solution of ethyl 2-amino-2-(methylthio)pyrimidin-4-yl)acetate (compound E12-3, 2.0 g, 6.55 mmol) in 20 ml of DCM. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated. The mixture was extracted with DCM (2×50 ml) and washed successively with water (20 ml) and brine (10 ml). The organic phase was dried (NaSO), filtered, and concentrated to give the crude title compound E12-4 as an oil, which was used in the next step without further purification. LC-MS: [M+H]=334.05.

[0361] To a solution of compound E12-4 (2.0 g, crude) in dioxane (20 ml), POCl (1.5 ml) was added dropwise. The reaction mixture was heated under reflux for 4 h. The mixture was cooled to room temperature and concentrated. Ice-cold water (50 ml) was added, and the pH was adjusted to 8 with saturated aqueous NaHCO solution. The mixture was extracted with DCM (2 × 50 ml), washed with brine (10 ml), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluted with 50–100% EtOAc / hexane) to give the title compound E12-5 as a white solid (1.42 g, 4.59 mmol) in 70% overall yield over two steps. LC-MS: [M+H] = 315.70. 1 H NMR (400MHz, DMSO d6): 8.67 (s, 1H), 7.99 (s, 1H), 4.33 (q, 2H), 2.76 (s, 3H), 1.34 (t, 3H).

[0362] To a solution of compound E12-5 (567 mg, 1.8 mmol, 1.0 equiv.) in DCM (18 mL) was added m-CPBA (464 mg, 2.7 mmol, ≦77%, 1.5 equiv.) at 0 °C. After 45 min, EtN (1 mL, 7.6 mmol, 4 equiv.) was added at 0 °C and stirred for 2 min, followed by compound A.1 (300 mg, 1.8 mmol). The reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography (eluted with 50–100% EtOAc / hexane) to give E12-7 (429 mg, 0.99 mmol) in 55% yield. LC-MS: [M+H]+ = 434.03. 1 H NMR(400MHz,DMSO-d6) δ 8.75(s,1H),8.65(t,J=5.1Hz,1H),7.68(s,1H),6.94(t,J=9.5Hz,1H),6.70(dd,J=8.7,3.9Hz,1H),4.68( d,J=5.0Hz,2H),4.54(t,J=8.7Hz,2H),4.29(q,J=7.1Hz,2H),3.27(t,J=8.8Hz,2H),1.32(t,J=7.1Hz,3H).

[0363] Palladium(II) acetate (70 mg, 0.31 mmol, 0.1 equiv.) and cataCXium A (221 mg, 0.62 mmol, 0.2 equiv.) were mixed together in DME (2.0 mL, degassed), and the resulting solution was added via pipette to a stirred solution of compound E12-7 (1.34 g, 3.1 mmol, 1.0 equiv.), compound B.1 (1.86 g, 6.2 mmol, 2.0 equiv.), bis-pinacolatodiboron (1.6 g, 6.2 mmol, 2.0 equiv.), and KCO (1.71 g, 12.4 mmol, 4.0 equiv.) in DME / HO (10:1, 22 mL, degassed) at 70 °C. The reaction mixture was stirred for 12 h. The reaction mixture was then concentrated, extracted with ethyl acetate (2 x 50 ml), washed with water and brine, and then dried over NaSO. The mixture was concentrated, and the residue was purified by HPLC to obtain the desired compound, which was treated with TFA / DCM to give the desired compound E12-8 (719 mg, 1.55 mmol) as a white solid in 50% yield. LC-MS: [M+H] = 464.16.

[0364] A mixture of E12-8 (40 mg, 0.090 mmol, 1 equiv.) and LiOH (20 mg, 0.90 mmol, 10 equiv.) in THF (4 ml) and water (1.0 ml) was heated at 70° C. overnight. 3N aqueous HCl was added dropwise at 0° C. to a pH of 2-3. The mixture was concentrated, and the residue was purified by HPLC to give the title compound E12-9 (35 mg, 0.081 mmol) as a white solid in 90% yield. LC-MS: [M+H]+ = 436.13.

[0365] To a cloudy mixture of 2,4,6-trichlorobenzoyl chloride (24 mg, 0.01 mmol, 1.5 equiv.), DIPEA (85 mg, 0.66 mmol, 10.0 equiv.), and DMAP (4 mg, 0.033 mmol, 0.5 equiv.) in toluene (2 mL) was slowly added a clear solution of seco-acid E12-9 (31 mg, 0.066 mmol) in toluene (1 mL) via cannula. After 2 h, the reaction mixture was concentrated. The crude product was extracted with ethyl acetate (2 × 10 mL), washed with brine, and dried over NaSO. The mixture was concentrated, and the residue was purified by HPLC to give compound No. 12 (16 mg, 0.039 mmol) as a white solid in 60% yield. LC-MS: [M+H] = 418.12. 1 H NMR(400MHz,acetone-d6) δ 8.77(s,1H),8.66(d,J=4.7Hz,1H),8.20(s,1H),8.04(d,J=7.9Hz,1H),7.75(s,1H),7.56(dd,J=8.0,4.6Hz,1H),6.90(t,J= 9.4Hz,1H),6.67(dd,J=8.6,3.8Hz,1H),6.04(s,1H),5.08(s,1H),4.90(s,2H),4.59(t,J=8.6Hz,2H),3.49(t,J=8.6Hz,2H). Example 2 Synthesis of 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4,5-dihydro-3H-2,4,6,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (compound no. 16): [ka]

[0366] Palladium(II) acetate (70 mg, 0.31 mmol, 0.1 equiv.) and cataCXium A (221 mg, 0.62 mmol, 0.2 equiv.) were mixed together in DME (2.0 mL, degassed), and the resulting solution was added via pipette to a stirred solution of compound E10-7 (1.34 g, 3.1 mmol, 1.0 equiv.), compound B.2 (1.77 g, 6.2 mmol, 2.0 equiv.), bis-pinacolatodiboron (1.6 g, 6.2 mmol, 2.0 equiv.), and KCO (1.71 g, 12.4 mmol, 4.0 equiv.) in DME / HO (10:1, 22 mL, degassed) at 70 °C. The reaction mixture was stirred for 12 h. The reaction mixture was then concentrated, extracted with ethyl acetate (2 x 50 ml), washed with water and brine, and then dried over NaSO. The mixture was concentrated, and the residue was purified by HPLC to give the title compound E16-1 (871 mg, 1.55 mmol) as a white solid in 50% yield. LC-MS: [M+H] = 563.16.

[0367] Compound E16-1 was treated with 25% TFA / DCM at room temperature for 1 hour, and then the volatiles were removed in vacuo. The crude was diluted with ethyl acetate and washed with saturated aqueous Na2CO3 solution and then with brine. The organic layer was evaporated on Na2SO4 and concentrated in vacuo to obtain compound E16-2, which was used crude for the next step.

[0368] A mixture of E16-2 (40 mg, 0.09 mmol, 1 equiv.) and LiOH (20 mg, 0.90 mmol, 10 equiv.) in THF (4 ml) and water (1.0 ml) was heated at 70° C. overnight. 3N aqueous HCl was added dropwise at 0° C. to a pH of 2-3. The mixture was concentrated, and the residue was purified by HPLC to give compound No. 16 as a white solid in 90% yield. LC-MS: [M+H]+ = 416.14. 1H NMR(400MHz,DMSO-d6) δ 8.82(s,1H),8.65(t,J=5.1Hz,1H),8.54(dd,J=4.8,1.6Hz,1H),8.47(s,1H),7.92(dd,J=7.8,1.6Hz,1H),7.53-7.48(m,2H),6.96(dd, J=10.3,8.7Hz,1H),6.72(dd,J=8.7,3.9Hz,1H),4.98-4.94(m,1H),4.75(s,2H),4.57-4.53(m,2H),4.03(m,1H),3.35(t,J=8.7Hz,2H). Example 3 Synthesis of 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-2,4,10,11a-tetraazadibenzo[cd,f]azulen-3(4H)-one (compound number 3): [ka]

[0369] Palladium(II) acetate (70 mg, 0.31 mmol, 0.1 equiv.) and cataCXium A (221 mg, 0.62 mmol, 0.2 equiv.) were mixed together in DME (2.0 mL, degassed), and the resulting solution was added via pipette to a stirred solution of compound E10-7 (1.34 g, 3.1 mmol, 1.0 equiv.), compound B.3 (1.05 g, 6.2 mmol, 2.0 equiv.), bis-pinacolatodiboron (1.6 g, 6.2 mmol, 2.0 equiv.), and KCO (1.71 g, 12.4 mmol, 4.0 equiv.) in DME / HO (10:1, 22 mL, degassed) at 70 °C. The reaction mixture was stirred for 12 h. The reaction mixture was then concentrated, extracted with ethyl acetate (2 x 50 ml), washed with water and brine, and then dried over NaSO. The mixture was concentrated, and the residue was purified by HPLC to give the title compound E3-1 (692 mg, 1.55 mmol) as a white solid in 50% yield. LC-MS: [M+H] = 563.16.

[0370] A mixture of E3-1 (40 mg, 0.090 mmol, 1 equiv.) and LiOH (20 mg, 0.90 mmol, 10 equiv.) in THF (4 ml) and water (1.0 ml) was heated at 70 °C overnight. 3N aqueous HCl was added dropwise at 0 °C to a pH of 2-3. The mixture was concentrated, and the residue was purified by HPLC to give compound No. 3 (32 mg, 0.081 mmol) as a white solid in 90% yield. LC-MS: [M+H] = 402.13. 1 H NMR(400MHz,DMSO-d6) δ 9.50(s,1H),8.67(s,1H),8.53(t,J=5.1Hz,1H),7.99(s,1H),7.88-7.80(m,1H),7.19(dd,J=6.1,1.6Hz,2H),7.02(ddd,J=8.3,6.1,2. 4Hz,1H),6.96(dd,J=10.3,8.7Hz,1H),6.71(dd,J=8.6,3.9Hz,1H),4.73(d,J=4.8Hz,2H),4.56(t,J=8.7Hz,2H),3.31(d,J=8.5Hz,2H). Example 4 Synthesis of 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. 36) [ka]

[0371] An aliquot of (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (E36-1) was dissolved in dry DCM (approximately 0.2 M). To this solution was then added 1.5 equivalents of Dess-Martin periodinane. The reaction mixture was stirred for 1 h and monitored by TLC. Upon completion, it was quenched with saturated NH4Cl solution, then extracted with DCM and washed with water and brine. The organic layers were collected, combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification was carried out by normal-phase silica gel column chromatography using increasing amounts of ethyl acetate in hexane to afford the desired aldehyde E36-2 (approximately 90% yield).

[0372] To the resulting aldehyde, methanol (approximately 0.2 M) was added, followed by the addition of 2.2 equivalents of cyclopropanamine, 2 equivalents of Na(CN)BH, and 2 equivalents of acetic acid under an ice bath. The ice bath was then removed, and the reaction mixture was stirred for 3 hours and monitored by TLC. Upon completion, the reaction mixture was concentrated, and the residue was purified by HPLC to give the title compound E36-3 in 70% yield. LC-MS: [M+H] = 294.99.

[0373] The resulting secondary amine was added with 1.5 equivalents of (Boc)2O and dissolved in dry DCM (approximately 0.2 M), followed by 3 equivalents of TEA. The reaction mixture was stirred for 1 hour and monitored by TLC. Upon completion, it was quenched with saturated NH4Cl solution, then extracted with DCM and washed with brine. The organic layers were collected, combined, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification was carried out by normal phase silica gel column chromatography using increasing amounts of ethyl acetate in hexane to give the Boc-protected secondary amine E36-4 (approximately 90% yield). LC-MS: [M+H]+ = 395.10.

[0374] Palladium(II) acetate (0.1 equiv.) and cataCXium A (0.2 equiv.) were mixed together in DME (0.5 ml, degassed), and the resulting solution was added via pipette to a mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 equiv.), Boc-protected secondary amine E36-4 (2 equiv.), bis-pinacolatodiboron (2.0 equiv.), and KCO (4.0 equiv.) in DME / HO (10:1, 10 ml, degassed) at 70 °C. The reaction mixture was stirred for 12 h. The reaction mixture was then concentrated, extracted with ethyl acetate (2 × 50 ml), washed with water and brine, and then dried over NaSO. The mixture was concentrated and the residue was purified by HPLC to give the title compound E36-5 in 40% yield. LC-MS: [M+H]+=671.25.

[0375] Compound E36-5 was treated with 25% TFA / DCM at 0° C. for 1 hour, then the volatiles were removed in vacuo and used as crude (E36-6) for the next step. LC-MS: [M+H]=571.25.

[0376] A mixture of compound E36-6 (1 equivalent) and LiOH (10 equivalents) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 70° C. overnight. The mixture was concentrated, and the residue was then purified by preparative HPLC to give E36 and compound E36-7 in a ratio of approximately 1:1.

[0377] To a mixture of compound E36-7 (1 equivalent) and HATU (2 equivalents) in DMF (5 ml / mmol) was added DIPEA (5 equivalents). The reaction mixture was stirred overnight. Then it was concentrated, and the residue was purified by preparative HPLC to compound No. 36. The combined yield of both compounds is approximately 90%. LC-MS: [M+H]+ = 525.15. 1H NMR (400MHz, methanol-d4) δ 8.84(s,1H),8.74(s,1H),7.86(s,1H),7.70(s,1H),6.86(t,J=9.6Hz,1 H),6.65(dd,J=8.7,4.0Hz,1H),5.42(d,J=14.7Hz,1H),4.81(d,J=6.1H z,2H),4.59(t,J=8.9Hz,2H),4.37(d,J=14.9Hz,1H),3.42(t,J=8.7Hz, 2H), 2.55 (s, 1H), 1.16 (s, 1H), 1.00 (d, J=5.5Hz, 2H), 0.94-0.77 (m, 1H). Example 5 Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-3H,5H-4-oxa-2,6,11,12a-tetraazabenzo[4,5]cycloocta[1,2,3-cd]inden-12-amine (Compound No. 2) [ka]

[0378] Compound E10-8 (25 mg, 0.053 mmol) in 2 ml of THF was treated with LAH (0.2 ml of a 1 M solution of LAH in THF) at 0 °C. The temperature was then raised to 50 °C and stirred overnight. After cooling to room temperature, the reaction was slowly quenched with saturated Na2SO4 at 0 °C. It was then filtered and washed several times with ethyl acetate. Purification by flash chromatography (0-10% MeOH in DCM) gave compound No. 2 (10 mg, 0.024 mmol) in 50% yield. LC-MS: [M+H]+ = 404.14. Example 6 Synthesis of 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide (Compound No. 95) [ka]

[0379] Synthesis of 8-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (E95-1):

[0380] 8-Bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (795 mg, 2.19 mmol), 3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridine (1.393 g, 4.38 mmol), palladium(II) acetate (0.1 equiv.), cataCXium A (0.2 equiv.), bis-pinacolatodiboron (2.0 equiv.), and KCO (5.0 equiv.) were mixed together in DME:water (10:1, 17.4 ml, degassed) under a N atmosphere. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was then concentrated, extracted with ethyl acetate (2 × 200 ml), washed with water and brine, and then dried over NaSO. The mixture was concentrated, and the residue was purified by HPLC to give the title compound E95-1 (304 mg, 0.585 mmol) in a 38% yield. LC-MS: [M+H]+ = 520.30.

[0381] Synthesis of 8-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodoimidazo[1,5-c]pyrimidin-5-amine (E95-2):

[0382] To a solution of 8-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (304 mg, 0.585 mmol) in DMF (5 mL) at 0 °C, NIS (125 mg, 0.95 mmol) was added and stirred for 15 min at room temperature. The mixture was extracted with EA (4 × 50 mL), washed with brine (30 mL), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 20–80% EtOAc / hexane) to give E95-2 as a yellow solid (190 mg, 0.29 mmol, 50%). LC-MS: [M+H] = 646.21.

[0383] Synthesis of (3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-iodoimidazo[1,5-c]pyrimidin-8-yl)-6-methylpyridin-2-yl)methanol (E95-3):

[0384] To a solution of 8-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodoimidazo[1,5-c]pyrimidin-5-amine (190 mg, 0.29 mmol) in THF (6 ml) was added TBAF (3 ml) and stirred at room temperature overnight. Upon completion, the mixture was extracted with EA (3 × 60 ml), washed with brine (30 ml), dried over NaSO, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 0–15% MeOH / DCM) to give E95-3 (125 mg, 0.24 mmol, 80%). LC-MS: [M+H] = 532.19.

[0385] Synthesis of S-((3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-iodoimidazo[1,5-c]pyrimidin-8-yl)-6-methylpyridin-2-yl)methyl)ethanethioate (E95-4):

[0386] MsCl (41 mg, 0.352 mmol) in THF (0.5 mL) was added dropwise to a solution of (3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-iodoimidazo[1,5-c]pyrimidin-8-yl)-6-methylpyridin-2-yl)methanol (125 mg, 0.24 mmol) and EtN (36 mg, 0.352 mmol) in THF (2 mL) at 0 °C. A white ppt of EtN hydrochloride salt formed immediately. The reaction mixture was stirred for 2-3 h, and upon completion, potassium thioacetate (81 mg, 0.704 mmol) in DMF (1.0 mL) was added, resulting in an orange solution that turned red after several hours. The reaction was monitored via UPLC, and upon completion, the reaction mixture was quenched, concentrated, and then dissolved in DCM. This mixture was washed twice with saturated LiCl, followed by water and brine. The saturated LiCl, brine, and water washes were combined and back-extracted separately with ethyl acetate. All organic layers were combined, dried over Na2SO4, filtered, and concentrated to a dark oil. Flash chromatography (silica gel, eluted with 20-100% EtOAc / hexanes) afforded E95-4 as a yellow solid (78 mg, 0.13 mmol, 56%). LC-MS: [M+H]+ = 590.03.

[0387] Synthesis of 8,8'-((disulfanediylbis(methylene))bis(6-methylpyridine-2,3-diyl))bis(N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodoimidazo[1,5-c]pyrimidin-5-amine) (E95-5):

[0388] To a solution of S-((3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-iodoimidazo[1,5-c]pyrimidin-8-yl)-6-methylpyridin-2-yl)methyl)ethanethioate (78 mg, 0.13 mmol) in methanol (5.0 mL, degassed) was added 0.9 equivalents of NaOMe (7 mg, 0.12 mmol) under a N atmosphere. The reaction mixture was refluxed at 80 °C for 1 h. Flash chromatography (silica gel, eluted with 20-100% EtOAc / hexane) afforded E95-5 as a yellow solid (57 mg, 0.052 mmol, 79%). LC-MS: [M / 2+H]+ = 547.14.

[0389] Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulen-11-amine (E95-6):

[0390] To a solution of 8,8'-((disulfanediylbis(methylene))bis(6-methylpyridine-2,3-diyl))bis(N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodoimidazo[1,5-c]pyrimidin-5-amine) (57 mg, 0.052 mmol) in DMF (3.0 ml, degassed) was added 1.2 equivalents of TCEP (18 mg, 0.0626 mmol) under N atmosphere. The reaction mixture was stirred at room temperature for 24 hours. The reaction was monitored by UPLC. Upon completion, it was purified by reverse-phase HPLC to give E95-6 as a pale yellow solid (38 mg, 0.091 mmol, 87%). LC-MS: [M+H]=420.15.

[0391] Synthesis of 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide (E95):

[0392] To a solution of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-6-methyl-4H-3-thia-2,5,10,11a-tetrahydrofuran[cd,f]azulen-11-amine (38 mg, 0.091 mmol) in a mixed solvent of MeOH:HO:THF (4.0 mL, 5:5:10) was added 5 equivalents of oxone (279 mg, 0.45 mmol). The reaction mixture was stirred for 5 hours. Upon completion, reverse phase HPLC afforded compound No. 95 as a pale yellow solid (17 mg, 0.038 mmol, 41%). LC-MS: [M+H]=452.25. Example 7 Synthesis of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (A.1) [ka]

[0393] To a solution of 3-bromo-4-fluorophenol (A.1-1, 50 g, 0.26 mol, 1 equiv.) and 2-bromo-1,1-diethoxyethane (67 g, 0.34 mol, 1.3 equiv.) in 250 ml of DMF, K2CO3 (109 g, 0.78 mol, 3 equiv.) was added in one portion. The suspension was heated at 110 °C and stirred overnight under N2. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate (2 × 500 ml). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. The residue was purified on silica gel (0–10% EtOAc / hexane) to give the title compound (A.1-2) as a yellow oil (60.12 g, 196 mmol, 75% yield). LC-MS: [M+H]+ = 307.02. 1 H NMR (400 MHz, methanol-d₄) δ 7.13 (d, 1H), 7.04 (dd, 1H), 6.84 (dd, 1H), 4.82 (t, 1H), 3.97 (d, 2H), 3.78 (q, 2H), 3.65 (q, 2H), 1.27 (t, 6H).

[0394] To a solution of PPA (132.4 g, 0.39 mol) and toluene (300 ml) heated to 100 °C, compound A.1-2 (81 g, 0.26 mol) in 50 ml of toluene was slowly added. The reaction mixture was heated at 100 °C for 4 h. After cooling to room temperature, 400 ml of ice water was added and extracted twice with hexane. The combined organic phase was washed with brine and dried over anhydrous Na2SO4. The residue was purified on silica gel (0-10% EtOAc / hexane) to give the title compounds (A.1-3 and A.1-4) as an inseparable diastereomeric mixture in 45% overall yield. LC-MS: [M+H]+ = 214.94.

[0395] To a solution of A.1-3 and A.1-4 (31 g, 0.144 mol) and Zn(CN) (25.3 g, 0.216 mol) in 100 ml of DMF, Pd(PPh) was added (16.2 g, 14 mmol). The reaction mixture was degassed with N and stirred at 100 °C for 24 h under N. After cooling to room temperature, water was added and extracted with ethyl acetate (2 × 100 ml). The combined organic phase was washed with brine and dried over anhydrous NaSO. The residue was purified on silica gel (0-20% EtOAc / hexane) to isolate the desired isomer (A.1-5) as a white solid. NMR was used to confirm the structure. LC-MS: [M+H] = 162.02. Compound A.1-5: 1 H NMR (400 MHz, methanol-d₄) δ 8.10 (dd, 1H), 7.89 (dd, 1H), 7.30 (dd, 1H), 7.07 (d, 1H).

[0396] The desired isomer A.1-5 (2.3 g, 14.55 mmol) in 10 ml of THF was treated with LAH (36 ml of a 1 M solution of LAH in THF) at 0 °C. The temperature was then raised to 50 °C and stirred overnight. After cooling to room temperature, the reaction was slowly quenched with saturated Na2SO4 at 0 °C. It was filtered and washed several times with ethyl acetate. Purification by flash chromatography (0–10% MeOH in DCM containing 1% trimethylamine) afforded the desired compound A.1-7 (1.63 g, 10.1 mmol) in 70% overall yield. LC-MS: [M+H]+ = 166.02.

[0397] To a solution of compound A.1-7 (1 g, 6.02 mmol) in MeOH (50 ml) was added Pd / C (100 mg, 10% by weight). The reaction mixture was degassed with H and stirred at 40 °C for 6 h under an H atmosphere. The mixture was then filtered through Celite and washed with MeOH. Concentration under reduced pressure followed by purification by flash chromatography (0-10% MeOH in DCM containing 1% trimethylamine) afforded the desired compound Intermediate A.1 (859 mg, 5.11 mmol) in 85% yield. LC-MS: [M+H] = 168.07. 1 H NMR (400 MHz, methanol-d4): 6.81 (dd, 1H), 6.59 (dd, 1H), 4.56 (t, 2H), 3.77 (s, 2H), 3.27 (t, 2H). Example 8 Synthesis of 3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridine (B.4) [ka]

[0398] H2SO4 (1.2 mL, 23.4 mmol, 1.0 equiv) was added to a solution of 3-bromo-6-methylpicolinic acid (B.4-1, 5.0 g, 23.4 mmol, 1.0 equiv) in MeOH (50 ml). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml), washed with water and saturated aqueous NaCl (2 x 100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column eluted with EtOAc / hexane (1:5) to give methyl 3-bromo-6-methylpicolinate (B.4-2, 4.7 g) in 90% yield. LC-MS [M+H]+ = 229.97

[0399] To a solution of methyl 3-bromo-6-methylpicolinate (B.4-2, 520 mg, 2.28 mmol) in DCM (15 ml) at −60°C, DIBAL-H (4.6 ml, 4.60 mmol, 1 M in cyclohexane) was added dropwise. The reaction mixture was maintained at −60°C to −15°C for 30 min, then warmed to room temperature and stirred for an additional 12 h. The reaction mixture was cooled to 0°C again and quenched with saturated aqueous NH4Cl (50 ml). The resulting mixture was extracted with DCM (3 × 100 ml), washed with brine (50 ml), dried (Na2SO4), filtered, and concentrated. The residue was purified on a silica gel column eluted with EtOAc / hexane (1:3) to give the title compound (B.4-3) as a colorless liquid (1.36 mmol, 273 mg, 60%). LC-MS [M+H]+ = 201.97

[0400] A solution of (3-bromo-6-methylpyridin-2-yl)methanol (B.4-3, 273 mg, 1.36 mmol), imidazole (138 mg, 2.04 mmol), and TBSCl (300 mg, 2.04 mmol) in DCM (10 ml) was stirred at room temperature for 3 h. HO (5 ml) was added and the layers were separated. The aqueous phase was extracted with DCM (2 × 20 ml), the combined organic extracts were dried (NaSO), and the solvent was removed under reduced pressure. The residue was purified on a silica gel column eluted with EtOAc / hexane (1:5) to give the title compound (B.4, 1.22 mmol, 386 mg, 90%) as a colorless liquid. LC-MS [M+H] = 316.06 Example 9 Synthesis of tert-butyl (2-bromo-5-(trifluoromethyl)benzyl)carbamate (B.5): [ka]

[0401] NaBH4 (0.66 g, 14.81 mmol) was charged to a 100 mL flask, followed by 20 mL of anhydrous THF. The mixture was cooled in an ice-water bath. TFA (1.5 mL) was added to THF (4 mL) at that temperature for 0.5 h. The ice-water bath was removed, and the resulting mixture was stirred at room temperature for 2 h. 2-Bromo-5-trifluoromethyl-benzonitrile (B.5-1, 2 g, 8.0 mmol) was dissolved in THF (10 mL). The TFA / NaBH4 mixture was again cooled in an ice-water bath, and the nitrile solution was added over 0.5 h. The mixture was allowed to reach ambient temperature with stirring for 16 h. LC analysis of an aliquot revealed the reaction to be complete. The mixture was cooled in an ice bath, and 10 mL of methanol was slowly added. The volatiles were removed in vacuo, and ethyl acetate (50 mL) was added. The mixture was washed with water (10 mL). The aqueous layer was washed with ethyl acetate (10 ml), and the combined organic layers were washed with brine (10 ml), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase Combiflash (eluted with 1-20% acetonitrile / H2O) to give the title compound (B.5-2, 1.6 g, 80%) as a colorless liquid. LC-MS [M+H]+ = 256.96

[0402] Compound (B.5-2, 512 mg, 2 mmol) was stirred with (Boc)2O (0.51 g, 2.4 mmol, 1.2 equiv.) and Et3N (2 equiv., 4 mmol, 380 mg) in 20 mL of DCM at room temperature for 3 h. The residue was then purified by column chromatography using 0-50% EtOAc / hexane to give the desired compound (B.5, 560 mg) in 80% overall yield. LC-MS [M+H]+ = 355.16 Example 10 Synthesis of 3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridine (B.6): [ka]

[0403] To a solution of methyl 3-bromo-6-(trifluoromethyl)picolinate (B.6-1, 1 g, 3.53 mmol) in MeOH (50 ml) at 0 °C was added NaBH (671 mg, 17.65 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (50 ml), washed with aqueous NH Cl (3 × 20 ml), dried over Na SO , filtered, and concentrated to give the title compound. The residue was purified by column chromatography (eluted with 0–50% EtOAc / hexane) to give the title compound (B.6-2, 3.17 mmol, 806 mg, 90%) as a colorless liquid. LC-MS [M+H] = 255.95

[0404] TBS protection was achieved as in Example 8. LC-MS [M+H]+ = 370.03 Example 11 Synthesis of tert-butyl ((5-bromo-2-(trifluoromethyl)pyridin-4-yl)methyl)carbamate (B.7): [ka]

[0405] A 500 ml round-bottom flask equipped with a stir bar, condenser, and nitrogen inlet was charged with 38.9 g (144 mmol) of 5-bromo-2-trifluoromethyl-isonicotinic acid. 250 ml of anhydrous DCM was added to the solid, followed by 13.2 ml (151 mmol, 1.05 equiv.) of oxalyl chloride. 0.5 ml of anhydrous DMF was added to the mixture, and the mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo. A 1-liter Erlenmeyer flask equipped with a stir bar was charged with 500 ml of aqueous NH4OH in an ice bath. The crude acid chloride was added dropwise to the cooled solution. The residue was transferred with a small amount of acetonitrile. After the addition, the mixture was stirred for 20 minutes. The resulting precipitate was collected by filtration and washed with water. The filter cake was dried under vacuum at 45° C. to give 5-bromo-2-trifluoromethyl-isonicotinamide (B.7-2, 118 mmol, 31.52 g, 82% yield) as an off-white solid. LC-MS [M+H]+ = 269.95

[0406] A 100 mL round-bottom flask equipped with a stir bar, condenser, and nitrogen inlet was charged with 5.2 g (19.3 mmol) of 5-bromo-2-trifluoromethylisonicotinamide (B.7-2). The solid was diluted with 12 mL of POCl. The mixture was heated at 70 °C for 3 h. The mixture was cooled to room temperature and poured onto ice. The mixture was neutralized by careful addition of 50% sodium hydroxide. The resulting off-white solid was collected by filtration, washed with water, and dried in vacuo at 50 °C for 18 h. This afforded 4.5 g of 5-bromo-2-trifluoromethyl-isonicotinonitrile (B.7-3, 4.53 g, 18.1 mmol) as an off-white solid in 94% yield. LC-MS [M+H] = 250.95 1 H NMR (CDCl3): δ,9.03(s,1H),7.91(s,1H).

[0407] Reduction of the nitrile and Boc protection was achieved as in Example 9. Example 12 Synthesis of tert-butyl((3-bromo-6-methylpyridin-2-yl)methyl)carbamate (B.8): [ka]

[0408] To a solution of 5-bromo-2-methylpyridine (B.8-1, 510 mg, 3.0 mmol, 1.0 equiv.) in CHCl3 (8 mL, 0.38 M), 77% mCPBA (5.44 g, 12.0 mmol, 4.0 equiv.) was added and heated at 60 °C for 20 h. After cooling to room temperature, Ca(OH)2 (1.5 g, 15.9 mmol, 5.3 equiv.) was added, and the resulting precipitate was stirred for 30 min. The precipitate was filtered and washed with 3:1 CHCl3 / methanol. The filtrate was concentrated in vacuo to give a solid, which was stirred in 30% ethyl acetate in hexanes and filtered to give the desired N-oxide. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography using 0–100% ethyl acetate in hexanes to give more of the desired N-oxide (B.8-2, 410 mg, 2.4 mmol).

[0409] To a solution of 5-bromo-2-methylpyridine 1-oxide (B.8-2, 372 mg, 2.0 mmol) in acetonitrile (10 mL, 0.2 M), trimethylsilyl cyanide (TMSCN) (793 mg, 8.0 mmol, 4.0 equiv.) and triethylamine (606 mg, 6.0 mmol, 3.0 equiv.) were added. The mixture was heated at 100 °C overnight. After cooling to room temperature, the solvent was concentrated in vacuo, and the residue was purified by column chromatography using 0-50% ethyl acetate in hexane to give 3-bromo-6-methylpicolinonitrile (B.8-3, 273 mg, 1.4 mmol, 70% yield).

[0410] 3-Bromo-6-methylpicolinonitrile (B.8-3, 273 mg, 1.4 mmol) was dissolved in 15 mL of dry THF. While stirring the solution, 3.5 mL of BH3DMS complex (2 M) (5 equiv.) was added dropwise. The mixture was then stirred overnight and then quenched by slowly adding 30 mL of MeOH at 0 °C. After stirring for 1 h, the organic layer was concentrated under reduced pressure and subsequently purified by flash chromatography (0–10% MeOH in DCM containing 1% trimethylamine) to give the desired compound (B.8-4, 199 mg, 0.98 mmol, 70% yield).

[0411] Boc protection was achieved as in Example 9. Example 13 Synthesis of N-(furan-2-ylmethyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (Compound No. 126): [ka]

[0412] (a) CH3COCl, MeOH, 79%, (b) Dibal-H, 56%, (c) DIAD, PPH 3、 Thalidomide, 70%, (d) NH2.NH2.H2O, EtOH, 80%, (e) HCO2H, Ac2O, 60.0%, (f) POCl3, dioxane, 47.0%, (g) (i) mCPBA, DCM, (ii) furan-2-ylmethanamine, room temperature, 3 hours, 52%, (h) phenylboronic acid, Pd(PPh3)4, K2CO3, dioxane-H2O, overnight at 90 °C, 88%.

[0413] Synthesis of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (E28-1):

[0414] Acetyl chloride (3.1 mL, 43.8 mmol) was added dropwise to methanol (50 ml) at 0-5 °C. The resulting mixture was stirred at this temperature for 5 minutes, and 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (5.5 g, 22.2 mmol) was added. The reaction mixture was heated to reflux for 1 hour and then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO3 (100 ml). The mixture was extracted with DCM (3 × 100 ml), washed with water (50 ml), dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from petroleum ether to give the title compound (E28-1) as a yellow solid (4.6 g, 34.6 mmol) in 79% yield. LC-MS: [M+H]+ = 263.10.

[0415] Synthesis of (5-bromo-2-(methylthio)pyrimidin-4-yl)methanol (E28-2):

[0416] To a solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (E28-1, 600 mg, 2.28 mmol) in DCM (15 ml) at -60 °C, DIBAL-H (4.6 ml, 4.60 mmol, 1 M in cyclohexane) was added dropwise. The reaction mixture was maintained at -60 to -15 °C for 30 min, then warmed to room temperature and stirred for an additional 12 h. The reaction mixture was cooled again to 0 °C and quenched with saturated aqueous NH4Cl (50 ml). The resulting mixture was extracted with DCM (3 × 100 ml), washed with brine (50 ml), dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (eluted with 0–50% EtOAc / hexane) to give the title compound (E28-2) as a yellow solid (300 mg) in 56% yield. LC-MS: [M+H]+ = 235.02.

[0417] Synthesis of 2-((5-bromo-2-(methylthio)pyrimidin-4-yl)methyl)isoindoline-1,3-dione (E28-3):

[0418] A THF solution (10 ml) of (5-bromo-2-(methylthio)pyrimidin-4-yl)methanol (1.69 g, 7.22 mmol), phthalimide (1.27 g, 8.66 mmol), and triphenylphosphine (2.19 g, 10.84 mmol) was mixed with DIAD (1.88 g, 10.84 mmol) under ice cooling and stirred overnight at room temperature. After completion of the reaction, it was diluted with ethyl acetate, and the organic layer was washed with saturated brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography (eluted with 0-50% EtOAc / hexane) to give the desired product (E28-3, 479 mg) in 70% yield. LC-MS: [M+H]+ = 363.12.

[0419] Synthesis of (5-bromo-2-(methylthio)pyrimidin-4-yl)methanamine (E28-4):

[0420] 2-((5-Bromo-2-(methylthio)pyrimidin-4-yl)methyl)isoindoline-1,3-dione (910 mg, 2.51 mmol) in ethanol (10 ml) was stirred with NH2NH2.HO (0.16 ml, 5.02 mmol) at room temperature for 4 hours. After completion of the reaction, the solid was filtered off with ethanol, and the filtrate was evaporated under reduced pressure. It was purified by reverse-phase Combiflash (eluting with 0-20% acetonitrile / HO) to give the title compound (E28-4) as a colorless liquid in 80% yield. LC-MS: [M+H]+ = 236.10.

[0421] Synthesis of N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methyl)formamide (E28-5):

[0422] A mixture of HC0H (4 ml) and Ac0 (4 ml) was heated at 50 °C for 1 h. The reaction mixture was cooled to room temperature and added to a solution of 5-bromo-2-(methylthio)pyrimidin-4-yl)methanamine (1.52 g, 6.55 mmol) in 20 ml of DCM. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated. The mixture was extracted with DCM (2 x 50 ml) and washed successively with water (20 ml) and brine (10 ml). The organic phase was dried (Na2SO4), filtered, and concentrated to give the crude title compound (E28-5) as an oil, which was used in the next step without further purification. LC-MS: [M+H] = 262.12.

[0423] Synthesis of 8-bromo-5-(methylthio)imidazo[1,5-c]pyrimidine (E28-6):

[0424] To a solution of N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methyl)formamide (800 mg, 3.06 mmol) in dioxane (30 ml), POCl (0.43 ml, 4.60 mmol) was added dropwise. The reaction mixture was heated under reflux for 2 h. Ice water (50 ml) was added and the pH was adjusted to 8 with saturated aqueous NaHCO. The mixture was extracted with DCM (4 x 50 ml), washed with brine (30 ml), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 0-50% EtOAc / hexane) to give the title compound (E28-6) as a yellow solid (350 mg, 47.0%). LC-MS: [M+H] = 244.0.

[0425] Synthesis of 8-bromo-N-(furan-2-ylmethyl)imidazo[1,5-c]pyrimidin-5-amine (E28-7):

[0426] To a solution of compound E28-6 (439 mg, 1.8 mmol, 1.0 equiv) in DCM (18 mL) was added m-CPBA (464 mg, 2.7 mmol, ≦77%, 1.5 equiv) at 0 °C. After 45 min, EtN (1 mL, 7.6 mmol, 4 equiv) was added at 0 °C and stirred for 2 min, followed by the addition of furan-2-ylmethanamine (175 mg, 1.8 mmol). The reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography (eluted with 50–100% EtOAc / hexane) to give the title compound E28-7 (274 mg, 0.93 mmol) in 52% yield. LC-MS: [M+H]+ = 294.12.

[0427] Synthesis of N-(furan-2-ylmethyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (Compound No. 126):

[0428] To a solution of 8-bromo-N-(furan-2-ylmethyl)imidazo[1,5-c]pyrimidin-5-amine (160 mg, 0.55 mmol) in a mixed solvent (dioxane / water = 10 mL:2.5 mL), potassium carbonate (227 mg, 1.64 mmol), phenylboronic acid (168 mg, 0.82 mmol), and Pd(PPh3)4 (63 mg, 0.055 mmol) were added. The resulting mixture was stirred overnight at 90 °C under N2. The mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (eluting with 0-10% MeOH / DCM) to give compound (126) (159 mg, 0.34 mmol) in 80% yield. LC-MS: [M+H]+ = 291.11; 1 H NMR(400MHz,CDCl3) δ 10.13(s,1H),7.66(s,1H),7.61(d,J=1.0Hz,1H),7.57-7.51(m,4H),7.51-7.45(m,1H),7.37 (dd,J=1.8,0.8Hz,1H),6.41(dd,J=3.2,0.8Hz,1H),6.34(dd,J=3.2,1.8Hz,1H),4.89(s,2H). Example 14 N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsulfonyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (Compound No. 99), N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-phenyl-1-(trifluoromethyl)imidazo[1,5-c]pyrimidin-5-amine (Compound No. 143) and Synthesis of (5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-phenylimidazo[1,5-c]pyrimidin-1-yl)dimethylphosphine oxide (Compound No. 144) [ka] (a) (5-Fluoro-2,3-dihydrobenzofuran-4-yl)methanamine, 40 °C, 24 h, 60%, (b) Phenylboronic acid, Pd(PPh3)4, K2CO3, dioxane-H2O, 90 °C overnight, 88%, (c) NIS, DMF, 0 °C, 70%, (d) Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, CuI, PdCl2(dppf)Cl2, DMF, 90 °C, 42%, (e) Dimethylphosphine oxide, Pd(dba)3, Xantphos, Et3N, dioxane, 40%, (f) MeSO2Na, CuI, DMSO, 50%

[0429] Synthesis of 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (E28-8):

[0430] A mixture of 8-bromo-5-(methylthio)imidazo[1,5-c]pyrimidine (E28-6, 1.0 g, 4.1 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (1.41 g, 8.2 mmol) was heated at 40 °C and stirred for 24 h. After cooling to room temperature, the crude mixture was purified by reverse-phase Combiflash (eluting with 0-70% acetonitrile / HO) to give the title compound (E28-8) as a yellow solid in 60% yield. LC-MS: [M+H] = 363.01; 1 H NMR (400 MHz, methanol-d₄) δ 8.58 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 6.91-6.80 (m, 1H), 6.65 (dd, J = 8.7, 3.9 Hz, 1H), 4.74 (s, 2H), 4.62-4.52 (m, 2H), 3.37 (s, 2H).

[0431] Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (E28-9):

[0432] To a solution of 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (200 mg, 0.55 mmol) in a mixed solvent (dioxane:water = 10 mL:2.5 mL), potassium carbonate (227 mg, 1.64 mmol), phenylboronic acid (168 mg, 0.82 mmol), and Pd(PPh3)4 (63 mg, 0.055 mmol) were added. The resulting mixture was stirred overnight at 90 °C under N2. The mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% MeOH / DCM to give the title compound E28-9 (174 mg, 0.34 mmol) in 88% yield. LC-MS: [M+H]+ = 361.13.

[0433] Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodo-8-phenylimidazo[1,5-c]pyrimidin-5-amine (E28-10):

[0434] To a solution of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (500 mg, 1.38 mmol) in DMF (10 mL) at 0 °C, NIS (278 mg, 1.24 mmol) was added and stirred at room temperature for 15 min. The mixture was extracted with DCM (4 × 50 mL), washed with brine (30 mL), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 20-50% EtOAc / hexane) to give the title compound (E28-10) as a yellow solid (610 mg, 1.26 mmol, 70%). LC-MS: [M+H] = 487.03.

[0435] Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-phenyl-1-(trifluoromethyl)imidazo[1,5-c]pyrimidin-5-amine (Compound No. 143):

[0436] A solution of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodo-8-phenylimidazo[1,5-c]pyrimidin-5-amine (50 mg, 0.1 mmol) in DMF (5 ml) was added to a mixture of copper(I) iodide (190 mg, 1.0 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (192 mg, 1.0 mmol), and PdCl(dppf)Cl (7 mg, 0.01 mmol). The reaction was stirred at 90 °C overnight, then cooled to room temperature and quenched by pouring into water. The mixture was filtered, and the filtrate was extracted with diethyl ether. The ether extract was concentrated, and the residue was purified by HPLC to give Compound No. 143 (16 mg, 0.04 mmol) in 42% yield. LC-MS: [M+H]+ = 429.12. 1H NMR(400MHz,DMSO-d6) δ 8.85(s,1H),8.61(s,1H),7.44-7.31(m,6H),6.94(t,J=8.8Hz,1H),6.71(dd, J=8.4,4.0Hz,1H),4.73(d,2H),4.54(t,J=8.8Hz,2H),3.31(t,J=8.8Hz,2H).

[0437] Synthesis of (5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-phenylimidazo[1,5-c]pyrimidin-1-yl)dimethylphosphine oxide (compound no. 144):

[0438] To a solution of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodo-8-phenylimidazo[1,5-c]pyrimidin-5-amine (50 mg, 0.1 mmol) in 2 ml of dioxane was added dimethylphosphine oxide (22 mg, 0.3 mmol), Pd(dba) (9 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and EtN (0.2 ml). The mixture was purged with argon and heated at 100 °C overnight. The mixture was concentrated, and the residue was purified by HPLC to give Cpd. No. 144 (17 mg, 0.04 mmol) in 40% yield. LC-MS: [M+H] = 437.14. 1 H NMR(400MHz,DMSO-d6) δ 8.85(s,1H),8.52(s,1H),7.58-7.56(m,2H),7.42-7.41(m,2H),7.29(s,1H),6.94(t,J=9.2Hz,1H),6.70(dd,J =8.4,4.0Hz,1H),4.73(d,J=4.0Hz,2H),4.54(t,J=8.8Hz,2H),3.31(t,J=8.8Hz,2H),1.21(s,1H),1.18(s,1H).

[0439] Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsulfonyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (Compound No. 99)

[0440] A mixture of compound E28-10 (50 mg, 0.1 mmol), MeSONa (30 mg, 0.3 mmol), and CuI (57 mg, 0.3 mmol) in DMSO (2 ml) was bubbled with N for 5 min, and then the sealed tube was heated in a microwave reactor at 120 °C for 20 min and then at 100 °C for 3 h. The mixture was concentrated, and the residue was purified by HPLC to give compound No. 99 (21 mg, 0.05 mmol) in 50% yield. 1 H NMR(400MHz,CDCl3) δ 8.60(s,1H),7.55-7.35(m,6H),6.77(dd,J=10.1,8.7Hz,1H),6.61(dd,J=8.7,3. 9Hz,1H),4.82(s,2H),4.61(t,J=8.7Hz,2H),3.40(t,J=8.7Hz,2H),2.86(s,3H). LC-MS: [M+H]+=439.12. Example 15 Synthesis of ethyl 5-((furan-2-ylmethyl)amino)-8-phenylimidazo[1,5-c]pyrimidine-1-carboxylate (Compound No. 127) and 5-((furan-2-ylmethyl)amino)-N-methyl-8-phenylimidazo[1,5-c]pyrimidine-1-carboxamide (Compound No. 128) [ka] (a) Ethyl 2-(diphenylmethyleneamino)acetate, NaH, room temperature, 2 hours, (b) 3N HCl in THF, room temperature, 1 hour, 70%, (c) HC0H, Ac0, room temperature, 2 hours, (d) POCl, dioxane, reflux, 4 hours, 70%, (e) (i) mCPBA, DCM, (ii) furan-2-ylmethanamine, room temperature, 3 hours, 55%, (f) phenylboronic acid, Pd(PPh), K0, dioxane-H0, 90°C overnight, 90%, (g) Li(OH), THF-H0, 90%, (h) NHMe.HCl, DIPEA, HATU, 90%

[0441] Synthesis of ethyl 2-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-((diphenylmethylene)amino)acetate (E29-1):

[0442] A solution of ethyl 2-(diphenylmethyleneamino)acetate (18.4 g, 69 mmol) in DMSO (50 ml) was added dropwise to a suspension of NaH (60%) (5.0 g, 125.5 mmol) in 70 ml of anhydrous DMSO at 0 °C. The reaction mixture immediately turned orange. After 5 min, 5-bromo-4-chloro-2-(methylthio)pyrimidine (15 g, 62.7 mmol) in 50 mL of DMSO was added dropwise. The mixture was then stirred at room temperature for 2 h. After that, the reaction mixture was quenched by carefully adding aqueous NH4Cl solution. The mixture was then extracted with ethyl acetate, washed with brine, dried, concentrated, and used crude in the next step. LC-MS: [M+H]+ = 470.01.

[0443] Synthesis of ethyl 2-amino-2-(5-bromo-2-(methylthio)pyrimidin-4-yl)acetate (E29-2):

[0444] To a solution of compound E29-1 (crude, 5.0 g, 10.6 mmol) in THF (50 ml) was added 10 ml of 3N HCl in water at 0 °C. The mixture was stirred at room temperature for 1 h, and then the reaction mixture was concentrated and subsequently basified to pH 8-9 with aqueous Na2CO3. The mixture was extracted with DCM and washed with brine. Concentration under reduced pressure followed by purification by flash chromatography (0-100% EtOAc / hexane) afforded the desired compound 8-2 (2.26 g) in 70% overall yield. LC-MS: [M+H]+ = 305.95.

[0445] Synthesis of ethyl 2-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-formamidoacetate (E29-3):

[0446] A mixture of HC0H (4 ml) and Ac0 (4 ml) was heated at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and added to a solution of ethyl 2-amino-2-(methylthio)pyrimidin-4-yl)acetate (2.0 g, 6.55 mmol) in 20 ml of DCM. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated. The mixture was extracted with DCM (2 x 50 ml) and washed successively with water (20 ml) and brine (10 ml). The organic phase was dried (NaSO), filtered, and concentrated to give the crude title compound E29-3 as an oil, which was used in the next step without further purification. LC-MS: [M+H] = 334.05.

[0447] Synthesis of ethyl 8-bromo-5-(methylthio)imidazo[1,5-c]pyrimidine-1-carboxylate (E29-4):

[0448] To a solution of compound E29-3 (2.0 g, crude) in dioxane (20 ml), POCl (1.5 ml) was added dropwise. The reaction mixture was heated under reflux for 4 h. The mixture was cooled to room temperature and concentrated. Ice-cold water (50 ml) was added, and the pH was adjusted to 8 with saturated aqueous NaHCO solution. The mixture was extracted with DCM (2 × 50 ml), washed with brine (10 ml), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluted with 50–100% EtOAc / hexane) to give the title compound E29-4 as a white solid (1.42 g, 4.59 mmol) in 70% overall yield over two steps. LC-MS: [M+H] = 315.70. 1 H NMR (400MHz, DMSO d6): 8.67 (s, 1H), 7.99 (s, 1H), 4.33 (q, 2H), 2.76 (s, 3H), 1.34 (t, 3H).

[0449] Synthesis of ethyl 8-bromo-5-((furan-2-ylmethyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (E29-5):

[0450] To a solution of compound E29-4 (567 mg, 1.8 mmol, 1.0 equiv) in DCM (18 mL) was added m-CPBA (464 mg, 2.7 mmol, ≦77%, 1.5 equiv) at 0 °C. After 45 min, EtN (1 mL, 7.6 mmol, 4 equiv) was added at 0 °C and stirred for 2 min, followed by the addition of furan-2-ylmethanamine (175 mg, 1.8 mmol). The reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography (eluted with 50–100% EtOAc / hexane) to give the title compound E29-5 (361 mg, 0.99 mmol) in 55% yield. LC-MS: [M+H]+ = 365.017. 1 H NMR(400MHz,MeOD) δ 8.58(s,1H),7.70(d,J=2.1Hz,1H),7.47(dd,J=1.8,1.0Hz,1H),6.39(dt,J= 3.2,1.1Hz,2H),4.78(t,J=0.9Hz,2H),4.46-4.36(m,2H),1.43-1.35(m,3H).

[0451] Ethyl 5-((furan-2-ylmethyl)amino)-8-phenylimidazo[1,5-c]pyrimidine-1-carboxylate (Compound No. 127):

[0452] To a solution of ethyl 8-bromo-5-((furan-2-ylmethyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (200 mg, 0.55 mmol) in a mixed solvent (dioxane:water = 10 mL:2.5 mL), potassium carbonate (227 mg, 1.64 mmol), phenylboronic acid (168 mg, 0.82 mmol), and Pd(PPh3)4 (63 mg, 0.055 mmol) were added. The resulting mixture was stirred overnight at 90 °C under N2. The mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (eluted with 0-10% MeOH / DCM) to give compound no. 127 (159 mg, 0.34 mmol) in 80% yield. LC-MS: [M+H]+ = 363.017. 1H NMR(400MHz,CDCl3) δ 8.81(s,1H),7.49(d,J=1.0Hz,1H),7.41(d,J=6.7Hz,3H),7.34(dq,J=3.3,1.7Hz,3H),6.35(d,J= 3.2Hz, 1H), 6.30 (dt, J = 3.1, 1.4Hz, 1H), 4.87 (s, 2H), 3.87 (q, J = 7.1Hz, 2H), 0.88 (t, J = 7.1Hz, 3H).

[0453] Synthesis of 5-((furan-2-ylmethyl)amino)-8-phenylimidazo[1,5-c]pyrimidine-1-carboxylic acid (E29-6):

[0454] A mixture of E29 (40 mg, 0.11 mmol, 1 equiv) and LiOH (26 mg, 1.10 mmol, 10 equiv) in THF (4 ml) and water (2.0 ml) was heated at 70 °C overnight. 3N aqueous HCl was added dropwise at 0 °C to a pH of 2-3. The mixture was concentrated, and the residue was purified by HPLC to give the title compound E29-6 (33 mg, 0.099 mmol) in 90% yield. LC-MS: [M+H] = 335.10.

[0455] N-(furan-2-ylmethyl)-1-(((methylamino)oxy)carbonyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (compound number 128):

[0456] To a solution of compound E29-6 (10 mg, 0.029 mmol) in DMF (1 ml) was added methylamine hydrochloride (4 mg, 0.058 mmol) and diisopropylethylamine (50 μL, 0.29 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and then HATU (11 mg, 0.029 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by HPLC to give compound No. 128 (9 mg, 0.026 mmol) in 90% yield. LC-MS: [M+H]+ = 348.13. 1H NMR (400MHz, CDCl3) δ 9.22(s,1H),7.55-7.43(m,3H),7.38-7.30(m,3H),6.40(s,1H),6.36(s,1H),6.31(brs,1H),4.86(s,2H),2.54(s,3H). Example 16 Synthesis of -(3,6-dihydro-2H-pyran-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine (Compound No. 146), 8-(3,6-dihydro-2H-pyran-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine (Compound No. 169): [ka]

[0457] Synthesis of 8-(3,6-dihydro-2H-pyran-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (E47-1):

[0458] To a solution (dioxane:water = 10 ml:2.5 ml), compound E28-8 (250 mg, 0.69 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (290 mg, 1.38 mmol), Pd(PPh3)4 (80 mg, 0.069 mmol), and 285 mg of Na2CO3 were added. The resulting mixture was stirred overnight at 90 °C under N2. The mixture was then cooled to room temperature, the solvent was removed in vacuo, and purified by column chromatography (DCM:MeOH = 20:1) to give the title compound E47-1 as a white solid in 80% yield. LC-MS: [M+H]+ = 366.14.

[0459] Synthesis of 8-(3,6-dihydro-2H-pyran-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-iodoimidazo[1,5-c]pyrimidin-5-amine (E47-2):

[0460] To a solution of compound E47-1 (160 mg, 0.43 mmol) in DMF (4 mL) at 0 °C, NIS (82 mg, 0.4 mmol) was added and stirred at room temperature for 15 min. The mixture was extracted with DCM (4 × 50 mL), washed with brine (30 mL), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 20-50% EtOAc / hexane) to give the title compound (E47-2) in 60% yield (127 mg, 0.25 mmol, 70%). LC-MS: [M+H] = 493.04.

[0461] Synthesis of 8-(3,6-dihydro-2H-pyran-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine (Compound No. 146):

[0462] A mixture of compound E47-2 (50 mg, 0.1 mmol), MeSONa (30 mg, 0.3 mmol), and CuI (57 mg, 0.3 mmol) in DMSO (2 ml) was bubbled with N for 5 min, and then the sealed tube was heated in a microwave reactor at 120 °C for 20 min and then at 100 °C for 0.3 h. The mixture was concentrated, and the residue was purified by HPLC to give compound No. 146 (21 mg, 0.05 mmol) in 50% yield. LC-MS: [M+H] = 445.12.

[0463] Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(methylsulfonyl)-8-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-c]pyrimidin-5-amine (Compound No. 169):

[0464] To a solution of Cpd. No. 146 (10 mg) in MeOH (1 ml) was added Pd / C (2 mg, 20 wt%). The reaction mixture was degassed with H and stirred at room temperature for 6 hours under an H atmosphere. The mixture was then filtered through Celite and washed with MeOH. Concentration under reduced pressure followed by purification by HPLC gave Cpd. No. 169 (10 mg) in quantitative yield. LC-MS: [M+H]+ = 447.14. Example 17 Synthesis of (S)-4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4,5,5a,6,8,9-hexahydro-3H-7-oxa-2,4,9a,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. 147) [ka]

[0465] General procedure for palladium-catalyzed amination reactions: An oven-dried 40 mL vial was charged with E28-8 (1.0 mmol), Pd(OAc)2 (5 mol%), DPEphos (10 mol%), K3PO4 (2.5 mmol), and the required amine (1.5 mmol). An inverted septum was placed on the vial and a needle was inserted (as a vent), while the resulting mixture was purged with argon through a second needle for several minutes. Dioxane (4 mL) was introduced through the septum. The resulting suspension was purged with argon for 3 minutes. The vial was then quickly capped and heated to 85 °C overnight. The mixture was absorbed onto silica gel and purified by flash chromatography (0–10% MeOH in DCM) to give the desired compound E1-1 (293 mg) in 50% yield. LC-MS: [M+H]+ = 586.27.

[0466] TBAF (1 M in THF, 1 ml, 1.0 mmol) was added dropwise to a solution of E1-1 (293 mg, 0.5 mmol) in THF (2 ml) at room temperature. The reaction mixture was stirred for 2 h, after which it was concentrated in vacuo. Purification by flash chromatography (0-10% MeOH in DCM) gave the desired compound E99-2 (188 mg, 0.4 mmol) in 80% yield. LC-MS: [M+H]+ = 472.19.

[0467] Compound (E1-2) was dissolved in dry DCM (approximately 0.2 M), and then 1.5 equivalents of DMP was added to the solution. The reaction mixture was stirred for 1 hour and monitored via TLC. Upon completion, it was quenched with saturated NH4Cl solution, then extracted with DCM and washed with water and brine. The organic layers were collected, combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification was carried out by normal phase silica gel column chromatography using increasing amounts of ethyl acetate in hexane to give the desired aldehyde.

[0468] To the resulting aldehyde was added methanol (approximately 0.2 M), followed by the addition of 2.2 equivalents of cyclopropanamine, 2 equivalents of Na(CN)BH, and 2 equivalents of acetic acid under ice bath conditions. The ice bath was then removed, and the reaction mixture was stirred for 3 hours and monitored by TLC. Upon completion, the reaction mixture was concentrated, and the residue was purified by HPLC to give compound E1-3 (100 mg, 0.2 mmol) in 50% yield over two steps. LC-MS: [M+H] = 511.23.

[0469] A mixture of compound E1-3 (1 equivalent) and LiOH (10 equivalents) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 70° C. overnight. The mixture was concentrated, and the residue was then purified by preparative HPLC to give compound No. 147 in 80% yield. Example 18 Synthesis of (5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-phenylimidazo[1,5-c]pyrimidin-1-yl)(imino)(methyl)-16-sulfanone (Compound No. 178), (5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-phenylimidazo[1,5-c]pyrimidin-1-yl)(methyl)(methylimino)-16-sulfanone (Compound No. 182), and 1-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-phenylimidazo[1,5-c]pyrimidin-1-yl)-3,4,5,6-tetrahydro-1,2-thiazine 1-oxide (Compound No. 186). [ka] Example 19 Synthesis of 6-fluorochroman-5-yl)methanamine (A.2): [ka]

[0470] To a round-bottom flask was added 2-bromo-3-fluoro-6-hydroxybenzaldehyde (1 equiv.), ethyl bromoacetate (1.5 equiv.), saturated aqueous NaHCO3 (2 ml / mmol), and PPh3 (1.4 equiv.) in 1 ml / mmol EtOAc. The reaction mixture was vigorously stirred overnight at room temperature. After consumption of the starting material, the reaction was diluted with water and extracted with EtOAc (×3). The organic phases were combined, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified on silica gel (0–10% EtOAc / hexanes) to afford A.2.2 in 80% yield. LC-MS: [M+H]+ = 288.97.

[0471] A mixture of A.2.2 (1 eq.), CuCl (1.1 eq.) in 20 mL of MeOH was cooled to 0 °C under an argon atmosphere. NaBH (2 eq.) was added portionwise. After consumption of the starting material, the reaction was diluted with water and extracted with EtOAc (x3). The organic phases were combined, washed with brine, dried over MgSO, concentrated in vacuo, and purified by flash chromatography to give A.2.3 as a white solid in 70% yield. LC-MS: [M+H] = 290.97.

[0472] To a solution of A.2.3 (1 eq.) in THF (4 mL) was added LAH (1 eq.) under an argon atmosphere at 0° C. The mixture was stirred at room temperature for 2 h, then quenched with water and extracted with EtOAc. The reaction mixture was then filtered and purified by flash chromatography to give A.2.4 in 65% yield. LC-MS: [M+H]+ = 248.98.

[0473] Iodine (1.30 equiv.) was added to a solution of triphenylphosphine (1.30 equiv.) and imidazole (1.35 equiv.) in 25 ml of dichloromethane at 0 °C. The reaction mixture was stirred for 15 min, followed by the addition of compound A.2.4 in dichloromethane. During a slightly exothermic reaction, the yellow precipitate disappeared and the imidazole hydrochloride precipitated as a white flocculent. The mixture was stirred at room temperature for at least 1 h, and 3 ml of methanol was added. Stirring was continued for 30 min. The solution was diluted with dichloromethane and washed with water and brine. The organic phase was dried over MgSO4 and evaporated on a rotary evaporator. The crude material obtained was used in the next step without further purification.

[0474] To a solution of 3-bromo-4-fluoro-2-(3-iodopropyl)phenol (1 equivalent) in acetone was added K2CO3 (2 equivalents). The mixture was stirred at 50 °C for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The reaction mixture was then purified by flash chromatography to give A.2.5 in 65% overall yield. LC-MS: [M+H]+ = 230.97.

[0475] To a solution of A.2.5 (1 equiv.) and Zn(CN) (2 equiv.) in DMF (2 ml / mmol) was added Pd(PPh) (0.1 equiv.). The reaction mixture was degassed with N and stirred at 100 °C for 24 h under N. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 100 ml). The combined organic phases were washed with brine and dried over anhydrous NaSO. The residue was purified on silica gel (0–20% EtOAc / hexane) to afford A.2.6 in 60% yield. LC-MS: [M+H] = 178.05.

[0476] A solution of A.2.6 (1 equiv.) in THF was treated with LAH (2 equiv., 1 M solution of LAH in THF) at 0 °C. The temperature was raised to 50 °C, and the reaction mixture was stirred overnight. After cooling to room temperature, the reaction was slowly quenched with saturated Na2SO4 at 0 °C. It was filtered and washed several times with ethyl acetate. Purification by flash chromatography (0-10% MeOH in DCM with 1% trimethylamine) gave the desired compound A.2 in 70% yield. LC-MS: [M+H]+ = 182.09. Example 20 Synthesis of 5-fluoro-2,3-dihydrobenzofuran-4-yl)methane-d2-amine (A.3): [ka]

[0477] To a solution of 5-fluorobenzo-4-carbonitrile (2.00 gm, 12.4 mmol, 1.0 equiv.) in DMSO (20 mL) was added HO (7.04 gm, 62.1 mmol, 6 mL) and KCO (1.72 gm, 12.4 mmol, 1.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, poured into ice water (5.0 mL), and stirred for 10 minutes. The reaction mixture was filtered and concentrated in vacuo to give 5-fluorobenzofuran-4-carboxamide (A.3.1, 1.80 gm, 10.1 mmol, 80% yield) as a white solid. LC-MS: [M+H] = 180.03.

[0478] To a solution of compound A.3.1 (1 gm, 5.05 mmol) in MeOH (50 ml) was added Pd / C (100 mg, 10% by weight). The reaction mixture was degassed with H and stirred at 40 °C for 6 h under an H atmosphere. The mixture was then filtered through Celite and washed with MeOH. Concentration under reduced pressure, followed by purification by flash chromatography (0-10% MeOH in DCM containing 1% trimethylamine) afforded the desired compound Intermediate A.3.2 (859 mg, 4.71 mmol) in 85% yield. LC-MS: [M+H] = 182.05.

[0479] Compound A.3.2 (2.3 gm, 12.63 mmol) in 15 ml of THF was treated with LAD (36 ml of a 1 M solution of LAD in THF) at 0 °C. The temperature was then raised to 50 °C, and the reaction mixture was stirred overnight. After cooling to room temperature, the reaction was slowly quenched with saturated NaSO at 0 °C. It was then filtered and washed several times with ethyl acetate. Purification by flash chromatography (0–10% MeOH in DCM with 1% trimethylamine) afforded the desired compound A.3 (1.50 gm, 8.84 mmol) in 70% yield. LC-MS: [M+H] = 170.08. 1 H NMR (400MHz, CDCl3):6.82-6.76(m,1H),6.59(dd,J=8.8,4.0Hz,1H),4.59(t,J=8.8Hz,2H),3.27(t,J=8.8Hz,2H). Example 21 Synthesis of N-((3-bromo-6-methylpyridin-2-yl)methyl)-2,2,2-trifluoroethan-1-amine (A.4) [ka]

[0480] To a solution of 5-bromo-2-ethylpyridine (A.4.1, 554 mg, 3.0 mmol, 1.0 equiv.) in CHCl3 (8 ml, 0.38 M), 77% mCPBA (5.44 gm, 12.0 mmol, 4.0 equiv.) was added, and the reaction mixture was stirred at room temperature overnight. After cooling to room temperature, Ca(OH)2 (1.5 gm, 15.9 mmol, 5.3 equiv.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 3:1 CHCl3 / methanol. The filtrate was then concentrated in vacuo, and the residue was purified by column chromatography using 0-100% ethyl acetate in hexane to give the desired N-oxide (A.4.2, 482 mg, 2.4 mmol). LC-MS: [M+H]+ = 201.97.

[0481] To a solution of 5-bromo-2-ethylpyridine 1-oxide (A.4.2, 400 mg, 2.0 mmol) in acetonitrile (10 ml, 0.2 M) was added trimethylsilyl cyanide (TMSCN) (793 mg, 8.0 mmol, 4.0 equiv.) and triethylamine (606 mg, 6.0 mmol, 3.0 equiv.). The mixture was heated at 100 °C overnight. After cooling to room temperature, the solvent was concentrated in vacuo, and the residue was purified by column chromatography using 0-50% ethyl acetate in hexane to give 3-bromo-6-ethylpicolinonitrile (A.4.3, 293 mg, 1.4 mmol, 70% yield). LC-MS: [M+H] = 210.97.

[0482] 3-Bromo-6-ethylpicolinonitrile (A.4.3, 1 gm, 4.78 mmol) was dissolved in concentrated hydrochloric acid (20 ml) and stirred at 100° C. for 2 days. The reaction mixture was cooled to room temperature and evaporated to dryness. The obtained product was used in the next step without further purification. LC-MS: [M+H]+ = 229.97.

[0483] 3-Bromo-6-ethylpicolinic acid (A.4.4, 5.33 gm, 23.3 mmol) was dissolved in MeOH (50 ml), cooled to 0 °C, and 1.0 ml of H2SO4 was added dropwise. The reaction was then stirred at 90 °C overnight. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (50 ml), washed with water and saturated aqueous NaCl (2 × 100 ml), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1:5) to give methyl 3-bromo-6-ethylpicolinate (A.4.5, 5.09 gm, 20.97 mmol) in 90% yield. LC-MS [M+H]+ = 243.98

[0484] To a solution of methyl 3-bromo-6-ethylpicolinate (A.4.5, 522 mg, 2.15 mmol) in DCM (15 ml) at -60 °C, DIBAL-H (4.6 ml, 4.60 mmol, 1 M in cyclohexane) was added dropwise. The reaction mixture was maintained at -60 °C to -15 °C for 30 min, then warmed to room temperature and stirred for an additional 12 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl (50 ml). The resulting mixture was extracted with DCM (3 × 100 ml), washed with brine (50 ml), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1:3) to give A.4.6 as a colorless liquid (1.36 mmol, 293 mg, 60%). LC-MS [M+H]+ = 215.99

[0485] An aliquot of (3-bromo-6-ethylpyridin-2-yl)methanol (A.4.6) was dissolved in dry DCM (approximately 0.2 M). To this solution was then added 1.5 equivalents of DMP, and the reaction mixture was stirred for 1 h. Upon completion (monitored by TLC), the reaction was quenched with saturated NH4Cl solution, then extracted with DCM and washed with water and brine. The organic layers were collected, combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification was carried out by normal phase silica gel column chromatography using increasing amounts of ethyl acetate in hexane to give the desired aldehyde.

[0486] To the aldehyde was added methanol (approximately 0.2 M), followed by the addition of 2.2 equivalents of 2,2,2-trifluoroethan-1-amine, 2 equivalents of Na(CN)BH, and 2 equivalents of acetic acid at 0 °C. The ice bath was removed, and the reaction mixture was stirred for 3 h. Upon completion (monitored by TLC), the reaction mixture was concentrated, and the residue was purified by HPLC to give A.4 in 70% yield. LC-MS: [M+H] = 297.01. Example 22 Synthesis of (5-bromo-2-(difluoromethyl)pyridin-4-yl)methanol (A.6): [ka]

[0487] To a 100 mL flask equipped with a stir bar was added copper powder (380 mg, 5.94 mmol, 2.25 equiv.) and (2,5-dibromopyridin-4-yl)triethylsilylmethanol (A.6.2, 1.006 g, 2.64 mmol, 1.0 equiv.). The flask was evacuated and backfilled with N2. Anhydrous DMSO (6 mL) and ethyl bromodifluoroacetate (589 mg, 2.90 mmol, 1.1 equiv.) were added. Stirring was initiated, and the mixture was heated to a 70 °C oil bath. After 2 h, an aliquot of the reaction mixture was diluted with 1.27 M aqueous KH2PO4 and EtOAc was added. After sonication, the upper organic layer was separated. KH2PO4 (1.27 M, 40 mL) was added slowly, maintaining the internal temperature below 10 °C. The mixture was stirred at 0 °C for 0.5 h before filtering through Celite. The cake was washed with EtOAc (40 ml). The two-phase filtrate layers were separated. The organic layer was washed with water and brine, then concentrated and purified by flash chromatography to give compound A.6.3 (825 mg, 74% yield).

[0488] To a solution of A.6.3 (825 mg, 1.95 mmol) in methanol (2 mL) cooled to 0 °C, 6 N NaOH (1 mL, 3.0 equiv.) was added dropwise. The resulting clear solution was stirred at 0 °C for 3 h, after which UPLC-MS analysis showed clean conversion to the desired product. The reaction mixture was acidified with 4 N HCl (1.5 mL) to pH 3 at 0 °C. HPLC purification afforded A.6.4 (412 mg, 1.46 mmol, 75%) as a pale yellow solid.

[0489] To a 50 ml flask equipped with a stir bar was added difluoroacid A.6.4 (412 mg, 1.46 mmol). The flask was evacuated and backfilled with N2 atmosphere. NMP (2 ml) and 85% H3PO4 (169 mg, 1.46 mmol) were added. The resulting mixture was heated to an oil bath at 145 °C and stirred. After 2 h, UPLC-MS showed complete conversion to the desired product. The mixture was cooled to 15 °C and quenched with 1 N NaOH. The mixture was purified by HPLC to give the desired compound A.6 (274 mg, 1.15 mmol, 79%) as a pale yellow solid. Example 23 Synthesis of 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(methyl-d3)-4-(2,2,2-trifluoroethyl)-4,5-dihydro-3H-2,4,6,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. 19): [ka]

[0490] To a flame-dried flask was added 3-bromo-6-methylpicolinic acid (1 gm, 4.67 mmol), followed by potassium tert-butoxide (1.0 gm, 9.34 mmol) and DMSO-d6 (12 mL), and the mixture was stirred under argon at room temperature for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The ethyl acetate layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product (E19.1) in 90% yield. LC-MS: [M+H]+ = 215.95.

[0491] H2SO4 (1.0 equiv.) was added to a solution of 3-bromo-6-(methyl-d3)picolinate-d (E19.1, 5.0 gm, 23.3 mmol, 1.0 equiv.) in MeOH (50 ml). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (50 ml), washed with water and saturated aqueous NaCl (2 x 100 ml), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1:5) to give methyl 3-bromo-6-methylpicolinate (E19.2, 4.7 gm) in 90% yield. LC-MS [M+H] + =232.99.

[0492] To a solution of methyl 3-bromo-6-(methyl-d3)picolinate (E19.2, 520 mg, 2.15 mmol) in DCM (15 mL) at -60 °C, DIBAL-H (4.6 mL, 4.60 mmol, 1 M in cyclohexane) was added dropwise. The reaction mixture was maintained at -60 °C to -15 °C for 30 min, then warmed to room temperature and stirred for an additional 12 h. The reaction mixture was cooled again to 0 °C and quenched with saturated aqueous NH4Cl (50 mL). The resulting mixture was extracted with DCM (3 × 100 mL), washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1:3) to give E.19.3 as a colorless liquid (1.36 mmol, 273 mg, 60%). LC-MS [M+H]+ = 204.99.

[0493] An aliquot of (3-bromo-6-(methyl-d3)pyridin-2-yl)methanol (E19.3) was dissolved in dry DCM (approximately 0.2 M). To this solution, 1.5 equivalents of DMP was added, and the reaction mixture was stirred for 1 hour (monitored by TLC). Upon completion, the reaction was quenched with saturated NH4Cl solution, extracted with DCM, and washed with water and brine. The organic layers were collected, combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification was carried out by normal phase silica gel column chromatography using increasing amounts of ethyl acetate in hexane to give the desired aldehyde.

[0494] To the aldehyde was added methanol (approximately 0.2 M), followed by the addition of 2.2 equivalents of trifluoroethan-1-amine, 2 equivalents of Na(CN)BH, and 2 equivalents of acetic acid at 0 °C. The ice bath was removed, and the reaction mixture was stirred for 3 hours. Upon completion, the reaction mixture was concentrated, and the residue was purified by HPLC to give E19.4 in 70% yield. LC-MS: [M+H] = 286.01.

[0495] Palladium(II) acetate (0.1 equiv.) and cataCXium A (0.2 equiv.) were mixed together in DME (0.5 ml, degassed), and the resulting solution was added by pipette to a mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 equiv.), secondary amine E19.4 (2 equiv.), bis-pinacolatodiboron (2.0 equiv.), and K2CO3 (4.0 equiv.) in DME / HO (10:1, 10 ml, degassed) at 70 °C. The reaction mixture was stirred for 12 h. The reaction mixture was concentrated, extracted with ethyl acetate (2 × 50 ml), washed with water and brine, and dried over Na2SO4. The mixture was concentrated, and the residue was purified by HPLC to give E19.5 in 50% yield. LC-MS: [M+H]+ = 561.21.

[0496] A mixture of compound E19.5 (1 equivalent) and LiOH (10 equivalents) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 70° C. overnight. The mixture was concentrated, and the residue was then purified by preparative HPLC to give E19.6 in 80% yield. LC-MS: [M+H]=534.18.

[0497] To a mixture of compound E19.6 (1 eq.) and HATU (2 eq.) in DMF (5 ml / mmol) was added DIPEA (5 eq.). The reaction mixture was stirred overnight and concentrated. The residue was purified by preparative HPLC to give compound No. E19 in 90% yield. LC-MS: [M+H] + =516.17. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.85(s,1H),8.71(t,J=5.1Hz,1H),7.93(d,J=8.0Hz,1H),7.54(s,1H),7.44(d,J= 8.1Hz,1H),6.96(dd,J=10.3,8.6Hz,1H),6.71(dd,J=8.7,3.9Hz,1H),5.46(d,J=1 5.0Hz,1H),4.75(d,J=4.5Hz,2H),4.71-4.61(m,1H),4.56(t,J=8.8Hz,2H),4.19( d,J=15.0Hz,1H),4.08(dq,J=15.2,9.0Hz,1H),3.34(t,J=8.7Hz,2H),2.57(s,3H). Example 24 Synthesis of 8-(6-cyclopropylpyridin-3-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-(methylsulfonyl)imidazo[1,5-a]pyridine-6-carbonitrile (compound number E26): [ka]

[0498] A mixture of 5-bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (E26.1, 120 mg, 0.55 mmol) and DIPEA (145 mg, 1.14 mmol) in POCl3 (2.0 mL) was refluxed for 3 hours. The resulting brown mixture was evaporated in vacuo, and 10 mL of EtOAc and 5 mL of aqueous NaHCO3 were added. The mixture was extracted with EtOAc (20 mL × 3), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, eluted with PE / EA = 1 / 3 to 1 / 5) to give E26.2 (70 mg, 54% yield) as a white solid. LC-MS: [M+H]+ = 230.1.

[0499] To a solution of 5-bromo-2-chloro-6-methylnicotinonitrile (4.46 gm, 19.4 mmol) and NBS (3.79 mg, 21.3 mmol) in CCl4 (80 ml) was added BPO (469 mg, 1.94 mmol) at room temperature. The resulting mixture was degassed and stirred at 80 °C for 4 hours under nitrogen. The reaction mixture was filtered, washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography on silica gel (eluting with 10% EtOAc / petroleum ether) to give 5-bromo-6-(bromomethyl)-2-chloronicotinonitrile (E26.3) as a yellow oil (4.1 gm, 74%). LC-MS: [M+H]+ = 308.83.

[0500] To a solution of 5-bromo-6-(bromomethyl)-2-chloronicotinonitrile (4.46 gm, 14.5 mmol) in DMF (50 ml) was added NaN (1.89 gm, 29 mmol). The mixture was stirred at room temperature for 2 hours, poured into water, and extracted with EtOAc (30 ml × 3). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated to give 6-(azidomethyl)-5-bromo-2-chloronicotinonitrile as a yellow oil (3.4 gm, yield: 87%), which was used directly in the next step. LC-MS: [M+H] = 271.92.

[0501] To a solution of 6-(azidomethyl)-5-bromo-2-chloronicotinonitrile (3.4 gm, 12.6 mmol) in THF (50 ml) and HO (5 ml) was added PPh (4.93 gm, 18.9 mmol). The resulting mixture was heated at 50° C. for 1 hour and concentrated. The residue was dissolved in 50 ml of aqueous HCl and washed with DCM (20 ml×2). The aqueous layer was basified by adding aqueous NaOH to pH 8 and extracted with EtOAc (30 ml×3). The organic layer was dried (NaSO), filtered, and concentrated to give the desired product, 6-(aminomethyl)-5-bromo-2-chloronicotinonitrile, as a yellow oil (2.28 gm, 74%). LC-MS: [M+H]=245.93.

[0502] To a solution of 6-(aminomethyl)-5-bromo-2-chloronicotinonitrile (2.25 gm, 9.3 mmol) in ethyl formate (40 ml) was added NaHCO3 (391 mg, 4.6 mmol). The mixture was stirred at room temperature for 24 hours and filtered. The filtrate was concentrated to give the desired compound as a brown oil (2.1 gm, 90%), which was used directly in the next step. LC-MS: [M+H]+ = 273.93.

[0503] To a solution of the crude compound in dioxane (30 ml) was added POCl3 (2.59 gm, 16.8 mmol). The mixture was refluxed for 3 hours. The reaction mixture was quenched with aqueous NaHCO3 and extracted with EtOAc (30 × 3). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude was purified by column chromatography on silica gel (10% EtOAc / petroleum) to give the desired compound (E.26.6) as a pale yellow solid (1.6 gm, 83%). LC-MS: [M+H]+ = 255.91.

[0504] A mixture of 8-bromo-5-chloroimidazo[1,5-a]pyridine-6-carbonitrile (60 mg, 0.24 mmol), (6-cyclopropylpyridin-3-yl)boronic acid (50 mg, 0.31 mmol), Pd(dppf)Cl (12 mg, 0.015 mmol), and NaCO (81 mg, 0.77 mmol) in HO (0.5 mL) and dioxane (1.5 mL) was heated at 110 °C for 1 h under N. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC to give 5-chloro-8-(6-cyclopropylpyridin-3-yl)imidazo[1,5-a]pyridine-6-carbonitrile (E26.7, 74 mg, yield: 90%). LC-MS: [M+H] = 295.06.

[0505] To a solution of 5-chloro-8-(6-cyclopropylpyridin-3-yl)imidazo[1,5-a]pyridine-6-carbonitrile (38 mg, 0.13 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (65 mg, 0.39 mmol) in NMP (0.5 ml) was added triethylamine (39 mg, 0.39 mmol) at room temperature. The resulting solution was heated at 130 °C in a microwave oven for 1 hour. The reaction mixture was concentrated and purified by column chromatography on silica gel (eluted with PE:EA = 1:1) to give a yellow solid (E26.8, 66%). LC-MS (m / z): 426.16 [M+H]+.

[0506] To a solution of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-phenylimidazo[1,5-c]pyrimidin-5-amine (500 mg, 1.38 mmol) in DMF (10 mL) at 0° C., NIS (278 mg, 1.24 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The mixture was extracted with DCM (4 × 50 mL), washed with brine (30 mL), dried (NaSO), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 20–50% EtOAc / hexane) to give the title compound (E26.9) as a yellow solid (610 mg, 1.26 mmol, 70%). LC-MS: [M+H]+ = 552.06.

[0507] A mixture of compound E26.9 (50 mg, 0.09 mmol), MeSONa (30 mg, 0.3 mmol), and CuI (57 mg, 0.3 mmol) in DMSO (2 ml) was bubbled with N for 5 minutes, and then the sealed tube was heated in a microwave reactor at 120 °C for 20 minutes and then at 100 °C for 0.3 hours. The mixture was concentrated, and the residue was purified by HPLC to give compound No. E26 (25 mg, 0.05 mmol) in 50% yield. LC-MS: [M+H] = 504.14. Example 25 Synthesis of N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-5-methyl-8-(trifluoromethyl)-6H-2,3,5a,9,12,13a-hexaazabenzo[4,5]cyclopenta[7,8]cycloocta[1,2,3-cd]inden-13-amine (Compound No. E10) [ka]

[0508] A 500 ml round-bottom flask equipped with a stir bar, condenser, and nitrogen inlet was charged with 38.9 gm (144 mmol) of 5-bromo-2-trifluoromethyl-isonicotinic acid (E10.1). 250 ml of anhydrous DCM was added to the solid, followed by 13.2 ml (151 mmol, 1.05 equiv.) of oxalyl chloride. 0.5 ml of anhydrous DMF was added to the mixture, and the mixture was stirred at ambient temperature for 2 hours. The solvent was removed under vacuum. A 1-liter Erlenmeyer flask equipped with a stir bar was charged with 500 ml of aqueous NH4OH in an ice bath. The crude acid chloride was added dropwise to the cooled solution. The residue was transferred with a small amount of acetonitrile. After the addition, the mixture was stirred for 20 minutes. The resulting precipitate was collected by filtration and washed with water. The filter cake was dried under vacuum at 45° C. to give 5-bromo-2-trifluoromethyl-isonicotinamide (E10.2, 118 mmol, 31.52 gm, 82% yield) as an off-white solid. LC-MS [M+H]+=269.95.

[0509] A 100 mL round-bottom flask equipped with a stir bar, condenser, and nitrogen inlet was charged with 5.2 gm (19.3 mmol) of 5-bromo-2-trifluoromethylisonicotinamide (E10.2). The solid was diluted with 12 mL of POCl. The mixture was heated at 70 °C for 3 hours. The mixture was cooled to room temperature and poured onto ice. The mixture was neutralized by careful addition of 50% sodium hydroxide. The resulting off-white solid was collected by filtration, washed with water, and dried under vacuum at 50 °C for 18 hours. This gave 4.5 gm of 5-bromo-2-trifluoromethyl-isonicotinonitrile (E10.3, 4.53 gm, 18.1 mmol) as an off-white solid in 94% yield. LC-MS [M+H]+ = 250.95. 1 H NMR (CDCl3): δ,9.03(s,1H),7.91(s,1H).

[0510] NaBH4 (0.66 g, 14.81 mmol) was charged to a 100 mL flask, followed by 20 mL of anhydrous THF. The mixture was cooled in an ice-water bath. TFA (1.5 mL) was added to THF (4 mL) at that temperature over 0.5 hours. The ice-water bath was removed, and the resulting mixture was stirred at room temperature for 2 hours. 5-Bromo-2-(trifluoromethyl)isonicotinonitrile (E10.3, 2 gm, 8.0 mmol) was dissolved in THF (10 mL). The TFA / NaBH4 mixture was again cooled in an ice-water bath, and the nitrile solution was added over 0.5 hours. The mixture was allowed to reach ambient temperature with stirring for 16 hours. LC analysis of an aliquot revealed the reaction was complete. The mixture was cooled in an ice bath, and 10 mL of methanol was added slowly. The volatiles were removed under vacuum, and ethyl acetate (50 mL) was added. The mixture was washed with water (10 mL). The aqueous layer was washed with ethyl acetate (10 ml), and the combined organic layers were washed with brine (10 ml), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase Combiflash (eluting with 1-20% acetonitrile / H0) to give the title compound (E10.4, 1.6 gm, 80%) as a colorless liquid. LC-MS [M+H] = 254.96.

[0511] Compound (E10.4, 512 mg, 2 mmol) was stirred with (Boc)2O (0.51 gm, 2.4 mmol, 1.2 eq) and Et3N (2 eq, 4 mmol, 380 mg) in 20 ml of DCM at room temperature for 3 h. The residue was purified by column chromatography using 0-50% EtOAc / hexane to give the desired compound (E10.5, 560 mg) in 80% overall yield. LC-MS [M+H]+ = 355.16.

[0512] Palladium(II) acetate (0.1 equiv.) and cataCXium A (0.2 equiv.) were mixed together in DME (0.5 ml, degassed), and the resulting solution was added by pipette to a mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 equiv.), secondary amine E10.5 (2 equiv.), bis-pinacolatodiboron (2.0 equiv.), and KCO (4.0 equiv.) in DME / HO (10:1, 10 ml, degassed) at 70 °C. The reaction mixture was stirred for 12 h. The reaction mixture was concentrated, extracted with ethyl acetate (2 × 50 ml), washed with water and brine, and then dried over NaSO. The mixture was concentrated and the residue was purified by HPLC to give E10.6 in 50% yield. LC-MS: [M+H]+=631.22

[0513] A mixture of compound E10.6 (1 equivalent) and LiOH (10 equivalents) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 70° C. overnight. The mixture was concentrated, and the residue was then purified by preparative HPLC to give E10.7 in 80% yield. LC-MS: [M+H]=603.19.

[0514] In a 250 ml round-bottom flask, a stirred solution of E10.7 (3.29 gm, 5.47 mmol) and prop-2-yn-1-amine (0.601 gm, 10.94 mmol) in DMF (15 mL) was treated sequentially with EDCI.HCl (2.28 gm, 11.94 mmol), HOBt (1.61 gm, 11.93 mmol), and EtN (2.03 ml, 14.92 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. Upon completion of the reaction (TLC), the reaction mixture was diluted with ice-cold water. The mixture was concentrated, and the residue was then purified by preparative HPLC to give E10.8 in 80% yield. LC-MS: [M+H]+ = 640.22

[0515] Compound E10.8 was treated with 25% TFA / DCM at room temperature for 1 hour, and the volatiles were removed in vacuo. The crude product was diluted with ethyl acetate and washed with saturated aqueous Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give compound E10.9, which was used crude for the next step. LC-MS: [M+H]+ = 540.22.

[0516] In a 20 ml microwave vial, a solution of compound E10.9 (0.22 g, 0.42 mmol) and (2-methoxyphenyl)methanamine (0.086 g, 0.63 mmol) in toluene (5 mL) was treated with Zn(OTf) (0.009 g, 0.021 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was subjected to microwave irradiation at 140 °C for 1 hour. Upon completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (30 mL). The organic extract was washed with saturated NaHCO and brine and dried over anhydrous NaSO. The solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give compound No. E10 in 40% yield. LC-MS: [M+H] = 522.15. Example 26 Synthesis of 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-4-(2,2,2-trifluoroethyl)-4,5-dihydro-3H-2,4,6,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. E45) [ka]

[0517] To a solution of 5-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine (5.00 g, 20.65 mmol) in DCM (100 ml) was slowly added 1.5 equivalents of mCPBA (5.35 g, 30.97 mmol). After 4 hours, the reaction mixture was quenched with 2.0 equivalents of Ca(OH) (3.90 g, 41.3 mmol), and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 3:1 DCM / methanol. The filtrate was concentrated in vacuo to give 5-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine 1-oxide as a crude solid, which was used in the next reaction without further purification.

[0518] To a solution of crude 5-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine 1-oxide (4.00 g, 15.63 mmol) obtained from the previous step in acetonitrile (78 ml, 0.2 M) was added 6.0 equivalents of trimethylsilyl cyanide (TMSCN) (9.48 g, 94.00 mmol) and 4.5 equivalents of triethylamine (5.26 g, 70.34 mmol). The mixture was heated at 100 °C overnight. After cooling to room temperature, the solvent was concentrated in vacuo and the residue was purified by HPLC (acetonitrile / HO). 、 Purification by HPLC (starting with 25% ACN and then 42% ACN in H2O to give the compound) gave 3-bromo-6-(tetrahydro-2H-pyran-4-yl)picolinonitrile (1.60 g, 5.97 mmol, 29% yield over two steps). LC-MS [M+H]+ = 266.97 / 268.96. 1 H NMR(400MHz,DMSO-d6) δ 8.30(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),3.96-3.93(m,2H),3.46-3.40(m,2H),3.05-2.98(m,1H),1.79-1.68(m,4H).

[0519] 3-Bromo-6-(tetrahydro-2H-pyran-4-yl)picolinonitrile (1.60 g, 5.97 mmol) was dissolved in 50 mL of dry DCM and cooled to -78 °C. While stirring, 2 equivalents of DIBAL-H solution in toluene (12 mL, 11.94 mmol) was added dropwise. The mixture was stirred for 5 hours, quenched by the slow addition of saturated aqueous Rochelle's salt (potassium sodium tartrate), warmed to room temperature, diluted with ethyl acetate, and stirred until two easily separable clear layers formed. HPLC purification afforded (3-bromo-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methanamine (1.12 g, 4.12 mmol, 69%) as a liquid. LC-MS [M+H]+ = 271.04 / 273.03. 1 H NMR(400MHz,DMSO-d6) δ 8.29(s,broad,2H),8.07(d,J=8.4Hz,1H),7.29(d,J=8.4Hz,1H),4.53-4.22(m,2H),3.48-3.42(m,2H),3.00-2.93(m,1H),1.91-1.69(m,4H).

[0520] To a solution of (3-bromo-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methanamine (181 mg, 0.67 mmol) in DCM (10 ml) was added 2.0 equivalents of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (311 mg, 1.34 mmol) and 2.0 equivalents of DIPEA (173 mg, 1.34 mmol). After 3 hours, the reaction mixture was quenched with TFA and HO, followed by HPLC purification to give N-((3-bromo-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methyl)-2,2,2-trifluoroethan-1-amine. LC-MS: [M+H]+ = 354.01.

[0521] After lyophilization, the compound was stirred with 2 equivalents of (Boc)O (292 mg, 1.34 mmol) and 3 equivalents of EtN (2.01 mmol, 203 mg) in 4 mL of DCM at room temperature for 5 hours. Upon completion, the residue was purified by combi-flash column chromatography using 0-100% EtOAc / hexanes to give compound tert-butyl ((3-bromo-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate (85 mg, 0.19 mmol, 28% yield over two steps). LC-MS [M+H]=454.07.

[0522] Palladium(II) acetate (0.2 equiv.) and cataCXium A (0.4 equiv.) were mixed together in DME (0.5 ml, degassed), and the resulting solution was added via pipette to a mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 equiv.), tert-butyl ((3-bromo-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)carbamate (83 mg, 0.18 mmol, 1.2 equiv.), bis-pinacolatodiboron (2 equiv.), and KCO (5 equiv.) in DME / HO (10:1, 5.0 ml, degassed) at 70 °C. The reaction mixture was stirred overnight. It was then concentrated, extracted with ethyl acetate (2 x 30 ml), washed with water and brine, and dried over anhydrous NaSO. The mixture was concentrated, followed by preparative HPLC purification to give E-2211.1. LC-MS: [M+H] = 729.29. Removal of the Boc protecting group of E-2211.1 gave E-2211.2. LC-MS: [M+H] = 629.21.

[0523] A mixture of compound E-2211.2 (1 equiv.) and LiOH (10 equiv.) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 80° C. overnight. The mixture was concentrated, and the residue was then purified by preparative HPLC to give E-2211.3 in 50% yield over three steps.

[0524] To a mixture of compound E-2211.3 (1 equivalent) and HATU (2 equivalents) in DMF (5 ml / mmol) was added DIPEA (5 equivalents). The reaction mixture was stirred for 2 hours and concentrated. The residue was purified by preparative HPLC to give compound No. E45 in quantitative yield. LC-MS: [M+H]+ = 583.09. 1 H NMR(400MHz,DMSO-d6) δ 8.83(s,1H),8.68(t,J=4.8Hz,1H),7.90(d,J=8.4Hz,1H),7.54(s,1H),7.43(d,J=8.4Hz,1 H),6.95(dd,J=9.6,8.8Hz,1H),6.72(dd,J=8.8,4.0Hz,1H),5.47(d,J=14.8Hz,1H),4.74( d,J=4.8Hz,2H),4.70-4.63(m,1H),4.55(t,J=8.8Hz,2H),4.16(d,J=14.8Hz,1H),4.07-4. 03(m,4H),3.45-3.51(m,2H),3.33(t,J=8.4Hz,2H),2.97-3.05(m,1H),1.75-1.84(m,4H). Example 27 Synthesis of 7-(tert-butyl)-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (compound number E46) [ka]

[0525] To a solution of 5-bromo-2-(tert-butyl)isonicotinic acid (2.5 g, 9.69 mmol, 1.0 equiv) in MeOH (25 ml) was added H2SO4 (0.5 mL, 9.69 mmol, 1.0 equiv). The resulting solution was stirred at reflux for 14 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml), washed with water and saturated aqueous NaCl (2 x 50 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane to give methyl 5-bromo-2-(tert-butyl)isonicotinate.

[0526] To a solution of methyl 5-bromo-2-(tert-butyl)isonicotinate in DCM (50 ml) at −78°C, DIBAL-H (18 ml, 18.90 mmol, 1.05 M in toluene) was added dropwise. The reaction mixture was maintained at −78°C to −15°C for 30 minutes, then warmed to room temperature and stirred for an additional 12 hours. The reaction mixture was cooled to 0°C and quenched with saturated aqueous NH4Cl (50 ml). The resulting mixture was extracted with DCM (3 × 250 ml), washed with brine (150 ml), dried over anhydrous (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane to give (5-bromo-2-(tert-butyl)pyridin-4-yl)methanol (1.78 g, 7.28 mmol, 75% over two steps). LC-MS [M+H]+ = 243.98 / 245.99.

[0527] An aliquot of (5-bromo-2-(tert-butyl)pyridin-4-yl)methanol (1.78 g, 7.28 mmol) was dissolved in dry DCM (approximately 0.2 M). To this solution was then added 1.3 equivalents of Dess-Martin periodinane (4.11 g, 9.46 mmol). The reaction mixture was stirred for 1 h and monitored by TLC. Upon completion, it was quenched with saturated NH4Cl solution and then extracted with DCM. The organic layers were collected, combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification was carried out by normal-phase silica gel column chromatography using increasing amounts of ethyl acetate in hexane to afford the desired 5-bromo-2-(tert-butyl)isonicotinaldehyde.

[0528] To 5-bromo-2-(tert-butyl)isonicotinaldehyde was added methanol (approximately 0.2 M), followed by the addition of 2.2 equivalents of 2,2,2-trifluoroethan-1-amine, 2 equivalents of Na(CN)BH, and 2 equivalents of acetic acid under an ice bath. The ice bath was removed, and the reaction mixture was stirred for 3 hours and monitored by TLC. Upon completion, the reaction mixture was concentrated, and the residue was purified by HPLC to give N-((5-bromo-2-(tert-butyl)pyridin-4-yl)methyl)-2,2,2-trifluoroethan-1-amine (800 mg, 2.27 mmol, 31% over two steps). LC-MS: [M+H] = 324.89 / 326.86.

[0529] Palladium(II) acetate (0.1 equiv.) and cataCXium A (0.2 equiv.) were mixed together in DME (0.5 ml, degassed), and the resulting solution was added by pipette to a mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 equiv.), N-((5-bromo-2-(tert-butyl)pyridin-4-yl)methyl)-2,2,2-trifluoroethan-1-amine (2 equiv.), bis-pinacolatodiboron (2 equiv.), and KCO (5 equiv.) in DME / HO (10:1, 22 ml, degassed) at 70 °C. The reaction mixture was stirred overnight. The reaction mixture was concentrated, extracted with ethyl acetate (2 x 50 ml), washed with water and brine, and dried over Na2SO4. The mixture was concentrated, and the residue was purified by HPLC to give E-2189.1 in about 15% yield. LC-MS: [M+H]+ = 601.20.

[0530] A mixture of compound E-2189.1 (1 equivalent) and LiOH (10 equivalents) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 80° C. overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give E-2189.2 and compound no. E46 in a ratio of approximately 5:1. LC-MS: [M+H]=573.15.

[0531] To a mixture of compound E-2189.2 (1 equivalent) and HATU (2 equivalents) in DMF (5 ml / mmol) was added DIPEA (5 equivalents). The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give compound No. E46 in a total yield of approximately 90%. LC-MS: [M+H]+ = 555.10. 1H NMR(400MHz,DMSO-d6) δ 8.85(s,1H),8.72(t,1H),8.65(d,J=2.4,1H),7.91(d,J=7.8Hz,1H),7.5 8(d,J=1.6Hz,1H),6.96(t,J=8.8Hz,1H),6.71(dd,J=8.8,4.0Hz,1H),5. 34(d,J=14.8Hz,1H),4.75(d,J=4.0Hz,2H),4.56(t,J=8.8Hz,2H),4.29( d,J=14.8Hz,1H),4.06-4.12(m,1H),3.34(t,J=8.8Hz,2H),1.40(s,9H). Example 28 Synthesis of 4-(2,2-difluoroethyl)-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-isopropyl-4,5-dihydro-3H-2,4,6,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. E47) [ka]

[0532] To a solution of 5-bromo-2-isopropylpyridine (1.00 g, 5.00 mmol) in DCM (20 ml) was added 1.5 equivalents of mCPBA. After 4 hours, the reaction mixture was quenched with 2.0 equivalents of Ca(OH) and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 3:1 DCM / methanol. The filtrate was concentrated in vacuo to give 5-bromo-2-isopropylpyridine 1-oxide as a crude solid, which was used in the next reaction without further purification.

[0533] To a solution of the crude 5-bromo-2-isopropylpyridine 1-oxide obtained from the previous step in acetonitrile (20 ml, 0.2 M) was added 6.0 equivalents of trimethylsilyl cyanide (TMSCN) and 4.5 equivalents of triethylamine. The mixture was heated at 100 °C overnight. After cooling to room temperature, the solvent was concentrated in vacuo, and the residue was purified by preparative HPLC to give 3-bromo-6-isopropylpicolinonitrile (443 mg, 1.97 mmol, 39% yield over two steps). LC-MS [M+H] = 225.01 / 227.03.

[0534] 3-Bromo-6-isopropylpicolinonitrile (443 mg, 1.97 mmol) was dissolved in 10 ml of dry DCM and cooled to -78°C. While the solution was stirred, 2 equivalents of DIBAL-H solution in toluene was added dropwise. The mixture was stirred for 5 hours and then quenched by the slow addition of saturated aqueous Rochelle's salt (potassium sodium tartrate). The reaction mixture was warmed, diluted with ethyl acetate, and stirred until two easily separable clear layers formed. HPLC purification gave (3-bromo-6-isopropylpyridin-2-yl)methanamine as a liquid. LC-MS [M+H]+ = 229.01 / 230.97. 1 H NMR(400MHz,DMSO-d6) δ 8.34(s, broad, 2H), 8.04(d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),4.24-4.23(m,2H),3.33-3.02(m,1H),1.26(d,J=6.8Hz,6H).

[0535] To a solution of (3-bromo-6-isopropylpyridin-2-yl)methanamine (107 mg, 0.47 mmol) in DCM (10 ml) was added 2.0 equivalents of 2,2-difluoroethyl 4-methylbenzenesulfonate (200 mg, 0.94 mmol) and 2.0 equivalents of DIPEA. After 3 hours, the reaction mixture was quenched with TFA and HO. HPLC purification afforded N-((3-bromo-6-isopropylpyridin-2-yl)methyl)-2,2-difluoroethan-1-amine. LC-MS [M+H] = 293.04 / 285.09.

[0536] After lyophilization, N-((3-bromo-6-isopropylpyridin-2-yl)methyl)-2,2-difluoroethan-1-amine (103 mg, 0.35 mmol) was stirred with 2 equivalents of (Boc)O (153 mg, 0.70 mmol) and 3 equivalents of EtN (203 mg, 1.05 mmol) in 3 mL of dry DCM at room temperature for 5 h. Upon completion, the residue was purified by combi-flash column chromatography using 0–100% EtOAc / hexanes to give tert-butyl ((3-bromo-6-isopropylpyridin-2-yl)methyl)(2,2-difluoroethyl)carbamate (52 mg, 0.13 mmol, 28% yield over two steps).

[0537] Palladium(II) acetate (0.2 equiv.) and cataCXium A (0.4 equiv.) were mixed together in DME (0.5 ml, degassed), and the resulting solution was added via pipette to a mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 equiv.), tert-butyl ((3-bromo-6-isopropylpyridin-2-yl)methyl)(2,2-difluoroethyl)carbamate (52 mg, 0.13 mmol, 1.2 equiv.), bis-pinacolatodiboron (2.0 equiv.), and KCO (5.0 equiv.) in DME / HO (10:1, 4.0 ml, degassed) at 70 °C. The reaction mixture was stirred overnight. It was then concentrated, extracted with ethyl acetate (2 x 30 ml), washed with water and brine, and dried over NaSO. The mixture was concentrated and purified by HPLC to give E-2206.1. LC-MS: [M+H] = 669.33. The Boc protecting group of E-2206.1 was removed to give E-2206.2. LC-MS: [M+H] = 569.17.

[0538] A mixture of compound E-2206.2 (1 equivalent) and LiOH (10 equivalents) in THF (10 ml / mmol) and water (5 ml / mmol) was heated at 80° C. overnight. The mixture was concentrated, and the residue was then purified by preparative HPLC to give E-2206.3. LC-MS: [M+H]=541.10.

[0539] To a mixture of E-2206.3 (1 equivalent) and HATU (2 equivalents) in DMF (3 ml / mmol) was added DIPEA (5 equivalents). The reaction mixture was stirred for 2 hours and concentrated. The residue was purified by preparative HPLC to give compound No. E47 in quantitative yield. LC-MS: [M+H]+ = 523.15. 1H NMR(400MHz,DMSO-d6) δ 8.80(s,1H),8.63(t,1H),7.85(d,J=8.0Hz,1H),7.49(s,1H),7.37(d,J=8.0Hz,1H),6.9 4(dd,J=9.6,8.8Hz,1H),6.70(dd,J=8.8,4.0Hz,1H),6.29(t,J=57.2Hz,1H),5.40(d,J=8 .4Hz,1H),4.72(d,J=3.6Hz,2H),4.54(t,J=8.8Hz,2H),4.14(d,J=14.8Hz,1H),4.09-4.0 3(m,1H),3.75-3.33(m,1H),3.33(t,J=8.8Hz,2H),3.10-3.03(m,2H),1.29-1.22(m,6H). Example 29 Synthesis of 7-(1,4-dioxan-2-yl)-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-4,5-dihydro-3H-2,4,6,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. E48) [ka]

[0540] Compound No. E48 can be prepared starting from 5-bromo-2-(1,4-dioxan-2-yl)pyridine using the methodology described in the examples above. Example 30 Synthesis of 7-((1,4-dioxan-2-yl)methyl)-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-4,5-dihydro-3H-2,4,6,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one (Compound No. E49) [ka]

[0541] Compound No. E49 can be prepared starting from 2-((1,4-dioxan-2-yl)methyl)-5-bromopyridine using the methodology described in the examples above.

[0542] Example 31 Compound characterization The compounds in Table 2 were prepared using methodologies described in Examples 1-17 (see, e.g., the "Synthetic Methods" column) and known in the art. All compounds were analyzed by mass spectrometry and / or NMR as TFA salts. 1 Characterized by 1 H NMR. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15] [Table 5-16] [Table 5-17]

[0543] Example 27 Biological assays Representative compounds of the disclosure were tested in the EED AlphaScreen binding assay to determine antiproliferative activity (IC 50 Values ​​were determined in Karpas 422 and Pfeiffer cell lines over 7 days of treatment. "N / A" stands for "not evaluated."

[0544] Analysis of cell proliferation:

[0545] Human B-cell lymphoma cells, KARPAS422, were purchased from the American Type Culture Collection (ATCC) and cultured using standard cell culture conditions in RPMI-1640 (Invitrogen, catalog no. 11875) supplemented with 10% FBS (Invitrogen, catalog no. 10099-141) in a humidified incubator at 37°C with 5% CO2. To assess the effect of PRC2 inhibition on cell proliferation, cells were seeded into 96-well cell culture plates at a density of 2,000–3,000 cells / well in 200 μL of culture medium and treated with serially diluted compounds for 7 days at 37°C in a 5% CO2 atmosphere. Cell proliferation was assessed by the lactate dehydrogenase-based WST-8 assay (Dojindo Molecular Technologies) using a Tecan Infinite M1000 multimode microplate reader (Tecan, Morrisville, NC). WST-8 reagent was added to the plate, incubated for 1–4 h, and read at 450 nm. Readings were normalized to DMSO-treated cells and IC was calculated by nonlinear regression analysis using GraphPad Prism 6 software. 50 was calculated.

[0546] AlphaScreen (α-screen) EED-H3K27Me3 peptide competitive binding assay:

[0547] To evaluate the efficacy of the EED-H3K27Me3 competitive binding assay, representative compounds of the present disclosure were serially diluted 3-fold with DMSO to obtain a total of 12 concentrations. Each concentration of compound (2.5 μl each) was transferred to a 384-well Perkin Elmer OptiPlate-384 white plate. 5 μl of a solution containing 20 nM EED(1-441)-His protein in buffer (25 mM HEPES, pH 8, 0.02% Tween-20, 0.5% BSA) was added to the wells and then incubated with the compound for 15 minutes. 2.5 μl of a solution containing 20 nM biotin-H3K27Me3(19-33) peptide in buffer (25 mM HEPES, pH 8, 0.02% Tween-20, 0.5% BSA) was added to the wells and then incubated with the compound for 30 minutes. The AlphaScreen detection bead mix was prepared immediately before use by mixing nickel chelate acceptor beads and streptavidin donor beads in a 1:1 ratio in the buffer described above (Perkin Elmer, product number 6760619C / M / R). Then, 10 μl of the detection bead mix was added to the plate and incubated for 1 hour at room temperature in the dark. The final concentrations of donor and acceptor beads were 10 μg / ml each. Plates were read on a CLARIOStar plate reader (BMG Labtech) using AlphaScreen settings adapted for optimal signal detection with a 615 nm filter after sample excitation at 680 nm. The 615 nm emission signal was used to quantify compound inhibition. The AlphaScreen signal was normalized based on the readings from the positive (maximum signal control) and negative (minimum signal control) controls to represent the percentage of remaining activity. The data were then fitted to a dose-response equation to determine the IC 50 The value was obtained.

[0548] The results are shown in Tables 2A and 2B. [Table 6-1] [Table 6-2] [Table 6-3] [Table 7]

[0549] Example 28 In vivo efficacy Animal experiments were performed using approved animal protocols and under the guidelines of the University of Michigan Committee on Animal Use and Care. Xenograft tumors were implanted subcutaneously on the dorsum of severe combined immunodeficient (SCID) mice obtained from Charles River, at 1 × 10 in 50% Matrigel. 7 One tumor was established per mouse by injecting Karpas 422 human B-cell lymphoma cells. Tumors were established approximately 100 mm 3 When the tumor volume reached 100 μg / kg, mice were randomly assigned to treatment and vehicle control groups. Animals were monitored daily for signs of toxicity and weighed 2-3 times per week during and at least weekly after treatment. Tumor size was measured 2-3 times per week using digital calipers during and at least weekly after treatment. Tumor volume was calculated as V = L × W. 2 The mean ± SEM was calculated as ρ / 2, where L is the length and W is the tumor width. The compound was formulated as a suspension in PEG 200 and administered by oral gavage at the specified doses. Where applicable, results are expressed as mean ± SEM. Graphing and statistical analysis were performed using GraphPad Prism 7.00 (GraphPad Software).

[0550] The antitumor activity of representative compounds of the present disclosure is provided in Figure 1. The body weights of treated animals are provided in Figure 2.

[0551] Having now fully described the methods, compounds, and compositions herein, one skilled in the art will recognize that the same can be practiced within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof.

[0552] All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety.

Claims

1. Formula (II): 【Chemical 1】 [In the formula, R １ is aralkyl, or a group represented by the formula: R １ -1: 【Chemistry 2】 [In the formula, R １２ａ , R １２ｂ , and R １２ｃ are each independently hydrogen, halo, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, and C １ -C ４ alkoxy; W is -CH ２ - and -C(=O)-; t is 1 or 2. is a group represented by R ２ is hydrogen and C １ -C ４ is selected from the group consisting of alkyl, X is -C(R ５ａ ) (R ５ｂ )-, -C(=O)-, and -S(=O) ２ - selected from the group consisting of R ５ａ and R ５ｂ are independently hydrogen and C １ -C ４ is selected from the group consisting of alkyl, Y is -C(R ６ａ ) (R ６ｂ )-, -S-, -O-, and -N(R ７ )- or X and Y together form a 5-membered heteroarylenyl; Z is -C(R ６ｃ ) (R ６ｄ ) - and R ６ａ and R ６ｂ are independently hydrogen and C １ -C ４ is selected from the group consisting of alkyl, Each R ６ｃ and R ６ｄ are independently hydrogen and C １ -C ４ is selected from the group consisting of alkyl, R ７ But hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ４ -C ８ selected from the group consisting of heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl; R ８ａ , R ８ｂ , and R ８ｃ are independently hydrogen, halo, C １ -C ４ Alkyl, C １－ C ４ Haloalkyl, C １ -C ４ Alkoxy, carboxamido, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, (heterocyclo)C １ -C ４ selected from the group consisting of alkyl, and alkylsulfonyl; 【Chemistry 3】 is a fused phenyl, a fused 5-membered heteroaryl, or a fused 6-membered heteroaryl. a compound of, or 【Chemistry 4】 or a pharmaceutically acceptable salt thereof. 【Request 2】 【Chemical 5】 In the formula, L is -C(R ８ｂ 2. The compound of claim 1 of formula III, wherein N is selected from the group consisting of -N= and -N=, or a pharmaceutically acceptable salt thereof. 【Request 3】 【Chemical 6】 In the formula, L is -C(R ８ｂ 2. The compound of claim 1 of formula IV, wherein N is selected from the group consisting of -N= and -N=, or a pharmaceutically acceptable salt thereof.

4. Z is -CH ２ 2. The compound of claim 1, wherein: -, or a pharmaceutically acceptable salt thereof.

5. X is -C(R ５ａ ) (R ５ｂ )-, -C(=O)-, and -S(=O) ２ - selected from the group consisting of Y is -C(R ６ａ ) (R ６ｂ )-, -S-, -O-, and -N(R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)-.

7. Y is -N(R ７ 2. The compound of claim 1, wherein R 1 is 1 or 2; or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X and Y together form a 5-membered heteroarylenyl.

9. R １２ａ But it is fluoro, R １２ｂ and R １２ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is independently selected from the group consisting of hydrogen and fluoro.

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from: 【Chemistry 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 【Chemistry 7-4】 【Chemistry 7-5】 【Chemistry 7-6】 【7-7】

11. 4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, 12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one, and 11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide, or a pharmaceutically acceptable salt thereof.

12. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. 10. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered to the subject.

14. The cancer is selected from the group consisting of: 【Table 1】 【Table 2】 The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is selected from the group consisting of:

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