Substituted indoles and methods of use thereof

Abstract

To provide a method for treating a disease.SOLUTION: The present disclosure provides substituted indole compounds of Formula I and pharmaceutically acceptable salts and solvates thereof, wherein R1a, R1e, G1, G2, Q1, Q2, Q3, and a symbol in the image below, represented by a horizontal line with three bars, are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disease, disorder, or condition such as cancer in a subject. As described in detail and demonstrated specifically in the present specification, it is surprisingly found that, according to the present invention, remarkable effects are achieved, and such remarkable effects could not have been easily anticipated by those skilled in the art based on the prior art.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] The present disclosure provides substituted indoles and methods of using the same. In some embodiments, the substituted indoles are SETD2 protein inhibitors. In some embodiments, the substituted indoles can be used in methods of treating diseases, disorders, or conditions in subjects. [Background technology]

[0002] The selective addition of methyl groups to specific amino acid sites on histones is controlled by the action of a family of enzymes known as histone methyltransferases (HMTs). The level of expression of a particular gene is influenced by the presence or absence of one or more methyl groups at the relevant histone site. The specific effect of a methyl group at a particular histone site persists until the methyl group is removed by a histone demethylase or until the modified histone is replaced by nucleosome turnover. In a similar manner, other enzyme classes can decorate DNA and histones with other chemical species, and still other enzymes can remove these species to achieve control of gene expression.

[0003] SETD2 is a human histone methyltransferase located at cytogenetic band p21.31 (3p21.31) on chromosome 3. The acronym "SETD2" stands for Suppressor of variegation, Enhancer of zeste, and Trithorax domain containing 2. The SETD2 protein contains three conserved functional domains: (1) a triad AWS-SET-PostSET domain; (2) a WW domain; and (3) a Set2-Rbp1 interaction ("SRI") domain. These three functional domains define the biological function of SETD2. See Li, J. et al., Oncotarget 7:50719-50734 (2016). SETD2 is thought to be a single human gene involved in the trimethylation of lysine 36 (Lys-36) of histone H3 (H3K36me3) using dimethylated Lys-36 as a substrate (H3K36me2). Edmunds, JWet al., The EMBO Journal 27:406-420 (2008). Human SETD2 has been shown to have tumor suppressor function (Li, J. et al., Oncotarget 7:50719-50734 (2016)). For example, inactivation of human SETD2 has been reported in renal cell carcinoma (RCC) (Larkin, J. et al., Nature Reviews 9:147-155 (2012)). It has also been reported that SETD2 expression levels in breast cancer samples are significantly lower than in adjacent non-cancer tissue (ANCT) samples (Newbold, RF and Mokbel, K., Anticancer Research 30:3309-3311 (2010)). Furthermore, biallelic and loss-of-function point mutations in SETD2 have been reported in patients with acute leukemia (Zhu, X. et al., Nature Genetics 46:287-293 (2014)). Mutations in SETD2 have also been reported in pediatric high-grade gliomas. Fontebasso, AM et al., Acta Neuropathol. 125:659-669 (2013). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Li, J. et al., Oncotarget 7:50719-50734(2016) [Non-patent document 2] Edmunds, JWet al., The EMBO Journal 27:406-420(2008) [Non-patent document 3] Larkin, J., et al., Nature Reviews 9:147-155(2012) [Non-patent document 4] Newbold,RFand Mokbel,K.,Anticancer Research 30:3309-3311(2010) [Non-Patent Document 5] Zhu, X. et al., Nature Genetics 46:287-293(2014) [Non-patent document 6] Fontebasso, AM et al., Acta Neuropathol. 125:659-669 (2013). Summary of the Invention [Means for solving the problem]

[0005] The present disclosure relates to the surprising and unexpected discovery that inhibiting the human SETD2 protein can be used to treat cancer, despite its known functionality as a tumor suppressor. The present disclosure also provides novel substituted indoles. In some embodiments, the substituted indoles are inhibitors of SETD2. In some embodiments, the substituted indoles can be used in methods of treating a disease, e.g., cancer, a disorder, or a condition, in a subject. In some embodiments, the substituted indoles exhibit selective antiproliferative effects in t(4;14) multiple myeloma cell lines.

[0006] In one aspect, the present disclosure provides substituted indoles represented by any one of the following formulas I, II, II-A, III, III-A, IV, IV-A, IV-B, IV-C, IV-D, V, VA, VB, VI, VII, VII-A, VII-B, VII-C, VII-D, VII-E, VII-F, VII-G, VII-H, VIII, VIII-A, and VIII-B, and pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "compounds of the present disclosure."

[0007] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and one or more pharmaceutically acceptable carriers.

[0008] In another aspect, the present disclosure provides a method of inhibiting SETD2 protein in a subject, the method comprising administering to the mammal an effective amount of at least one compound of the present disclosure.

[0009] In another aspect, the disclosure provides a method of treating a disease, disorder, or condition, e.g., cancer, in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure.

[0010] In another aspect, the present disclosure provides a method for treating a disease, disorder, or condition, e.g., cancer, that is responsive to inhibition of SETD2 protein, comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure.

[0011] In another aspect, the present disclosure provides the use of a compound of the present disclosure as an inhibitor of SETD2 protein.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SETD2 protein, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure in admixture with one or more pharmaceutically acceptable carriers.

[0013] In another aspect, the present disclosure provides a method for treating cancer, e.g., multiple myeloma, in a subject in need thereof. Compounds of the present disclosure are provided for use in performing a method in a subject.

[0014] In another aspect, the disclosure provides a compound of the disclosure for use in the manufacture of a medicament for treating cancer in a mammal.

[0015] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure.

[0016] In another aspect, the present disclosure provides a method of treating a subject having multiple myeloma, the method comprising: (a) determining whether a chromosomal translocation is present or absent in a biological sample obtained from the subject; and (b) administering a therapeutically effective amount of a compound of the present disclosure to the subject if the chromosomal translocation is present in the biological sample.

[0017] Additional embodiments and advantages of the disclosure will be set forth in part in the description that follows, or will be obvious from the description, or may be learned by 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.

[0018] 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]

[0019] [Figure 1] FIG. 1 is a scatter plot showing the selective antiproliferative effect of Compound No. 15 in t(4;14) and non-t(4;14) multiple myeloma cell lines. [Figure 2]1 is a line graph showing that KMS-34, a t(4;14) multiple myeloma cell line, has a cytotoxic response to Compound No. 15 in a 14-day assay with a proliferation IC50 of 80 nM. The Y-axis is cell number at each time point on a log scale. Each line represents the indicated dose of Compound No. 15. [Figure 3] 1 is a line graph comparing the H3K36me3 inhibitory potency and antiproliferative potency of representative compounds of the present disclosure, with each point representing the trend of a compound of the present disclosure in the A549 H3K36me3 assay and the KMS-34 proliferation assay. [Figure 4] 1 is a line graph showing the antitumor activity of Compound No. 15 in a KMS11 xenograft model. [Figure 5] 1 is a line graph showing the antitumor activity of Compound No. 15 in the MM.1S xenograft model. DETAILED DESCRIPTION OF THE INVENTION

[0020] The compounds of the present disclosure are useful for treating a disease, disorder or condition, such as cancer, in a subject. In one embodiment, the disease, disorder or condition is responsive to SETD2 protein inhibition. In some embodiments, the compounds of the present disclosure are SETD2 inhibitors.

[0021] I. Compounds of the Present Disclosure In one embodiment, the compounds of the present disclosure have Formula I: [ka] (In the formula, R 1a is selected from the group consisting of halogen, alkyl, alkoxy, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl; Q 1 is -C(R 1b )= and -N=; Q 2 is -C(R 1c )= and -N=; Q 3is -C(R 1d )= and -N=; However, Q 1 , Q 2 or Q 3 At least one of each is -C(R 1b )=, -C(R 1c )= or -C(R 1d )=and; R 1b , R 1c and R 1d are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; R 1e is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl; [ka] is a single or double bond; G 1is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, optionally substituted cycloalkyl, (aryl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl, (amino)(aryl)alkyl, (heteroaryl)(aryl)alkyl, (heteroaryl)(heterocyclo)alkyl, (heteroaryl)(carboxamido)alkyl, (heteroaryl)(cycloalkyl)alkyl, (aryl)(alkoxycarbonyl)alkyl, (cycloalkyl)alkyl, (heteroaryl)(amino) is selected from the group consisting of (cycloalkyl)(alkoxycarbonyl)alkyl, (heteroaryl)(alkoxycarbonyl)alkyl, (heterocyclo)(cycloalkyl)alkyl, (aryl)(cycloalkyl)alkyl, (aryl)(hydroxy)alkyl, (cycloalkyl)(hydroxy)alkyl, (hydroxy)alkyl, optionally substituted alkyl, (aryl)(haloalkyl)alkyl, (cycloalkyl)(haloalkyl)alkyl, (hydroxy)(haloalkyl)alkyl and (alkoxycarbonyl)(haloalkyl)alkyl; and G 2 is selected from the group consisting of hydrogen and alkyl; or G 1 and G 2 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclo or a pharmaceutically acceptable salt or solvate thereof.

[0022] In another embodiment, the compound having formula I is [ka] N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-7-methyl-1H-indole-2-carboxamide; [ka] N-((1r,4r)-4-(3-aminopropanamido)cyclohexyl)-7-methyl-1H-indole-2-carboxamide; or [ka] N-((1r,4r)-4-aminocyclohexyl)-7-methyl-1H-indole-2-carboxamide isn't it.

[0023] In another embodiment, the compounds of the present disclosure are compounds having formula I (In the formula, R 1a is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, (hydroxy)C 1~6 Alkyl and (C3-C6 cycloalkyl)C 1~6 selected from the group consisting of alkyl; R 1b , R 1c and R 1d are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, (hydroxy)C1-C6 alkyl, and C1-C6 alkoxy; R 1e is selected from the group consisting of hydrogen and C1-C6 alkyl; G 1 is an optionally substituted C6-C 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclo, optionally substituted C3-C8 cycloalkyl, (C6-C 10 aryl)C1-C6 alkyl, (5-10 membered heteroaryl)C1-C6 alkyl, (3-10 membered heterocyclo)C1-C6 alkyl, (amino)(C6-C 10 aryl) C1-C6 alkyl, (5-14 membered heteroaryl) (C6-C 10aryl)C1-C6 alkyl, (5-10 membered heteroaryl)(3-10 membered heterocyclo)C1-C6 alkyl, (5-10 membered heteroaryl)(carboxamido)C1-C6 alkyl, (5-10 membered heteroaryl)(C3-C6 cycloalkyl)C1-C6 alkyl, (C6-C 10 aryl)(alkoxycarbonyl)C1-C6 alkyl, (C3-C6 cycloalkyl)C1-C6 alkyl, (5-10 membered heteroaryl)(amino)C1-C6 alkyl, (C3-C6 cycloalkyl)(alkoxycarbonyl)C1-C6 alkyl, (5-14 membered heteroaryl)(alkoxycarbonyl)C1-C6 alkyl, (3-14 membered heterocyclo)(C3-C8 cycloalkyl)C1-C6 alkyl, (C 6~10 aryl)(C3-C8 cycloalkyl)C1-C6 alkyl, (C6-C 10 aryl)(hydroxy)C1-C6 alkyl, (C3-C6 cycloalkyl)(hydroxy)C1-C6 alkyl, (hydroxy)C1-C6 alkyl, optionally substituted C1-C6 alkyl, (C6-C 10 aryl)(C1-C6 haloalkyl)C1-C6 alkyl, (C3-C6 cycloalkyl)(C1-C6 haloalkyl)C1-C6 alkyl, (hydroxy)(C1-C6 haloalkyl)C1-C6 alkyl; and (alkoxycarbonyl)(C1-C6 haloalkyl)C1-C6 alkyl; and G 2 is selected from the group consisting of hydrogen and C1-C6 alkyl; or G 1 and G 2 together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocycle or a pharmaceutically acceptable salt or solvate thereof.

[0024] In another embodiment, the compounds of the present disclosure are compounds having formula I (In the formula, R 1a is halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, (hydroxy)C 1~4Alkyl and (C3-C6 cycloalkyl)C 1~4 selected from the group consisting of alkyl; R 1b , R 1c and R 1d are each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C2-C4 alkenyl, (hydroxy)C1-C4 alkyl, and C1-C3 alkoxy; R 1e is selected from the group consisting of hydrogen and C1-C3 alkyl; G 1 is an optionally substituted C6-C 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclo, optionally substituted C3-C8 cycloalkyl, (C6-C 10 aryl)C1-C4 alkyl, (5-10 membered heteroaryl)C1-C6 alkyl, (3-10 membered heterocyclo)C1-C4 alkyl, (amino)(C6-C 10 aryl) C1-C6 alkyl, (5-14 membered heteroaryl) (C6-C 10 aryl)C1-C4 alkyl, (5-10 membered heteroaryl)(3-10 membered heterocyclo)C1-C4 alkyl, (5-10 membered heteroaryl)(carboxamido)C1-C4 alkyl, (5-10 membered heteroaryl)(C3-C6 cycloalkyl)C1-C4 alkyl, (C6-C 10 aryl)(alkoxycarbonyl)C1-C4 alkyl, (C3-C6 cycloalkyl)C1-C4 alkyl, (5-10 membered heteroaryl)(amino)C1-C4 alkyl, (C3-C6 cycloalkyl)(alkoxycarbonyl)C1-C4 alkyl, (5-14 membered heteroaryl)(alkoxycarbonyl)C1-C4 alkyl, (3-14 membered heterocyclo)(C3-C6 cycloalkyl)C1-C4 alkyl, (C 6~10 aryl)(C3-C6 cycloalkyl)C1-C4 alkyl, (C6-C 10aryl)(hydroxy)C1-C4 alkyl, (C3-C6 cycloalkyl)(hydroxy)C1-C4 alkyl, (hydroxy)C1-C4 alkyl, optionally substituted C1-C4 alkyl, (C6-C 10 aryl)(C1-C4 haloalkyl)C1-C4 alkyl, (C3-C6 cycloalkyl)(C1-C4 haloalkyl)C1-C4 alkyl, (hydroxy)(C1-C4 haloalkyl)C1-C4 alkyl, and (alkoxycarbonyl)(C1-C4 haloalkyl)C1-C4 alkyl; and G 2 is selected from the group consisting of hydrogen and C1-C4 alkyl; or G 1 and G 2 together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocycle or a pharmaceutically acceptable salt or solvate thereof.

[0025] In another embodiment, the compounds of the present disclosure are compounds having formula I, wherein: [ka] is a double bond) or a pharmaceutically acceptable salt or solvate thereof.

[0026] In another embodiment, the compounds of the present disclosure are compounds having formula I, where Q 1 and Q 2 is -C(H)=) or a pharmaceutically acceptable salt or solvate thereof.

[0027] In another embodiment, the compounds of the present disclosure are compounds having formula I, where Q 3 is -C(R 1d ) =; and R 1d is selected from the group consisting of hydrogen and halo) or a pharmaceutically acceptable salt or solvate thereof.

[0028] In another embodiment, the compounds of the present disclosure are compounds having formula I, where R 1e is hydrogen or a pharmaceutically acceptable salt or solvate thereof.

[0029] In another embodiment, the compounds of the present disclosure are compounds having formula I, where R 1a is C1-C3 alkyl) or a pharmaceutically acceptable salt or solvate thereof.

[0030] In another embodiment, the compounds of the present disclosure are compounds having formula I, wherein G 2 is hydrogen) or a pharmaceutically acceptable salt or solvate thereof.

[0031] In another embodiment, the compounds of the present disclosure have Formula II: [ka] (In the formula, R 1d and G 1 is as defined in relation to formula I) or a pharmaceutically acceptable salt or solvate thereof.

[0032] In another embodiment, the compounds of the present disclosure are compounds having formula I or II, where R 1d is selected from the group consisting of hydrogen and fluoro) or a pharmaceutically acceptable salt or solvate thereof.

[0033] In another embodiment, the compound of the present disclosure has formula II-A: [ka] (In the formula, G 1 is as defined in relation to formula II) or a pharmaceutically acceptable salt or solvate thereof.

[0034] In another embodiment, the compounds of the present disclosure are compounds having formula I, II, or II-A, where G1 is an optionally substituted C6-C 10 Aryl, optionally substituted 5- to 9-membered heteroaryl, optionally substituted 3- to 10-membered heterocyclo, optionally substituted C6-C8 cycloalkyl, (5- to 9-membered heteroaryl)C1-C6 alkyl, (5- to 9-membered heteroaryl)(C 6~10 (aryl)C1-C4 alkyl, (5- to 9-membered heteroarylheteroaryl)(C3-C6 cycloalkyl)C1-C4 alkyl, and (C3-C6 cycloalkyl)C1-C4 alkyl), or a pharmaceutically acceptable salt or solvate thereof.

[0035] In another embodiment, the compounds of the present disclosure have formula III: [ka] (In the formula, A 1 -N= and -C(R 2a )= selected from the group consisting of; R 2a is selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl; R 2b is optionally substituted alkyl, optionally substituted heterocyclo, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, (carboxamido)alkyl, -OR 10c , amino, (heterocyclo)alkyl, (amino)alkyl, (hydroxy)alkyl, carboxamido, (heteroaryl)alkyl, -S(=O)R 9b , -S(=O)2R 9b and -C(=O)R 9c selected from the group consisting of: A 2 -N= and -C(R 2c )= selected from the group consisting of; R 2c is selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl; R 2dis selected from the group consisting of hydrogen, alkyl, halogen, cyano, and haloalkyl; R 2e is selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl; R 9b is selected from the group consisting of amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl; R 9c is selected from the group consisting of amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl; and R 10c is selected from the group consisting of alkyl, (hydroxy)alkyl, and (amino)alkyl; and R 1d is as defined in relation to formula I) or a pharmaceutically acceptable salt or solvate thereof.

[0036] In another embodiment, the compounds of the present disclosure have formula III-A: [ka] (In the formula, R 1d , R 2a , R 2b , R 2c , R 2d and R 2e is as defined in relation to formula III) or a pharmaceutically acceptable salt or solvate thereof.

[0037] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A. (In the formula, R 2a is selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, and C1-C4 haloalkyl; R2b teeth, (A) Unsubstituted 4- to 10-membered heterocyclo; (B)(i)-N(R 3a )C(=O)R 4a ;(ii)-NR 5a R 5b (iii) unsubstituted 4- to 10-membered heterocyclo; (iv) hydroxy, -NR 5c R 5d , C1-C4 alkyl, C1-C6 alkoxy, -C(R 6a )(R 6b )C(=O)NR 5e R 5f , -C(=O)R 4b (v) unsubstituted C3-C6 cycloalkyl; (vi) (hydroxy)C1-C4 alkyl; (vii) C1-C6 alkyl; (viii) -C(=O)NR 5g R 5h ;(ix) halo;(x)-C(=O)R 4c (xi) C1-C6 haloalkyl; (xii) hydroxy; (xiii) (amino) C1-C4 alkyl; (xiv) (C1-C4 alkoxy) C1-C4 alkyl; (xv) -S(=O)2R 9a (xvi) (3-8 membered heterocyclo) C1-C4 alkyl; (xvii) C1-C6 alkoxy; (xviii) (C3-C6 cycloalkyl) C 1~4 Alkyl; (xix) (C 6~10 (aryl) C1-C4 alkyl; and (xxii) -OR 10b a substituted 4- to 10-membered heterocyclo having 1, 2, 3, or 4 substituents independently selected from the group consisting of: (C) unsubstituted C3-C8 cycloalkyl; (D) (i) unsubstituted 4- to 10-membered heterocyclo; (ii) substituted 4- to 10-membered heterocyclo having one or two substituents independently selected from the group consisting of amino and C1-C4 alkyl; (iii) unsubstituted 5- or 6-membered heteroaryl; (iv) substituted 5- or 6-membered heteroaryl having one, two, or three substituents independently selected from the group consisting of halo, C1-C4 alkyl, (3- to 8-membered heterocyclo)alkyl, hydroxy, and amino; (v) -NR 5i R 5j (vi) cyano; (vii) -N(R 3d )C(=O)R 4f (viii) hydroxy; and (ix) a substituted C3-C8 cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C4 alkyl; (E) unsubstituted 5-10 membered heteroaryl; (F) (i) halo; (ii) C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; C3-C6 cycloalkyl; (amino)C1-C4 alkyl; unsubstituted C3-C6 cycloalkyl; -NR 5g R 5h a substituted C3-C6 cycloalkyl having one, two, three, or four substituents independently selected from the group consisting of: an unsubstituted 4-14 membered heterocyclo; a substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; -NR 5q R 5r and (ix) a substituted 5-10 membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of (3-8 membered heterocyclo)C1-C4 alkyl; (G) Unsubstituted C6~C 10 aryl; (H) (i) halo; (ii) C1-C4 alkyl; (iii) -CH2N(H)S(=O)2R 8 (iv) (5-9 membered heteroaryl) C1-C4 alkyl; (v) -OR 10a ;(vi)-N(R 3b )C(=O)R 4b(vii) (amino) C1-C4 alkyl; and (viii) (hydroxy) C1-C4 alkyl, having 1, 2, 3, or 4 substituents independently selected from the group consisting of: 10 aryl; (I) (Carboxamido) C1-C4 alkyl; (J)-OR 10c ; (K)-NR 5o R 5p ; (L) (3-8 membered heterocyclo) C1-C4 alkyl; (M) (amino) C1-C4 alkyl; (N)(hydroxy)C1-C4 alkyl; (O)-C(=O)NR 5s R 5t ; (P) (5-9 membered heteroaryl) C1-C4 alkyl; and (Q)-S(=O)2R 9b selected from the group consisting of: R 2c is selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, and C1-C4 haloalkyl; R 2d is selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, cyano, and C1-C4 haloalkyl; R 2e is selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, and C1-C4 haloalkyl; R 3a , R 3b , R 3c and R 3d are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 4-14 membered heterocyclo; R 4a , R 4b , R 4c , R 4d , R 4e and R 4fis C1-C6 alkyl; C1-C6 haloalkyl; C3-C6 cycloalkyl; C1-C6 alkoxy; (C1-C4 alkoxy)C1-C4 alkyl; (C 6~10 (aryl)C1-C4 alkyl; (5-9 membered heteroaryl)C1-C4 alkyl; (amino)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; (cyano)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted C6-C 10 aryl; substituted C6-C aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo and C1-C4 alkyl; 10 aryl; unsubstituted 5- or 6-membered heteroaryl; and substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo and C1-C4 alkyl; R 5a and R 5b are independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; R 5c and R 5dare independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5c and R 5d taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5e and R 5f are independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5e and R 5f taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5g and R 5h is hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C Independently selected from the group consisting of 1-C4 alkyl; (5-9 membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5g and R 5h taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5i and R 5j are independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5i and R 5j taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5k and R 5lare independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5k and R 5l taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5m and R 5n are independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5m and R 5n taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5o and R 5pare independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; or R 5o and R 5p taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 5q and R 5r is hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C Independently selected from the group consisting of 1-C4 alkyl; (5-9 membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; R 5s and R 5tare independently selected from the group consisting of hydrogen; C1-C4 alkyl; C1-C4 haloalkyl; (hydroxy)C1-C4 alkyl; (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of halo and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; R 6a , R 6b , R 6c and R 6d are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R 8 is C1-C6 alkyl; R 9a is selected from the group consisting of C1-C6 alkyl; unsubstituted C3-C8 cycloalkyl; and substituted C3-C8 cycloalkyl having one or two substituents independently selected from the group consisting of halo, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; R 9b is selected from the group consisting of C1-C6 alkyl and amino; R 10a is selected from the group consisting of alkyl, (hydroxy)C1-C4 alkyl, and (amino)C1-C4 alkyl; R 10b is (amino)C1-C4 alkyl; and R 10c is (amino) C1-C4 alkyl) or a pharmaceutically acceptable salt or solvate thereof.

[0038] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is an optionally substituted 3- to 10-membered heterocycle linked to the remainder of the molecule through a nitrogen atom, e.g., R 2b teeth, [ka] etc.).

[0039] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A. (In the formula, R 2b teeth, [ka] selected from the group consisting of: R a1 is -N(R 3a )C(=O)R 4a ;-NR 5a R 5b ;Unsubstituted 4-10 membered heterocyclo;Hydroxy, -NR 5c R 5d , C1-C4 alkyl, C1-C6 alkoxy, -C(R 6a )(R 6b )C(=O)NR 5e R 5f , -C(=O)R 4b , (hydroxy) C1-C4 alkyl, and halo; a substituted 4- to 10-membered heterocyclo having a substituent selected from the group consisting of: R a2 and R a3 are each hydrogen; or R a2 and R a3 together with the carbon atom to which they are attached to form a C(=O) group; R a4 is selected from the group consisting of hydrogen, halo, and hydroxy; R a5 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R b1 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R c1is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c selected from the group consisting of: R c2 and R c3 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; or R c2 and R c3 together with the carbon atom to which they are attached to form a C(=O) group; R c4 is selected from the group consisting of hydrogen and C1-C4 alkyl; m is 1 or 2; R d1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c and R d2 and R d3 are each independently selected from the group consisting of hydrogen and fluoro; R e1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c selected from the group consisting of: R f1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c is selected from the group consisting of R g1 is hydrogen, C1-C4 alkyl, -C(=O)R 4c , C1-C4 haloalkyl, (C1-C4 alkoxy)C1-C4 alkyl; R h1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c selected from the group consisting of: R h2 is selected from the group consisting of hydrogen and C1-C4 alkyl; R h3 and R h4 are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; or R h3 and R h4together with the carbon atom to which they are attached to form a C(=O) group; R i1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (hydroxy)C1-C4 alkyl, -N(R 3a )C(=O)R 4a and (amino) C1-C4 alkyl; Z 1 is selected from the group consisting of -CH2- and -O-; R j1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c selected from the group consisting of: R k1 is C1-C4 alkyl, unsubstituted 4-14 membered heterocyclo and -NR 5a R 5b selected from the group consisting of: R k2 is selected from the group consisting of hydrogen, hydroxy, and C1-C4 alkyl; r is 0, 1 or 2; Z 2 is -O- and -N(R m3 )-selected from the group consisting of; R m3 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R n3 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R o1 is hydroxy, (hydroxy)C1-C4 alkyl, (amino)C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, C1-C4 alkoxy, -NR 5a R 5b , unsubstituted 4- to 14-membered heterocyclo, substituted 4- to 14-membered heterocyclo having 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy. 14-membered heterocyclo; R o2is selected from the group consisting of hydrogen, C1-C4 alkyl, and (C1-C4 alkoxy)C1-C4 alkyl; R o3 is selected from the group consisting of hydrogen, fluoro, and C1-C4 alkyl; R p1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: Z 3 is -O- and -N(R q1 )-selected from the group consisting of; R q1 is selected from the group consisting of hydrogen and C1-C4 alkyl; R r1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R s1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R t1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R u1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R v1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R w1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R x1 is hydrogen, C1-C4 alkyl and -C(=O)R 4c selected from the group consisting of: R y1 is selected from the group consisting of hydrogen and C1-C4 alkyl; and R z1 is selected from the group consisting of hydrogen and C1-C4 alkyl or a pharmaceutically acceptable salt or solvate thereof.

[0040] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b teeth, [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0041] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -1, R 2b -1A, R 2b -1B, R 2b -1C or R 2b -1D) or a pharmaceutically acceptable salt or solvate thereof. a1 is -N(R 3a )C(=O)R 4a In another embodiment, R a1 is -NR 5a R 5b In another embodiment, R a1 is -NR 5a R 5b and R 5a and R 5b are independently selected from the group consisting of hydrogen and C1-C4 alkyl. a1 is an optionally substituted 4-10 membered heterocyclo.

[0042] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -2, R 2b -2A or R 2b -2b) or a pharmaceutically acceptable salt or solvate thereof. b1 is C1-C4 alkyl.

[0043] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -3, R 2b -3A or R2b -3B) or a pharmaceutically acceptable salt or solvate thereof. c1 is C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c In another embodiment, R c2 and R c3 are each hydrogen. In another embodiment, R c2 and R c3 taken together with the carbon atom to which they are attached form a C(=O) group. In another embodiment, R c4 is hydrogen. In another embodiment, m is 1.

[0044] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -4) or a pharmaceutically acceptable salt or solvate thereof. d1 is C(=O)R 4c In another embodiment, R d2 and R d3 are each hydrogen or fluoro.

[0045] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -5, R 2b -5A or R 2b -5B) or a pharmaceutically acceptable salt or solvate thereof. e1 is -C(=O)R 4c is.

[0046] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -6, R 2b -6A or R 2b -6B) or a pharmaceutically acceptable salt or solvate thereof. f1 is C(=O)R 4cis.

[0047] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -7) or a pharmaceutically acceptable salt or solvate thereof. g1 is C(=O)R 4c is.

[0048] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -8, R 2b -8A, R 2b -8B, R 2b -8C or R 2b -8D) or a pharmaceutically acceptable salt or solvate thereof. h1 is -C(=O)R 4c In another embodiment, R h2 is selected from the group consisting of hydrogen and C1-C3 alkyl. h3 is hydrogen.

[0049] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -9) or a pharmaceutically acceptable salt or solvate thereof.

[0050] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -10, R 2b -10A, R 2b -10B, R 2b -10C and R 2b -10d) or a pharmaceutically acceptable salt or solvate thereof.

[0051] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R2b is R 2b -11, R 2b -11A and R 2b -11B) or a pharmaceutically acceptable salt or solvate thereof.

[0052] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -12) or a pharmaceutically acceptable salt or solvate thereof. j1 is -C(=O)R 4c is.

[0053] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -13, R 2b -13A, R 2b -13B, R 2b -13C, R 2b -13D, R 2b -13E and R 2b -13F) or a pharmaceutically acceptable salt or solvate thereof.

[0054] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -14) or a pharmaceutically acceptable salt or solvate thereof.

[0055] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -15) or a pharmaceutically acceptable salt or solvate thereof.

[0056] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -16, R 2b -16A and R 2b-16B) or a pharmaceutically acceptable salt or solvate thereof. n3 is -C(=O)R 4c is.

[0057] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -17) or a pharmaceutically acceptable salt or solvate thereof.

[0058] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A (formula Medium, R 2b is R 2b -18) or a pharmaceutically acceptable salt or solvate thereof.

[0059] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -19) or a pharmaceutically acceptable salt or solvate thereof.

[0060] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -20) or a pharmaceutically acceptable salt or solvate thereof.

[0061] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -21, R 2b -21A and R 2b -21B) or a pharmaceutically acceptable salt or solvate thereof.

[0062] In another embodiment, the compounds of the present disclosure are compounds having formula III, where R 2b is R 2b -22, R 2b -22A and R2b -22B) or a pharmaceutically acceptable salt or solvate thereof.

[0063] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -23) or a pharmaceutically acceptable salt or solvate thereof.

[0064] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -24) or a pharmaceutically acceptable salt or solvate thereof.

[0065] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -25) or a pharmaceutically acceptable salt or solvate thereof.

[0066] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -26, R 2b -26A and R 2b -26B) or a pharmaceutically acceptable salt or solvate thereof.

[0067] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -27, R 2b -27A and R 2b -27B) or a pharmaceutically acceptable salt or solvate thereof.

[0068] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -28, R 2b -28A and R2b -28B) or a pharmaceutically acceptable salt or solvate thereof.

[0069] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -29) or a pharmaceutically acceptable salt or solvate thereof.

[0070] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is R 2b -30, R 2b -30A or R 2b -30B) or a pharmaceutically acceptable salt or solvate thereof.

[0071] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2b is the R provided in relation to formula IV 11a groups, see below) or a pharmaceutically acceptable salt or solvate thereof.

[0072] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 4c is C1-C4 alkyl) or a pharmaceutically acceptable salt or solvate thereof.

[0073] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2d is selected from the group consisting of hydrogen, fluoro and chloro) or a pharmaceutically acceptable salt or solvate thereof.

[0074] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2d is hydrogen) or a pharmaceutically acceptable salt or solvate thereof.

[0075] In another embodiment, the compound of the present disclosure is a compound having Formula III in any of the embodiments described above, wherein A 1 and A 2 is -C(H)=;R 2e is hydrogen; and R 2d is selected from the group consisting of hydrogen and halogen) or a pharmaceutically acceptable salt or solvate thereof.

[0076] In another embodiment, the compounds of the present disclosure are compounds having formula III or formula III-A, where R 2d is fluoro) or a pharmaceutically acceptable salt or solvate thereof.

[0077] In another embodiment, the compounds of the present disclosure have formula IV: [ka] (In the formula, Z 4 -O-, -C(R 28a )(R 28b )- and -N(R 23 )-; or Z 4 is non-existence; Z 5 is selected from the group consisting of -CH2- and -CH2CH2-; R 11a is an optionally substituted alkyl, an optionally substituted heterocyclo, an optionally substituted heteroaryl, and —N(R 12b )C(=O)R 13c selected from the group consisting of: R 12b is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and heterocyclo; R 13cis selected from the group consisting of alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycle, amino, (amino)alkyl, (C3-C6 cycloalkyl)oxy, and (4-8 membered heterocyclo)oxy; R 23 is selected from the group consisting of hydrogen and C1-C4 alkyl; R 28a and R 28b are independently selected from the group consisting of hydrogen, alkyl, and halo; and R 1d is as defined in relation to formula I) or a pharmaceutically acceptable salt or solvate thereof.

[0078] In another embodiment, the compounds of the present disclosure are compounds having formula IV, wherein Z 4 is selected from the group consisting of —O— and —CH2—; or Z 4 is absent) or a pharmaceutically acceptable salt or solvate thereof.

[0079] In another embodiment, the compound of the present disclosure is a compound having formula IV (In the formula, Z 4 is selected from the group consisting of —O— and —CH2—; or Z 4 is non-existence; Z 5 is selected from the group consisting of -CH2- and -CH2CH2-; R 13c is selected from the group consisting of alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycle; and R 1d is as defined in relation to formula I) or a pharmaceutically acceptable salt or solvate thereof.

[0080] In another embodiment, the compounds of the present disclosure have formula IV-A: [ka] (In the formula, R 1d , R 11a and Z 4 is as defined in relation to formula IV) or a pharmaceutically acceptable salt or solvate thereof.

[0081] In another embodiment, the compounds of the present disclosure have formula IV-B: [ka] (In the formula, R 1d , R 11a and Z 4 is as defined in relation to formula IV) or a pharmaceutically acceptable salt or solvate thereof.

[0082] In another embodiment, the compounds of the present disclosure have formula IV-C: [ka] (In the formula, R 1d , R 11a and Z 4 is as defined in relation to formula IV) or a pharmaceutically acceptable salt or solvate thereof.

[0083] In another embodiment, the compounds of the present disclosure have formula IV-D: [ka] (In the formula, R 1d , R 11a and Z 4 is as defined in relation to formula IV) or a pharmaceutically acceptable salt or solvate thereof.

[0084] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D. (In the formula, R 11a (A) unsubstituted 4- to 14-membered heterocyclo; (B) —N(R 12a )C(=O)R 13a ;-C(=O)R 13b ;C1-C4 alkyl;(C1-C4 alkoxy)C1-C4 alkyl;(hydroxy)C1-C4 alkyl;C1-C4 haloalkyl;Amino;Hydroxy;-N(R 12a )S(=O)2R 24 ;-S(=O)2R 24 unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one, two, or three substituents independently selected from the group consisting of substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (C) unsubstituted 5-10 membered heteroaryl; (D) substituted 5- or 6-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of halo, C1-C4 alkyl, and (amino) alkyl; (E) C1-C6 alkyl; and (F) —N(R 12b )C(=O)R 13c selected from the group consisting of: R 12a and R 12b are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl; R 13a , R 13b and R 13cis C1-C6 alkyl; C1-C6 haloalkyl; unsubstituted C3-C6 cycloalkyl; C1-C6 alkoxy; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; (cyano) alkyl; unsubstituted C6-C 10 aryl; substituted C6-C aryl having one, two, three or four substituents independently selected from the group consisting of halo, amino, hydroxy and C1-C4 alkyl; 10 aryl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclo; substituted 4- to 14-membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; amino; (amino)alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclo)oxy; and R 24 is selected from the group consisting of C1-C4 alkyl and (hydroxy)C1-C4 alkyl is.

[0085] In another embodiment, the compounds of the present disclosure have formula IV, IV-A, IV-B, IV-C, or I A compound having VD (wherein Z 4 is -C(R 28a )(R 28b )- and R 28a and R 28b are independently selected from the group consisting of hydrogen, C1-C4 alkyl and fluoro) or a pharmaceutically acceptable salt or solvate thereof.

[0086] In another embodiment, the compounds of the present disclosure are compounds having formula IV, IV-A, IV-B, IV-C, or IV-D, where Z 4 is -C(R 28a )(R 28b )-and;R 28a is hydrogen; and R 28bis selected from the group consisting of C1-C4 alkyl and fluoro) or a pharmaceutically acceptable salt or solvate thereof.

[0087] In another embodiment, the compounds of the present disclosure are compounds having formula IV, IV-A, IV-B, IV-C, or IV-D, where Z 4 is -C(R 28a )(R 28b )- and R 28a and R 28b are independently C1-C4 alkyl) or a pharmaceutically acceptable salt or solvate thereof.

[0088] In another embodiment, the compounds of the present disclosure are compounds having formula IV, IV-A, IV-B, IV-C, or IV-D, where Z 4 is -O-, -CH2- and -N(R 23 ) or Z 4 is absent) or a pharmaceutically acceptable salt or solvate thereof.

[0089] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, wherein Z 4 is —CH—) or a pharmaceutically acceptable salt or solvate thereof.

[0090] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is an optionally substituted 3- to 10-membered heterocycle linked to the remainder of the molecule through a nitrogen atom, e.g., R 11a teeth, [ka] etc.).

[0091] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D. (In the formula, R 11a teeth, [ka] is a substituted 4- to 14-membered heterocyclo selected from the group consisting of: R 12a is selected from the group consisting of hydrogen, C1-C3 alkyl, (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl; R 13a is selected from the group consisting of C1-C4 alkyl; amino; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; R 13b is selected from the group consisting of C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4-8 membered heterocyclo)oxy; R 21 is hydrogen, -C(=O)R 13b , C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted 4-14 membered heterocyclo and -S(=O)2R 24 selected from the group consisting of: R 22is C1-C4 alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4-14 and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; R 24 is selected from the group consisting of C1-C4 alkyl and (hydroxy)C1-C4 alkyl; R 25 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 25b and R 25c are independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl; R 26 is selected from the group consisting of unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; and R 21a and R 25a together with the atom to which they are attached form an optionally substituted 4- to 8-membered heterocycle or a pharmaceutically acceptable salt or solvate thereof.

[0092] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D. (In the formula, R 11a teeth, [ka] [ka] is selected from the group consisting of R 27a and R 27bis hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, (C1 (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl; R 27c is hydrogen; -C(=O)R 13b C1-C4 alkyl; C1-C4 haloalkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; and -S(=O)2R 24 selected from the group consisting of: R 27d is selected from the group consisting of hydrogen; C1-C4 alkyl; and C1-C4 haloalkyl; R 13b is selected from the group consisting of C1-C4 alkyl; amino C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4-8 membered heterocyclo)oxy; and R 24 is selected from the group consisting of C1-C4 alkyl and (hydroxy)C1-C4 alkyl or a pharmaceutically acceptable salt or solvate thereof.

[0093] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a teeth, [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0094] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is an unsubstituted 4- to 14-membered heterocyclo; -N(R 12a )C(=O)R 13a , -C(=O)R 13b and C1-C4 alkyl; unsubstituted 5- to 10-membered heteroaryl; and substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C1-C4 alkyl), or a pharmaceutically acceptable salt or solvate thereof.

[0095] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a teeth, [ka] or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R 12a is selected from the group consisting of hydrogen and C1-C3 alkyl; R 13a is C1-C4 alkyl; and R 13b is C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof. 12a is selected from the group consisting of hydrogen and methyl; R 13a is methyl; and R 13b is methyl, or a pharmaceutically acceptable salt or solvate thereof.

[0096] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R provided in relation to formula III 2b groups, see above) or a pharmaceutically acceptable salt or solvate thereof.

[0097] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D. (In the formula, R 11a teeth, [ka] and R a1 , R a2 , R a3 , R a4 、 R a5 , R b1 , R c1 , R c2 , R c3 , R c4 , m, R d1 , R d2 , R d3 , R e1 , R f1 , R g1 , R h1 , R h2 , R h3 , R h4 , R i1 , Z 1 , R j1 , R k1 , R k2 , r, Z 2 , R n3 , R o1 , R o2 , R o3 , R p1 、 Z 3 、 R r1 、 R s1 , R t1 , R u1 , R v1 , Rw1 , R x1 , R y1 and R z1 is as defined in relation to formula III) or a pharmaceutically acceptable salt or solvate thereof.

[0098] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D. (In the formula, R 11a teeth, [ka] [ka] and R a1 , R a5 , R b1 , R e1 , R f1 , R h1 , R h2 , R h3 , R k1 , R n3 , R s1 , R t1 , R w1 , R x1 and R y1 is as defined in relation to formula III) or a pharmaceutically acceptable salt or solvate thereof.

[0099] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -1, R 11a -1A, R 11a -1B, R 11a -1C or R 11a -1D) or a pharmaceutically acceptable salt or solvate thereof. a1 is -N(R 3a )C(=O)R 4aIn another embodiment, R a1 is -NR 5a R 5b In another embodiment, R a1 is -NR 5a R 5b and R 5a and R 5b are independently selected from the group consisting of hydrogen and C1-C4 alkyl. a1 is an optionally substituted 4-10 membered heterocyclo.

[0100] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -2, R 11a -2A or R 11a -2b) or a pharmaceutically acceptable salt or solvate thereof. b1 is C1-C4 alkyl.

[0101] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -3, R 11a -3A or R 11a -3B) or a pharmaceutically acceptable salt or solvate thereof. c1 is C1-C4 alkyl, C3-C6 cycloalkyl and -C(=O)R 4c In another embodiment, R c2 and R c3 are each hydrogen. In another embodiment, R c2 and R c3 taken together with the carbon atom to which they are attached form a C(=O) group. In another embodiment, R c4 is hydrogen. In another embodiment, m is 1.

[0102] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -4) or a pharmaceutically acceptable salt or solvate thereof. d1 is C(=O)R 4c In another embodiment, R d2 and R d3 are each hydrogen or fluoro.

[0103] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D (R 11a is R 11a -5, R 11a -5A or R 11a -5B) or a pharmaceutically acceptable salt or solvate thereof. e1 is -C(=O)R 4c is.

[0104] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -6, R 11a -6A or R 11a -6B) or a pharmaceutically acceptable salt or solvate thereof. f1 is C(=O)R 4c is.

[0105] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -7) or a pharmaceutically acceptable salt or solvate thereof. g1 is C(=O)R 4c is.

[0106] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -8, R 11a -8A, R 11a -8B, R 11a -8C or R 11a -8D) or a pharmaceutically acceptable salt or solvate thereof. h1 is -C(=O)R 4c In another embodiment, R h2 is selected from the group consisting of hydrogen and C1-C3 alkyl. h3 is hydrogen.

[0107] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -9) or a pharmaceutically acceptable salt or solvate thereof.

[0108] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -10, R 11a -10A, R 11a -10B, R 11a -10C and R 11a -10d) or a pharmaceutically acceptable salt or solvate thereof.

[0109] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -11, R 11a -11A and R 11a -11B) or a pharmaceutically acceptable salt or solvate thereof.

[0110] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -12) or a pharmaceutically acceptable salt or solvate thereof. j1 is -C(=O)R 4c is.

[0111] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -13, R 11a -13A, R 11a -13B, R 11a -13C, R 11a -13D, R 11a -13E and BiR 11a -13F) or a pharmaceutically acceptable salt or solvate thereof.

[0112] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -14) or a pharmaceutically acceptable salt or solvate thereof.

[0113] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -15) or a pharmaceutically acceptable salt or solvate thereof.

[0114] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -16, R 11a -16A and R 11a-16B) or a pharmaceutically acceptable salt or solvate thereof. n3 is -C(=O)R 4c is.

[0115] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -17) or a pharmaceutically acceptable salt or solvate thereof.

[0116] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -18) or a pharmaceutically acceptable salt or solvate thereof.

[0117] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -19) or a pharmaceutically acceptable salt or solvate thereof.

[0118] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -20) or a pharmaceutically acceptable salt or solvate thereof.

[0119] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -21, R 11a -21A and R 11a -21B) or a pharmaceutically acceptable salt or solvate thereof.

[0120] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D (R 11a is R 11a -22, R 11a -22A and R 11a -22B) or a pharmaceutically acceptable salt or solvate thereof.

[0121] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -23) or a pharmaceutically acceptable salt or solvate thereof.

[0122] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -24) or a pharmaceutically acceptable salt or solvate thereof.

[0123] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -25) or a pharmaceutically acceptable salt or solvate thereof.

[0124] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -26, R 11a -26A and R 11a -26B) or a pharmaceutically acceptable salt or solvate thereof.

[0125] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -27, R11a -27A and R 11a -27B) or a pharmaceutically acceptable salt or solvate thereof.

[0126] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -28, R 11a -28A and R 11a -28B) or a pharmaceutically acceptable salt or solvate thereof.

[0127] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -29) or a pharmaceutically acceptable salt or solvate thereof.

[0128] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas IV, IV-A, IV-B, IV-C, or IV-D, where R 11a is R 11a -30, R 11a -30A or R 11a -30B) or a pharmaceutically acceptable salt or solvate thereof.

[0129] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV-A, IV-B, IV-C, or IV-D. (In the formula, Z 4 is -CH2-; R 11a teeth, [ka] is selected from the group consisting of R 12a is selected from the group consisting of hydrogen and C1-C3 alkyl; R 21 is -C(=O)R13b and; R 27c is -C(=O)R 13b and; R 13b is selected from the group consisting of C1-C4 alkyl and (hydroxy)C1-C4 alkyl; R 24 is C1-C4 alkyl; R 25 is selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; and R 25b and R 25c are independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl or a pharmaceutically acceptable salt or solvate thereof.

[0130] In another embodiment, the compound of the present disclosure is a compound having any one of formulas IV-A, IV-B, IV-C, or IV-D. (In the formula, Z 4 is -CH2-; R 11a teeth, [ka] selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0131] In another embodiment, the compounds of the present disclosure have formula V: [ka] (In the formula, R 14a is selected from the group consisting of optionally substituted alkyl and optionally substituted heteroaryl; R 14bis selected from the group consisting of optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted cycloalkyl, and carboxamido; and p is 0, 1, 2 or 3 or a pharmaceutically acceptable salt or solvate thereof.

[0132] In another embodiment, the compounds of the present disclosure have the formula VA: [ka] (In the formula, R 1d , R 14a , R 14d and p is as defined in relation to formula V). or a pharmaceutically acceptable salt or solvate thereof.

[0133] In another embodiment, the compounds of the present disclosure have formula VB: [ka] (In the formula, R 1d , R 14a , R 14d and p is as defined in relation to formula V). or a pharmaceutically acceptable salt or solvate thereof.

[0134] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas V, VA, or VB (In the formula, R 14a (A) unsubstituted 5-10 membered heteroaryl; (B) (i) halo; (ii) C1-C4 alkyl; (iii) C1-C4 alkoxy; (iv) (3-8 membered heterocyclo)C1-C4 alkyl; (v) (5-9 membered heteroaryl)C1-C4 alkyl; (vi) -C(=O)NR 15a R 15b(vii) unsubstituted 5-10 membered heteroaryl; (viii) halo, C1-C4 alkyl, (3-8 membered heterocyclo)C1-C4 alkyl, 5-9 membered heteroaryl and -NR 15e R 15f (ix) a substituted 5- or 10-membered heteroaryl having one, two, or three substituents independently selected from the group consisting of: 16 (x) unsubstituted C3-C6 cycloalkyl; (xi) C1-C4 alkyl and -N(R 17a )C(=O)R 18a (xii) cyano; (xiii) unsubstituted 4-14 membered heterocyclo; (xiv) substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of C1-C4 alkyl, (5-9 membered heteroaryl)C1-C4 alkyl; (xv) (carboxy)C1-C4 alkyl; (xvi) (carboxamido)C1-C4 alkyl; and (xvii) substituted 5- or 10-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of carboxy; and (C) C1-C6 alkyl; R 14b (A) unsubstituted 5- to 10-membered heteroaryl; (B) substituted 5- or 10-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, and (C3-C6 cycloalkyl)C1-C4 alkyl; (C) unsubstituted C6-C 10 aryl; (D) a substituted C6-C alkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, and (3- to 8-membered heterocyclo)C1-C4 alkyl; 10 Aryl; (E) unsubstituted 4- to 14-membered heterocyclo; (F) substituted 4- to 14-membered heterocyclo having 1, 2, 3, or 4 substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; (G) -C(=O)N R 15c R 15d (H) unsubstituted C3-C6 cycloalkyl; and (I) C1-C6 alkyl; p is 0, 1, 2 or 3; R 15a and R 15b (A) hydrogen; (B) C1-C6 alkyl; (C) C1-C6 haloalkyl; (D) (C1-C4 alkoxy)C1-C4 alkyl; (E) (hydroxy)C1-C4 alkyl; (F) (cyano) alkyl; (G) unsubstituted C6-C 10 aryl; (H) substituted C6-C aryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; 10 Aryl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; (K) unsubstituted 4- to 14-membered heterocyclo; (L) substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (M) unsubstituted C3-C8 cycloalkyl; and (N) C1-C6 alkyl and -NR 15g R 15h or R 15a and R 15b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 15c and R 15d (A) hydrogen; (B) C1-C6 alkyl; (C) C1-C6 haloalkyl; (D) (C1-C4 alkoxy)C1-C4 alkyl; (E) (hydroxy)C1-C4 alkyl; (F) (cyano) alkyl; (G) unsubstituted C6-C 10 aryl; (H) substituted C6-C aryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; 10Aryl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; (K) unsubstituted 4- to 14-membered heterocyclo; (L) substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (M) unsubstituted C3-C8 cycloalkyl; and (N) C1-C6 alkyl and -NR 15g R 15h or R 15c and R 15d taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 15e and R 15f (A) hydrogen; (B) C1-C6 alkyl; (C) C1-C6 haloalkyl; (D) (C1-C4 alkoxy)C1-C4 alkyl; (E) (hydroxy)C1-C4 alkyl; (F) (cyano) alkyl; (G) unsubstituted C6-C 10 aryl; (H) substituted C6-C aryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; 10 Aryl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; (K) unsubstituted 4- to 14-membered heterocyclo; (L) substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (M) unsubstituted C3-C8 cycloalkyl; and (N) C1-C6 alkyl and -NR 15g R 15h or R15e and R 15f taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 15g and R 15h (A) hydrogen; (B) C1-C6 alkyl; (C) C1-C6 haloalkyl; (D) C1-C6 alkoxy; (E) (C1-C4 alkoxy) C1-C4 Alkyl; (F) (Hydroxy) C1-C4 alkyl; (G) (Cyano) alkyl; (H) Unsubstituted C6-C 10 Aryl; (I) a substituted C6-C aryl having one, two, three or four substituents independently selected from the group consisting of halo, amino, hydroxy and C1-C4 alkyl. 10 Aryl; (J) unsubstituted 5- or 6-membered heteroaryl; (K) substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; (L) unsubstituted 4- to 14-membered heterocyclo; (M) substituted 4- to 14-membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (N) unsubstituted C3-C8 cycloalkyl; and (O) C1-C6 alkyl and -NR 15g R 15h or R 15g and R 15g taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 16 is (amino)(hydroxy)C1-C4 alkyl; R 17a is selected from the group consisting of hydrogen and C1-C4 alkyl; R 18a(A) C1-C6 alkyl; (B) C1-C6 haloalkyl; (C) C1-C6 alkoxy; (D) (C1-C4 alkoxy)C1-C4 alkyl; (E) (hydroxy)C1-C4 alkyl; (F) (cyano) alkyl; (G) unsubstituted C6-C 10 aryl; (H) substituted C6-C aryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; 10 (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, amino, hydroxy, and C1-C4 alkyl; (K) unsubstituted 4-14-membered heterocyclo; (L) substituted 4-14-membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (M) unsubstituted C3-C8 cycloalkyl; and (N) substituted C3-C8 cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl. or a pharmaceutically acceptable salt or solvate thereof.

[0135] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas V, VA, or VB, where R 14a represents unsubstituted 5- to 10-membered heteroaryl; and C1-C4 alkyl; C1-C4 alkoxy; (3- to 8-membered heterocyclo)C1-C4 alkyl; (5- to 9-membered heteroaryl)C1-C4 alkyl; -C(=O)NR 15a R 15b a substituted 5- or 10-membered heteroaryl having one, two, or three substituents independently selected from the group consisting of: unsubstituted 5- to 10-membered heteroaryl; halo, C1-C4 alkyl, (3- to 8-membered heterocyclo)C1-C4 alkyl, 5- to 9-membered heteroaryl, and -NR 15e R 15f substituted 5- or 10-membered heteroaryl having one, two, or three substituents independently selected from the group consisting of: unsubstituted C3-C6 cycloalkyl; and C1-C4 alkyl and -N(R 17a)C(=O)R 18a or a pharmaceutically acceptable salt or solvate thereof.

[0136] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas V, VA, or VB, where R 14a is C1-C4 alkyl; C1-C4 alkoxy; (3-8 membered heterocyclo)C1-C4 alkyl; (5-9 membered heteroaryl)C1-C4 alkyl; -C(=O)NR 15a R 15b substituted pyridyl having one, two, or three substituents independently selected from the group consisting of: unsubstituted 5-10 membered heteroaryl; halo, C1-C4 alkyl, (3-8 membered heterocyclo)C1-C4 alkyl, 5-9 membered heteroaryl, and -NR 15e R 15f having one, two or three substituents independently selected from the group consisting of Substituted 5-10 membered heteroaryl; unsubstituted C3-C6 cycloalkyl; and C1-C4 alkyl and -N(R 17a )C(=O)R 18a or a pharmaceutically acceptable salt or solvate thereof.

[0137] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas V, VA, or VB, where R 14b is an unsubstituted 5- to 10-membered heteroaryl; a substituted 5- to 10-membered heteroaryl having one or two substituents independently selected from the group consisting of C1-C4 alkyl and (C3-C6 cycloalkyl)C1-C4 alkyl; an unsubstituted C6-C 10 aryl; substituted C6-C having one or two substituents independently selected from the group consisting of C1-C4 alkyl and (3- to 8-membered heterocyclo)C1-C4 alkyl; 10aryl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino, and C1-C4 alkyl; and unsubstituted C3-C6 cycloalkyl), or a pharmaceutically acceptable salt or solvate thereof.

[0138] In another embodiment, the compounds of the present disclosure are compounds having any one of formulas V, VA, or VB, where R 14b is selected from the group consisting of unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of C1-C4 alkyl and (C3-C6 cycloalkyl)C1-C4 alkyl; unsubstituted phenyl; substituted phenyl having one or two substituents independently selected from the group consisting of C1-C4 alkyl and (3-8 membered heterocyclo)C1-C4 alkyl; and unsubstituted C3-C6 cycloalkyl), or a pharmaceutically acceptable salt or solvate thereof.

[0139] In another embodiment, the compound of the present disclosure is a compound having any one of formulas V, VA, or VB, wherein p is 0, or a pharmaceutically acceptable salt or solvate thereof.

[0140] In another embodiment, the compound of the present disclosure is a compound having any one of formulas V, VA, or VB, wherein p is 1, or a pharmaceutically acceptable salt or solvate thereof.

[0141] In another embodiment, the compound of the present disclosure has formula VI: [ka] (In the formula, R 19 is selected from the group consisting of unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; R 20is selected from the group consisting of hydrogen, halo, and C1-C4 alkyl; and q is 1, 2 or 3 or a pharmaceutically acceptable salt or solvate thereof.

[0142] In another embodiment, the compound of the present disclosure is a compound having formula VI, wherein q is 1.

[0143] In another embodiment, the compounds of the present disclosure have formula VII: [ka] (In the formula, R 11b is selected from the group consisting of C1-C4 alkyl, halo, and C1-C4 haloalkyl; and R 1d and R 11a is as defined in relation to formula IV) or a pharmaceutically acceptable salt or solvate thereof.

[0144] In another embodiment, the compound of the present disclosure has formula VII-A: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0145] In another embodiment, the compound of the present disclosure has formula VII-B: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0146] In another embodiment, the compound of the present disclosure has formula VII-C: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0147] In another embodiment, the compound of the present disclosure has formula VII-D: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0148] In another embodiment, the compound of the present disclosure has formula VII-E: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0149] In another embodiment, the compound of the present disclosure has formula VII-F: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0150] In another embodiment, the compound of the present disclosure has formula VII-G: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0151] In another embodiment, the compound of the present disclosure has formula VII-H: [ka] (In the formula, R 1d , R 11a and R 11b is as defined in relation to formula VII) or a pharmaceutically acceptable salt or solvate thereof.

[0152] In another embodiment, the compounds of the present disclosure have formula VIII: [ka] (In the formula, R 30 is hydrogen; C1-C6 alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; -C(=O)R 13b and -S(=O)2R 24 selected from the group consisting of: R 13bis selected from the group consisting of C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4-8 membered heterocyclo)oxy; R 24 is selected from the group consisting of C1-C4 alkyl and (hydroxy)C1-C4 alkyl; u is 0, 1, 2 or 3; and R 1d is as defined in relation to formula I) or a pharmaceutically acceptable salt or solvate thereof.

[0153] In another embodiment, the compounds of the present disclosure have formula VIII-A: [ka] (In the formula, R 1d , R 30 and u is as defined in relation to formula VIII. or a pharmaceutically acceptable salt or solvate thereof.

[0154] In another embodiment, the compound of the present disclosure has formula VIII-B: [ka] (In the formula, R 1d , R 30 and u is as defined in relation to formula VIII. or a pharmaceutically acceptable salt or solvate thereof.

[0155] In another embodiment, the compounds of the present disclosure are compounds of Table 1 and pharmaceutically acceptable salts or solvates thereof. Mass spectrometry and representative biological data for the compounds of the present disclosure are provided in Table 1B. The "SMYD2" and "SYMD3" assays in Table 1B are described in WO 2016 / 040515.

[0156] In another embodiment, the compound of the present disclosure is selected from the group consisting of compound numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 824, 828, 839, 870, 922, 930, 942, 995, 1007, 1025, 1043, 1044, 1045, 1048, 1051, 1055, 1070, 1078, 1083, 1097, 1117, 1138, 1180, 1184, and 1192, and pharmaceutically acceptable salts or solvates thereof. In another embodiment, the compound of the present disclosure is selected from the group consisting of compound numbers 15, 922, 930, 942, 1055, 1070, 1117, 1180, 1184, and 1192, and pharmaceutically acceptable salts or solvates thereof.

[0157] [Table 1]

[0158] [Table 2]

[0159] [Table 3]

[0160] [Table 4]

[0161] [Table 5]

[0162]

Table 6

[0163]

Table 7

[0164]

Table 8

[0165]

Table 9

[0166]

Table 10

[0167]

Table 11

[0168]

Table 12

[0169]

Table 13

[0170]

Table 14

[0171]

Table 15

[0172] Table 16

[0173]

Table 17

[0174]

Table 18

[0175]

Table 19

[0176] Table 20

[0177] Table 21

[0178] Table 22

[0179] Table 23

[0180] Table 24

[0181] Table 25

[0182] Table 26

[0183] Table 27

[0184] Table 28

[0185] Table 29

[0186]

Table 30

[0187] Table 31

[0188] Table 32

[0189] Table 33

[0190] Table 34

[0191] Table 35

[0192] Table 36

[0193] Table 37

[0194] Table 38

[0195] Table 39

[0196] Table 40

[0197] Table 41

[0198] Table 42

[0199] Table 43

[0200] Table 44

[0201] Table 45

[0202] Table 46

[0203] Table 47

[0204] Table 48

[0205] Table 49

[0206] Table 50

[0207] Table 51

[0208] Table 52

[0209] Table 53

[0210] Table 54

[0211] Table 55

[0212] Table 56

[0213] Table 57

[0214] Table 58

[0215] Table 59

[0216] Table 60

[0217] Table 61

[0218] Table 62

[0219] Table 63

[0220] Table 64

[0221] Table 65

[0222] Table 66

[0223] Table 67

[0224] Table 68

[0225] Table 69

[0226] Table 70

[0227] Table 71

[0228] Table 72

[0229] Table 73

[0230] Table 74

[0231] Table 75

[0232] Table 76

[0233] Table 77

[0234] Table 78

[0235] Table 79

[0236] Table 80

[0237] Table 81

[0238] Table 82

[0239] Table 83

[0240] Table 84

[0241] Table 85

[0242] Table 86

[0243] Table 87

[0244] Table 88

[0245] Table 89

[0246] Table 90

[0247]

Table 91

[0248] Table 92

[0249]

Table 93

[0250] Table 94

[0251]

Table 95

[0252] Table 96

[0253] Table 97

[0254] Table 98

[0255]

Table 99

[0256]

Table 100

[0257] Table 101

[0258] Table 102

[0259] Table 103

[0260] Table 104

[0261] Table 105

[0262] Table 106

[0263] Table 107

[0264] Table 108

[0265] Table 109

[0266] Table 110

[0267] Table 111

[0268] Table 112

[0269] Table 113

[0270] Table 114

[0271] Table 115

[0272] Table 116

[0273] Table 117

[0274] Table 118

[0275] Table 119

[0276] Table 120

[0277] Table 121

[0278] Table 122

[0279] Table 123

[0280] Table 124

[0281] Table 125

[0282] Table 126

[0283] Table 127

[0284] Table 128

[0285] The present disclosure encompasses the preparation and use of salts of the disclosed compounds, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and base salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, and the like; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; and amino acid salts such as alginate, aspartate, glutamate, and the like. The term "pharmaceutically acceptable salt," as used herein, refers to any salt obtained, for example, by reaction of a compound of the present disclosure with an acid or base that is physiologically acceptable in a target subject (e.g., a mammal, e.g., a human).

[0286] Acid addition salts can be formed by mixing a solution of a particular compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc. Base salts can be formed by mixing a solution of a compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.

[0287] 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. The term "solvate," as used herein, refers to a combination, physical association, and / or solvation of a compound of the present disclosure with solvent molecules, e.g., a disolvate, a monosolvate, or a hemisolvate, wherein the ratio of solvent molecules to the compound of the present disclosure 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, the 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 disclosed compounds may be presented in solvated forms with pharmaceutically acceptable solvents, such as water, methanol, ethanol, etc., and the present disclosure is intended to encompass both solvated and unsolvated forms of the disclosed compounds. 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. Similar preparations of solvates, hemisolvates, hydrates, etc. are described by EC van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004) and A.L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting process for preparing solvates 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, which are isolated by known methods, such as filtration. Analytical techniques, such as infrared spectroscopy, can be used to confirm the presence of solvent in the solvate crystals.

[0288] II. Treatment method The present disclosure generally relates to methods of treating a disease, condition, or disorder in a subject suffering from or at risk of suffering from the disease, condition, or disorder, comprising administering to the subject an effective amount of a compound of the present disclosure. In one embodiment, the disease, condition, or disorder is responsive to or mediated by inhibition of SETD2 protein.

[0289] The present disclosure also relates to a method of inhibiting SETD2 protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0290] In one aspect, the disclosure provides a method of treating a disease, disorder, or condition in a subject, comprising administering a therapeutically effective amount of a compound of the disclosure.

[0291] In another aspect, the present disclosure provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure. While not limited to a particular mechanism, in some embodiments, the compounds of the present disclosure inhibit SETD2 protein by inhibiting the SETD2 protein. Examples of treatable cancers include, but are not limited to, those listed in Table 2.

[0292] [Table 129]

[0293] [Table 130]

[0294] [Table 131]

[0295] In another embodiment, the cancer is pancreatic cancer or esophageal cancer.

[0296] In another embodiment, the cancer is selected from the group consisting of esophageal cancer, renal cancer, gastric cancer, hepatocellular carcinoma, glioblastoma, central nervous system (CNS) cancer, soft tissue cancer, lung cancer, breast cancer, bladder / urinary tract cancer, head and neck cancer, prostate cancer, blood cancer, pancreatic cancer, skin cancer, endometrial cancer, ovarian cancer, and colorectal cancer.

[0297] In another embodiment, the cancer or cancer cells are hematological cancers. Exemplary hematological cancers include, but are not limited to, those listed in Table 3.

[0298] [Table 132]

[0299] In another embodiment, the cancer is multiple myeloma.

[0300] In another embodiment, the multiple myeloma is characterized as having a chromosomal translocation involving the immunoglobulin heavy chain locus at 14q32, hi another embodiment, the chromosomal translocation is a t(4;14) translocation, i.e., the multiple myeloma is a t(4;14) multiple myeloma.

[0301] In another embodiment, the present disclosure provides a method of treatment for modulating protein methylation, gene expression, cell proliferation, cell differentiation, and / or apoptosis in vivo in the above cancers by administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment.

[0302] The present disclosure provides the following specific embodiments. Embodiment I. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the subject has cancer. Embodiment II. The method of embodiment I, wherein the cancer is any one or more of the cancers in Table 2. Embodiment III. The method of embodiment I, wherein the cancer is a hematological cancer. Embodiment IV. The method of embodiment III, wherein the hematological cancer is any one or more of the cancers in Table 3, e.g., multiple myeloma. Embodiment V. The method of embodiment IV, wherein the hematological cancer is t(4;14) multiple myeloma. Embodiment VI. The method of any one of embodiments I-V, further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of cancer. Embodiment VII. A pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier for use in treating cancer. Embodiment VIII. The pharmaceutical composition of embodiment VII, wherein the cancer is any one or more of the cancers in Table 2. Embodiment IX. The pharmaceutical composition of embodiment VII, wherein the cancer is a hematological cancer. Embodiment X. The pharmaceutical composition of embodiment IX, wherein the hematological cancer is any one or more of the cancers in Table 3, e.g., multiple myeloma. Embodiment XI. The pharmaceutical composition of embodiment X, wherein the hematological cancer is t(4;14) multiple myeloma. Embodiment XII. A compound of the present disclosure for use in the treatment of cancer. Embodiment XIII. The compound for use according to embodiment XII, wherein the cancer is any one or more of the cancers in Table 2. Embodiment XIV. The compound for use according to embodiment XII, wherein the cancer is a hematological cancer. Embodiment XV. The compound for use according to embodiment XIV, wherein the hematological cancer is any one or more of the cancers in Table 3, for example multiple myeloma. Embodiment XVI. The compound for use according to embodiment XV, wherein the hematological cancer is t(4;14) multiple myeloma. Embodiment XVII. Use of a compound of the present disclosure for the manufacture of a medicament for the treatment of cancer. Embodiment XVIII. The use of embodiment XVII, wherein the cancer is any one or more of the cancers in Table 2. Embodiment XVIII. The use of embodiment XVII, wherein the cancer is a hematological cancer. Embodiment XIX. The use of embodiment XVII, wherein the hematological cancer is any one or more of the cancers in Table 3, e.g., multiple myeloma. Embodiment XX. The use of embodiment XIX, wherein the hematological cancer is t(4;14) multiple myeloma. Embodiment XXI. The use of any one of embodiments XVII-XX to include one or more additional therapeutic agents. Embodiment XXII. A kit comprising a compound of the present disclosure and instructions for administering the compound of the present disclosure to a subject with cancer. Embodiment XXIII. The kit of embodiment XXII, wherein the cancer is any one or more of the cancers in Table 2. Embodiment XXIV. The kit of embodiment XXII, wherein the cancer is a hematological cancer. Embodiment XXV. The kit of embodiment XXIV, wherein the hematological cancer is any one or more of the cancers in Table 3, e.g., multiple myeloma. Embodiment XXVI. The kit of embodiment XXV, wherein the hematological cancer is t(4;14) multiple myeloma. Embodiment XXVII. The kit of any one of Embodiments XXII-XXVI, further comprising one or more additional therapeutic agents.

[0303] The compounds of the present disclosure can be administered to a subject in the form of raw chemicals, without the presence of any other components. The compounds of the present disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound, combined with a suitable pharmaceutically acceptable carrier. Such a carrier can be selected from pharmaceutically acceptable additives and auxiliaries. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any standard pharmaceutical carrier, solvent, surfactant, or vehicle. Suitable pharmaceutically acceptable vehicles include aqueous and non-aqueous vehicles. Standard pharmaceutical carriers and their formulations can be found in Remington's Pharmaceutical Sciences, Mac K Publishing Co., Easton, PA, 19th ed. 1995.

[0304] Pharmaceutical compositions within the scope of the present disclosure include all compositions in which a compound of the present disclosure is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compound of the present disclosure is present in the composition in an amount effective to achieve its intended therapeutic purpose. While individual needs may vary, determining the optimal range of effective amounts of each compound is within the skill of the art. Typically, compounds of the present disclosure can be orally administered to a mammal, e.g., a human, at a daily dose of about 0.0025 to about 1500 mg per kg of mammalian body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, to treat a particular disorder. A useful oral dose of a compound of the present disclosure administered to a mammal is about 0.0025 to about 50 mg per kg of mammalian body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about half the oral dose.

[0305] A unit oral dose may contain about 0.01 mg to about 1 g of a compound of the present disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, or 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg of compound. The unit dose may be administered one or more times daily, e.g., as one or more tablets or capsules, each containing about 0.01 mg to about 1 g of compound or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0306] The compounds of the present disclosure or pharmaceutical compositions comprising the compounds of the present disclosure can be administered to any subject who may experience the beneficial effects of the compounds of the present disclosure, such as a cancer patient in need thereof. Foremost among such subjects are mammals, such as humans and companion animals, although the present disclosure is not intended to be so limited. In one embodiment, the subject is a human.

[0307] The pharmaceutical compositions of the present disclosure can be administered by any means that achieves their intended purpose. For example, administration can be oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, vaginal, or buccal routes, or by inhalation. The dosage administered and the route of administration will vary depending on the circumstances of the particular subject and will take into consideration factors such as the recipient's age, sex, health, and weight, the condition or disorder being treated, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect.

[0308] In one embodiment, the pharmaceutical compositions of the present disclosure can be administered orally. In another embodiment, the pharmaceutical compositions of the present disclosure can be administered orally and are formulated into tablets, dragees, capsules, or oral liquid preparations. In one embodiment, the oral formulation comprises extruded multiparticulates comprising a compound of the present disclosure.

[0309] Alternatively, the pharmaceutical compositions of the present disclosure can be administered rectally and are formulated as suppositories.

[0310] Alternatively, the pharmaceutical compositions of the present disclosure can be administered by injection.

[0311] Alternatively, the pharmaceutical compositions of the present disclosure can be administered transdermally.

[0312] Alternatively, the pharmaceutical compositions of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.

[0313] Alternatively, the pharmaceutical compositions of the present disclosure can be administered by the vaginal route.

[0314] Pharmaceutical compositions of the present disclosure can contain about 0.01 to 99 weight percent, e.g., about 0.25 to 75 weight percent, of a compound of the present disclosure, such as about 1 weight percent, about 5 weight percent, about 10 weight percent, about 15 weight percent, about 20 weight percent, about 25 weight percent, about 30 weight percent, about 35 weight percent, about 40 weight percent, about 45 weight percent, about 50 weight percent, about 55 weight percent, about 60 weight percent, about 65 weight percent, about 70 weight percent, or about 75 weight percent of a compound of the present disclosure.

[0315] The pharmaceutical compositions of the present disclosure are manufactured in a manner known per se in light of the present disclosure, for example, using conventional mixing, granulating, dragee-making, dissolving, extruding or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compound with a solid additive, optionally milling the mixture thus obtained, adding suitable auxiliaries as required or needed, and then processing the mixture of granules to obtain tablets or dragee cores.

[0316] Suitable additives include fillers such as sugars (e.g., lactose, sucrose, mannitol, or sorbitol), cellulose preparations, calcium phosphate (e.g., tricalcium phosphate or calcium hydrogen phosphate), and binders such as starch paste (e.g., using corn starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethylstarch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0317] Auxiliaries are typically flow regulators and lubricants, such as silica, talc, stearic acid or its salts (e.g., magnesium stearate or calcium stearate) and polyethylene glycol. The dragee core is provided with a suitable coating that is resistant to gastric juice. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To produce a coating that is resistant to gastric juice, suitable cellulose preparations, such as solutions of acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, can be used. For example, dyes or pigments can be added to the tablets or dragee coatings for identification or to characterize the dosage combination of the active compound.

[0318] Other examples of pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin or soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the compound in the form of granules or extruded multiparticulates, which can be mixed with fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid, such as fatty oils or liquid paraffin. Additionally, stabilizers can be added.

[0319] Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which are composed of one or more active compounds and a suppository base.Suitable suppository bases include, among others, natural and synthetic triglycerides and paraffin hydrocarbons.It is also possible to use gelatin rectal capsules, which are composed of active compounds and a base material, such as liquid triglycerides, polyethylene glycol or paraffin hydrocarbons.

[0320] Suitable formulations for parenteral administration include water-soluble forms such as water-soluble salts, alkaline solutions or The aqueous solution of the active compound in acidic solution is included. Alternatively, the suspension of the active compound can be prepared as an oily suspension. For example, suitable lipophilic solvents or vehicles for suspensions can include fatty oils (e.g., sesame oil), synthetic fatty acid esters (e.g., ethyl oleate), triglycerides or polyethylene glycols, such as polyethylene glycol-400 (PEG-400). Aqueous suspensions can contain one or more substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension can optionally contain a stabilizer.

[0321] 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, e.g., a sealed bottle or vessel, with 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. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit can further include a device suitable for administering the composition by the intended route of administration.

[0322] III. Biomarkers In another embodiment, the present disclosure provides a method of treating a subject with cancer, e.g., multiple myeloma, comprising: (a) determining whether a biomarker is present or absent in a biological sample obtained from the subject; and (b) administering a therapeutically effective amount of a compound of the present disclosure to the subject if the biomarker is present in the biological sample. See, e.g., Goossens et al., Transl Cancer Res. 4:256-269 (2015); Kamel and Al-Amodi, Genomics Proteomics Bioinformatics 15:220-235 (2017); and Konikova and Kusenda, Neoplasma 50:31-40 (2003).

[0323] The term "biomarker," as used herein, refers to any biological compound, such as a gene, protein, protein fragment, peptide, polypeptide, nucleic acid, etc., or chromosomal abnormality, such as a chromosomal translocation, that can be detected and / or quantified in vivo in a cancer patient or in a biological sample, e.g., cancer cells, obtained from a cancer patient. A biomarker can be the entire intact molecule or a portion or fragment thereof. In one embodiment, the expression level of a biomarker is measured. The expression level of a biomarker can be measured, for example, by detecting the level of protein or RNA, e.g., mRNA, of the biomarker. In some embodiments, a portion or fragment of a biomarker can be detected or measured, for example, by an antibody or other specific binding agent. In some embodiments, a measurable aspect of a biomarker is associated with a given condition of the patient, e.g., a particular stage of cancer. For biomarkers detected at the protein or RNA level, such measurable aspect can include, for example, the presence, absence, or concentration, i.e., expression level, of the biomarker in the cancer patient or in a biological sample obtained from the cancer patient. For biomarkers detected at the nucleic acid level, such measurable aspects may include, for example, the allelic version of the biomarker or the type, rate and / or degree of mutation of the biomarker, also referred to herein as mutation status.

[0324] For biomarkers detected based on protein or RNA expression levels, the expression levels measured between different phenotypic statuses can be considered different if, for example, the mean or median expression levels of the biomarkers in different groups are calculated to be statistically significant. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal-Wallis, Wilcoxon, Mann-Whitney, and Mann-Whitney. These include microarray significance analyses, odds ratios, etc. Biomarkers, alone or in combination, provide a measure of the relative likelihood that a subject belongs to one phenotypic status or another. They are therefore useful, inter alia, as markers of disease and as indicators of the likelihood that a particular therapeutic treatment regimen will result in a beneficial patient outcome.

[0325] Biomarkers include, but are not limited to, chromosomal translocations in cancer, e.g., multiple myeloma, cells, and WHSC1 / NSD2 / MMSET expression. In one embodiment, a measurable aspect of a biomarker is its expression status. In one embodiment, a measurable aspect of a biomarker is its mutation status.

[0326] In one embodiment, the biomarker is WHSC1 / NSD2 / MMSET expression that is differentially present in subjects of one phenotypic status, e.g., subjects with hematological cancer, compared to another phenotypic status, e.g., normal, non-diseased subjects or patients with cancer without overexpression of WHSC1 / NSD2 / MMSET. In one embodiment, the biomarker is overexpression of WHSC1 / NSD2 / MMSET.

[0327] Biomarker standards can be determined in advance, simultaneously, or after the biological sample is obtained from the subject. Biomarker standards for use with the methods described herein can include, for example, data from samples from subjects without cancer; data from samples from subjects with non-metastatic cancer, such as breast cancer; and data from samples from subjects with metastatic cancer, such as breast cancer. Comparisons can be made to establish predetermined threshold biomarker standards for different classes of subjects, such as diseased subjects versus non-diseased subjects. Standards can be performed in the same assay or can be known standards from previous assays.

[0328] A biomarker is differentially present between different phenotypic status groups if the mean or median expression or mutation level of the biomarker is calculated to be different, i.e., higher or lower, between the groups. In this way, the biomarker provides an indication that a subject, e.g., a cancer patient, belongs to one phenotypic status or another.

[0329] In addition to individual biological compounds, such as WHSC1 / NSD2 / MMSET, the term "biomarker," as used herein, is meant to include a group, set, or array of multiple biological compounds. For example, the combination of WHSC1 / NSD2 / MMSET expression status and one or more chromosomal translocations can comprise a biomarker. The term "biomarker" can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, or more biological compounds.

[0330] Determining the expression level or mutation status of a biomarker in a patient can be performed using any of a number of methods known in the art. Any method known in the art for quantifying specific proteins and / or detecting the expression and / or chromosomal translocation of WHSC1 / NSD2 / MMSET or the expression or mutation level of any other biomarker in a patient or biological sample can be used in the methods of the present disclosure. Examples include, but are not limited to, PCR (polymerase chain reaction) or RT-PCR, flow cytometry, Northern blot, Western blot, ELISA (enzyme-linked immunosorbent assay), RIA (radioimmunoassay), gene chip analysis of RNA expression, immunohistochemistry, or immunofluorescence. See, e.g., Slagle et al., Cancer 83:1401 (1998); Hudlebusch et al., Clin Cancer Res 17:2919-2933 (2011). Certain embodiments of the present disclosure include methods in which biomarker RNA expression (transcription) is determined. Other embodiments of the present disclosure include methods in which protein expression in a biological sample is determined. For example, H See Arlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, (1988); Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York 3rd Edition, (1995); Kamel and Al-Amodi, Genomics Proteomics Bioinformatics 15:220-235 (2017). For Northern blot or RT-PCR analysis, RNA is isolated from tumor tissue samples using RNase-free techniques. Such techniques are generally known in the art.

[0331] In one embodiment of the present disclosure, a biological sample is obtained from a patient and the biological sample is assayed for determination of biomarker expression or mutation status.

[0332] In another embodiment of the present disclosure, Northern blot analysis of biomarker transcription in tumor cell samples is performed. Northern analysis is a standard method for detecting and / or quantifying mRNA levels in a sample. First, RNA is isolated from the sample to be assayed using Northern blot analysis. In the analysis, the RNA sample is first separated by size via electrophoresis in an agarose gel under denaturing conditions. The RNA is then transferred to a membrane, crosslinked, and hybridized with a labeled probe. Northern hybridization typically involves in vitro polymerization of radiolabeled or nonisotopically labeled DNA or the generation of oligonucleotides as hybridization probes. Typically, the membrane holding the RNA sample is prehybridized or blocked prior to probe hybridization to prevent the probe from coating the membrane and thus reduce nonspecific background signals. After hybridization, unhybridized probe is typically removed by washing with several changes of buffer. The stringency of washing and hybridization conditions can be designed, selected, and implemented by those skilled in the art with routine skill. Detection is achieved using a detectably labeled probe and an appropriate detection method. Radiolabeled and non-radiolabeled probes and their uses are well known in the art. The presence and / or relative level of expression of the assayed biomarker can be quantified using, for example, densitometry.

[0333] In another embodiment, biomarker expression and / or mutation status is determined using RT-PCR. RT-PCR allows for the detection of the progress of PCR amplification of target genes in real time. The design of primers and probes required to detect the expression and / or mutation status of biomarkers of the present disclosure is within the skill of one of ordinary skill in the art. RT-PCR can be used to determine the level of RNA encoding the biomarkers of the present disclosure in tumor tissue samples. In one embodiment of the present disclosure, RNA from a biological sample is isolated under RNase-free conditions and then converted to DNA by treatment with reverse transcriptase. Methods for reverse transcriptase conversion of RNA to DNA are well known in the art. Descriptions of PCR are provided in the following references: Mullis et al., Cold Spring Harbor Symp. Quant. Biol. 51:263 (1986); EP 50,424; EP 84,796; EP 258,017; EP 237,362; EP 201,184; U.S. Pat. Nos. 4,683,202; 4,582,788; and 4,683,194.

[0334] RT-PCR probes are DNA polymerases used for PCR that hydrolyze oligonucleotides hybridized to target amplicons (biomarker genes). The RT-PCR probe is determined by the 5'-3' nuclease activity of the polymerase. RT-PCR probes are oligonucleotides with a fluorescent reporter dye attached to the 5' end and a quencher moiety coupled to the 3' end (or vice versa). These probes are designed to hybridize to internal regions of PCR products. In the unhybridized state, the proximity of the fluorophore and quencher molecules prevents detection of the fluorescent signal from the probe. During PCR amplification, when the polymerase replicates the template onto which the RT-PCR probe is bound, the 5'-3' nuclease activity of the polymerase cleaves the probe. This decouples the fluorescent and quenching dyes, and FRET no longer occurs. Thus, fluorescence increases with each cycle in a manner proportional to the amount of probe cleavage. The fluorescent signal emanating from the reaction can be measured or tracked over time using commercially available equipment using conventional techniques.

[0335] In another embodiment of the present disclosure, the expression of proteins encoded by biomarkers is detected by Western blot analysis. Western blot (also known as immunoblot) is a method for protein detection in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate denatured proteins by mass. The proteins are then transferred from the gel to a membrane (e.g., nitrocellulose or polyvinylidene fluoride (PVDF)), where they are detected using a primary antibody that specifically binds to the protein. The bound antibody can then be detected by a secondary antibody conjugated with a detectable label (e.g., biotin, horseradish peroxidase, or alkaline phosphatase). Detection of the secondary label signal indicates the presence of the protein.

[0336] In another embodiment of the present disclosure, expression of proteins encoded by biomarkers is detected by enzyme-linked immunosorbent assay (ELISA). In one embodiment of the present disclosure, a "sandwich ELISA" comprises coating a plate with a capture antibody; adding the sample (wherein any antigen present binds to the capture antibody); adding a detection antibody that also binds the antigen; adding an enzyme-linked secondary antibody that detects the detection antibody; and adding a substrate that is converted to a detectable form by the enzyme on the secondary antibody. Detection of a signal from the secondary antibody indicates the presence of the biomarker antigen protein.

[0337] Multiple myeloma is a heterogeneous plasma cell disorder characterized by genetic abnormalities, including chromosomal translocations, deletions, duplications, and gene mutations. Translocations involving the immunoglobulin heavy chain region at chromosome 14q32 are observed in approximately 40% of patients with multiple myeloma. Translocation of oncogenes to this region can result in increased expression, contributing to disease initiation, disease progression, and treatment resistance. For example, the t(4;14) translocation is associated with upregulation of fibroblast growth factor receptor 3 (FGFR3) and myeloma SET domain proteins. Subjects with t(4;14) exhibit a poor overall prognosis that is only partially alleviated using existing chemotherapeutic agents. Unmet medical needs remain for subjects with this abnormality. IgH translocations in patients with multiple myeloma are presented in Table 4. See, for example, Kalff and Spencer, Blood Cancer Journal 2:e89 (2012).

[0338] [Table 133]

[0339] WHSC1 / NSD2 / MMSET is a histone methyltransferase located at the chromosome 4p16 locus. In a subset of multiple myeloma, a chromosomal translocation occurs in which this region is fused to chromosome 14q32. This translocation is commonly known as t(4;14). The result of t(4;14) in multiple myeloma is that the WHSC1 / NSD2 / MMSET gene is placed under the transcriptional control of the IgH promoter. This results in strong upregulation of WHSC1 / NSD2 / MMSET (Chesi et al., Blood 92:3025-3034 (1998)). Increased WHSC1 / NSD2 / MMSET leads to increased dimethylation of histone H3 at lysine 36 (H3K36) (Kuo et al., Mol. Cell 44:609-620 (2011)). Like WHSC1 / NSD2 / MMSET, SETD2 also methylates H3K36, but adds three methyl groups instead of two. Based on the sensitivity of t(4;14) multiple myeloma cell lines to SETD2 inhibition, the oncogenic function resulting from increased H3K36me2 conferred by WHSC1 overexpression likely also requires the ability of SETD2 to add additional methyl groups.

[0340] In one embodiment, the present disclosure provides a method of treating a subject having multiple myeloma, the method comprising: (a) determining whether a chromosomal translocation is present or absent in a biological sample obtained from the subject; and (b) if the chromosomal translocation is present in the biological sample, administering a therapeutically effective amount of a compound of the present disclosure to the subject.

[0341] In another embodiment, the disclosure provides a method of treating a subject having multiple myeloma, the method comprising administering a therapeutically effective amount of a compound of the disclosure to a subject having a chromosomal translocation.

[0342] In another embodiment, the present disclosure provides a method of identifying whether a subject having multiple myeloma is a candidate for treatment with a compound of the present disclosure, the method comprising: (a) determining whether a chromosomal translocation is present or absent in a biological sample taken from the subject; (b) if the chromosomal translocation is present, identifying the subject as a candidate for treatment; or (c) if the chromosomal translocation is not present, identifying the subject as not a candidate for treatment.

[0343] In another embodiment, the present disclosure provides a method of predicting treatment outcome in a subject with multiple myeloma, the method comprising determining whether a chromosomal translocation is present or absent in a biological sample obtained from the subject, wherein: (a) the presence of the chromosomal translocation in the biological sample. indicates that administering a compound of the present disclosure to a subject is likely to result in a favorable therapeutic response; and (b) the absence of a chromosomal translocation in the biological sample indicates that administering a compound of the present disclosure to a subject is likely to result in an unfavorable therapeutic response.

[0344] In another embodiment, the present disclosure provides a method comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof, wherein (a) the subject has multiple myeloma; and (b) the multiple myeloma is characterized as having a chromosomal translocation.

[0345] In any of the above embodiments, the chromosomal translocation is a t(4;14) translocation.

[0346] In one embodiment, the present disclosure provides a method of treating a subject with multiple myeloma, the method comprising: (a) determining whether overexpression of WHSC1 / NSD2 / MMSET is present or absent in a biological sample taken from the subject; and (b) administering a therapeutically effective amount of a compound of the present disclosure to the subject if overexpression of WHSC1 / NSD2 / MMSET is present in the biological sample.

[0347] In one embodiment, the present disclosure provides a method of treating a subject having multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure if overexpression of WHSC1 / NSD2 / MMSET is present in the subject.

[0348] In another embodiment, the present disclosure provides a method for identifying whether a subject having multiple myeloma is a candidate for treatment with a compound of the present disclosure, the method comprising: (a) determining whether overexpression of WHSC1 / NSD2 / MMSET is present or absent in a biological sample taken from the subject; (b) identifying the subject as a candidate for treatment if overexpression of WHSC1 / NSD2 / MMSET is present; or (c) identifying the subject as not a candidate for treatment if overexpression of WHSC1 / NSD2 / MMSET is not present.

[0349] In another embodiment, the present disclosure provides a method for predicting treatment outcome in a subject with multiple myeloma, the method comprising determining whether overexpression of WHSC1 / NSD2 / MMSET is present or absent in a biological sample obtained from the subject, wherein (a) the presence of overexpression of WHSC1 / NSD2 / MMSET in the biological sample indicates that administering a compound of the present disclosure to the subject is likely to result in a favorable therapeutic response; and (b) the absence of overexpression of WHSC1 / NSD2 / MMSET in the biological sample indicates that administering a compound of the present disclosure to the subject is likely to result in an unfavorable therapeutic response.

[0350] In another embodiment, the present disclosure provides a method comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof, wherein (a) the subject has multiple myeloma; and (b) the multiple myeloma is characterized as having overexpression of WHSC1 / NSD2 / MMSET.

[0351] IV. Definition The term "halo," as used herein, by itself or as part of another group, refers to -Cl, -F, -Br, or -I.

[0352] The term "nitro," as used herein, by itself or as part of another group, refers to --NO.sub.2.

[0353] The term "cyano" as used herein by itself or as part of another group means and refers to -CN.

[0354] The term "hydroxy," as used herein, by itself or as part of another group, refers to --OH.

[0355] 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 to C6). 12 alkyl) or a straight or branched chain aliphatic hydrocarbon containing the indicated number of carbon atoms (e.g., C alkyl, e.g., methyl, C alkyl, e.g., ethyl, etc.). In one embodiment, alkyl is a C 10 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-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, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0356] 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 1, 2, or 3 substituents, where each substituent 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 , -S(=O)2R 58 , -N(R 56a )C(=NR 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=NR 60 )R 61 or -C(=C-NO2)R 64 and; 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-C 10 aryl or optionally substituted heteroaryl; R 56c is hydrogen or alkyl; R 56dis 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, amino, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cyano cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, (C3-C6 cycloalkyl)oxy or (4-8 membered heterocyclo)oxy; 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; R 60 is cyano, nitro, hydroxy, C1-C6 alkoxy, -C(=O)R 62 and -S(=O)2R 62 selected from the group consisting of: R 61 is C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b selected from the group consisting of: R 62 is C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b selected from the group consisting of: R 63a is selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 63b is selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; or R 63a and R 63b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 6-membered heterocyclo; R 64 is C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63c R 63d selected from the group consisting of: R 63c is selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 63d is selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; or R 63c and R63d taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 6-membered heterocycle.

[0357] In one embodiment, the optionally substituted alkyl is unsubstituted or substituted with 1, 2, or 3 substituents, where each substituent 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 is.

[0358] In another embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. In another embodiment, the optionally substituted alkyl is an optionally substituted C1-C6 alkyl. In another embodiment, the optionally substituted alkyl is an optionally substituted C1-C4 alkyl. In one embodiment, the optionally substituted alkyl is an optionally substituted C1 or C2 alkyl. Non-limiting exemplary optionally substituted alkyl groups include -CH(CO2Me)CH2CO2Me and -CH(CH3)CH2N(H)C(=O)O(CH3)3.

[0359] 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-C6 alkenyl group. An alkenyl group is a C2-C4 alkenyl group. In another embodiment, an alkenyl group has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0360] 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, where each substituent 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.

[0361] 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 has one carbon-carbon triple bond. In another embodiment, an alkynyl is a C1-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.

[0362] 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, where each substituent 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 -CH≡CHPh.

[0363] 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 is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted with one, two, or three 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.

[0364] The term "hydroxyalkyl" or "(hydroxy)alkyl", as used herein, by itself or as part of another group, refers to a group having one, two, or three hydroxy groups. It refers to a substituted alkyl group. 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.

[0365] 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. In another embodiment, the alkyl is a C1-C4 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0366] 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 is a C1-C6 alkyl. 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.

[0367] 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.

[0368] The term "alkoxyalkyl" or "(alkoxy)alkyl," as used herein, by itself or as part of another group, refers 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, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0369] The term "heteroalkyl," as used herein, by itself or as part of another group, refers to a stable, straight- or branched-chain hydrocarbon group containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, where the sulfur atom can be optionally oxidized. The heteroatom can be present at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, a heteroalkyl contains two oxygen atoms. In another embodiment, a heteroalkyl contains one oxygen and one nitrogen atom. In another embodiment, a heteroalkyl contains two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -OCHCHNH, -NHCHCHOCH, and -OCHCHOCH.

[0370] The term "cycloalkyl," as used herein, by itself or as part of another group, refers to a cycloalkyl group containing 3 to 12 carbon atoms (i.e., C 3~12 cycloalkyl) or the indicated number of carbons (e.g., C3 cycloalkyl, e.g., cyclopropyl; C4 cycloalkyl, e.g., 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 is C 3~8 In another embodiment, cycloalkyl is C 3~6 In 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.

[0371] 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, where each substituent 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 59 , -N(R 56a )C(=NR 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=NR 60 )R 61 or -C(=C-NO2)R 64 where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 60 , R 61 and R64 is as defined in connection with the term "optionally substituted alkyl" and R 59 is (hydroxy)alkyl or (amino)alkyl. Non-limiting exemplary optionally substituted cycloalkyl groups include 3-(4-acetylpiperazin-1-yl)cyclohexyl, 3-(3-(N-methylacetamido)pyrrolidin-1-yl)cyclohexyl, 3-morpholinocyclohexyl, and 3-(pyrimidin-5-yl)cyclohexyl. In one embodiment, the optionally substituted cycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents, where each substituent 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 and-OR 59 is.

[0372] The term "heterocyclo," as used herein, by itself or as part of another group, refers to saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic groups containing 3 to 14 ring members, i.e., 3- to 14-membered heterocyclos containing 1, 2, 3, or 4 heteroatoms. 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).

[0373] 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.

[0374] The term heterocyclo also includes groups having an optionally substituted fused aryl or optionally substituted heteroaryl group, 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.

[0375] In one embodiment, a heterocyclo group is a 4- to 8-membered ring containing one ring and one or two oxygen atoms (e.g., tetrahydrofuran or tetrahydropyran), one or two nitrogen atoms (e.g., pyrrolidine, piperidine, or piperazine), or one oxygen and one nitrogen atom (e.g., morpholine), optionally with one —CH— group replaced with one —C(═O)— group (e.g., pyrrolidin-2-one or piperazin-2-one). In another embodiment, a heterocyclo group is a 5- to 8-membered ring containing one ring and one or two nitrogen atoms, optionally with one —CH— group replaced with one —C(═O)— group. In another embodiment, a heterocyclo group is a 5- or 6-membered ring containing one ring and one or two nitrogen atoms, optionally with one —CH— group replaced with one —C(═O)— group. In another embodiment, a heterocyclo group is an 8-12 membered ring group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the remainder of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include: [ka] Includes:

[0376] The term "optionally substituted heterocyclo," as used herein, by itself or as part of another group, refers to a heterocyclo group that is unsubstituted or substituted with 1 to 4 substituents, where each substituent 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, carboxy, amide, sulfonamide, 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 59 , -N(R 56a )C(=NR 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=NR 60 )R 61 or -C(=C-NO2)R 64 where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 59 , R 60, R 61 and R 64 is as defined in connection with the term "optionally substituted cycloalkyl." Substitution can occur on any available carbon or nitrogen atom of the heterocyclo group. In one embodiment, the optionally substituted heterocyclo is unsubstituted or substituted with 1 to 4 substituents, where each substituent is 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 59 is.

[0377] Non-limiting exemplary optionally substituted heterocyclo groups include: [ka] Includes:

[0378] 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-C6. 14 "aryl" refers to an aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, an aryl group is phenyl or naphthyl. In another embodiment, an aryl group is phenyl.

[0379] 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, where the substituents are each independently selected from halo, nitro, cyano, hydro oxy, 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 59 , -N(R 56a )C(=NR60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=NR 60 )R 61 or -C(=C-NO2)R 64 where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 59 , R 60 , R 61 and R 64 is as defined in relation to the term "optionally substituted cycloalkyl." In one embodiment, the optionally substituted aryl 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 59is.

[0380] 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 optionally substituted fused cycloalkyl groups and optionally substituted fused 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]azepine-2 -yl, 1,2,3,4-tetrahydroisoquinolin-1-yl and 2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl.

[0381] 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., 5-14 membered heteroaryls containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, a heteroaryl has 3 heteroatoms. In another embodiment, a heteroaryl has 2 heteroatoms. In another embodiment, a heteroaryl has 1 heteroatom. In another embodiment, a heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, a heteroaryl has 5 ring atoms (e.g., thienyl, which is a 5-membered heteroaryl having 4 carbon atoms and 1 sulfur atom). In another embodiment, a heteroaryl has 6 ring atoms (e.g., pyridyl, which is a 6-membered heteroaryl having 5 carbon atoms and 1 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, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, 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., For example, pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-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), oxazolyl (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.

[0382] The term "optionally substituted heteroaryl," as used herein, by itself or as part of another group, refers to heteroaryl that is unsubstituted or substituted with 1 to 4 substituents, where the substituents are 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, 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 59 , -N(R 56a )C(=NR 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=NR 60 )R 61 or -C(=C-NO2)R 64 where R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 59 , R 60, R 61 and R 64 is as defined in relation to the term "optionally substituted cycloalkyl." In one embodiment, the optionally substituted heteroaryl is unsubstituted or substituted with 1 to 4 substituents, wherein the substituents are 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 59 is.

[0383] 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.

[0384] 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-.

[0385] 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-.

[0386] 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-.

[0387] The term "(cycloalkyl)oxy," as used herein, by itself or as part of another group, refers to a cycloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary cycloalkyloxy groups include: [ka] is.

[0388] The term "(heterocyclo)oxy," as used herein, by itself or as part of another group, refers to a heterocyclo group attached to a terminal oxygen atom. An exemplary (heterocyclo)oxy group is [ka] is.

[0389] 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.

[0390] The term "(cycloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with one optionally substituted cycloalkyl group. In one embodiment, the cycloalkyl group 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. Non-limiting exemplary (cycloalkyl)alkyl groups include: [ka] Includes:

[0391] The term "sulfonamide," as used herein, by itself or as part of another group, refers to a group of the formula -SO2NR 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 an optionally substituted 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamide groups include -SONH, -SON(H)CH, and -SON(H)Ph.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 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.

[0396] The term "mercaptoalkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with an --SH group.

[0397] The term "carboxy," used by itself or as part of another group, refers to a group of formula -C(=O)OH.

[0398] 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; R51b 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 an optionally substituted 4- to 8-membered heterocyclo group. Non-limiting exemplary ureido groups include -NH-C(C=O)-NH and -NH-C(C=O)-NHCH.

[0399] 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; 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 an optionally substituted 4- to 8-membered heterocyclo group; R 53 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include -NH-C(C=NH)-NH, -NH-C(C=NCN)-NH, and -NH-C(C=NH)-NHCH.

[0400] 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 optionally substituted 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 linked to the alkyl group via a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include: [ka] Includes:

[0401] 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.

[0402] 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, the alkyl group is substituted with one optionally substituted 5-14 membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-14 membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5-9 membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-9 membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- or 6-membered heteroaryl groups. In one embodiment, the alkyl group is a C1-C6 alkyl. In another embodiment, the alkyl group is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. Non-limiting exemplary (heteroaryl)alkyl groups include: [ka] Includes:

[0403] The term "(heteroaryl)(aryl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted heteroaryl group and one optionally substituted aryl group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the aryl is an optionally substituted phenyl group or an optionally substituted naphthyl group. 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 (heteroaryl)(aryl)alkyl groups include: [ka] Includes:

[0404] The term "(heteroaryl)(heterocyclo)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted heteroaryl group and one optionally substituted heterocyclo group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the heterocyclo is an optionally substituted 5- to 8-membered heterocyclo. In another embodiment, the heterocyclo is an optionally substituted 5- or 6-membered heterocyclo. 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 (heteroaryl)(heterocyclo)alkyl groups include: [ka] is.

[0405] The term "(heteroaryl)(carboxamido)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted heteroaryl group and one carboxamido group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. 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-C3 alkyl. Non-limiting exemplary (heteroaryl)(carboxamido)alkyl groups include: [ka] Includes:

[0406] The term "carboxamide," as used herein, by itself or as part of another group, refers to a group of the formula -C(=O)NR 55a R 55b where R 55a and R 55b 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 55a and R 55btaken together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocyclo group. Non-limiting exemplary carboxamide groups include morpholine-4-carbonyl, N,N-dimethylaminocarbonyl, N-(1-methylpiperidin-4-yl)aminocarbonyl, 4-methylpiperazine-1-carbonyl, N-(3-aminocyclopentyl)aminocarbonyl, N-(pyridin-3-yl)aminocarbonyl, and N-(tetrahydrofuran-3-yl)aminocarbonyl.

[0407] The term "(heteroaryl)(cycloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted heteroaryl group and one optionally substituted cycloalkyl group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the cycloalkyl is an optionally substituted C3-C6 cycloalkyl. 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-C3 alkyl. Non-limiting exemplary (heteroaryl)(C3-C6 cycloalkyl)alkyl groups include: [ka] is.

[0408] The term "(aryl)(alkoxycarbonyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted aryl group and one alkoxycarbonyl group. In one embodiment, the aryl is an optionally substituted phenyl group or an optionally substituted naphthyl group. In another embodiment, the aryl is an optionally substituted phenyl group. 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)(alkoxycarbonyl)alkyl groups include: [ka] is.

[0409] The term "alkoxycarbonyl," as used herein, by itself or as part of another group, refers to a carbonyl group substituted with a C1-C6 alkoxy group, i.e., -C(=O)-. In one embodiment, the alkoxy group is a C1-C4 alkoxy. In another embodiment, the alkoxy group is a C1-C3 alkoxy. Non-limiting exemplary alkoxycarbonyl groups include -CO2Me and -CO2Et.

[0410] The term "(heteroaryl)(amino)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted heteroaryl group and one amino group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. 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 (heteroaryl)(amino)alkyl groups include: [ka] is.

[0411] The term "(cycloalkyl)(alkoxycarbonyl)alkyl" as used herein by itself or as part of another group refers to one optionally substituted cycloalkyl. It refers to a cycloalkyl group and an alkyl group substituted with one alkoxycarbonyl group. In one embodiment, the cycloalkyl is an optionally substituted C3-C6 cycloalkyl. 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 (cycloalkyl)(alkoxycarbonyl)alkyl groups include: [ka] is.

[0412] The term "(heteroaryl)(alkoxycarbonyl)alkyl," as used herein, by itself or as part of another group, refers to an optionally substituted heteroaryl group and an alkyl group substituted with an alkoxycarbonyl group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. 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 (heteroaryl)(alkoxycarbonyl)alkyl groups include: [ka] Includes:

[0413] The term "(heterocyclo)(cycloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted heterocyclo group and one optionally substituted cycloalkyl group. In one embodiment, the heterocyclo is an optionally substituted 5-8 membered heterocyclo. In another embodiment, the heterocyclo is an optionally substituted 5- or 6-membered heterocyclo. In one embodiment, the cycloalkyl is an optionally substituted C3-C6 cycloalkyl. 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 (heterocyclo)(cycloalkyl)alkyl groups include: [ka] is.

[0414] The term "(aryl)(cycloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one optionally substituted aryl group and one optionally substituted cycloalkyl group. In one embodiment, the aryl is an optionally substituted phenyl group or an optionally substituted naphthyl group. In another embodiment, the aryl is an optionally substituted phenyl group. In one embodiment, the cycloalkyl is an optionally substituted C3-C6 cycloalkyl. 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)(cycloalkyl)alkyl groups include: [ka] is.

[0415] The term "aralkyl" or "(aryl)alkyl," as used herein, by itself or as part of another group, refers 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 optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl is 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.

[0416] The term "(aryl)(hydroxy)alkyl," as used herein, by itself or as part of another group, refers to an optionally substituted aryl group and an alkyl substituted with one hydroxyl group. In one embodiment, the aryl is an optionally substituted phenyl group or an optionally substituted naphthyl group. In another embodiment, the aryl is an optionally substituted phenyl group. 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)(hydroxy)alkyl groups include: [ka] Includes:

[0417] The term "(cycloalkyl)(hydroxy)alkyl" as used herein means In the case of (cycloalkyl)(hydroxy)alkyl, by itself or as part of another group, it refers to an optionally substituted cycloalkyl group and an alkyl group substituted with one hydroxyl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. 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 (cycloalkyl)(hydroxy)alkyl groups include: [ka] is.

[0418] The term "(alkoxycarbonyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with one or two alkoxycarbonyl groups. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (alkoxycarbonyl)alkyl groups include: [ka] is.

[0419] The term "(aryl)(haloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an optionally substituted aryl group and an alkyl substituted with a haloalkyl group. In one embodiment, the aryl is an optionally substituted group or an optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the haloalkyl is a C1-C4 haloalkyl. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (aryl)(haloalkyl)alkyl groups include: [ka] is.

[0420] The term "(cycloalkyl)(haloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an optionally substituted cycloalkyl group and an alkyl substituted with one haloalkyl group. In one embodiment, the cycloalkyl is an optionally substituted C3-C6 cycloalkyl. In one embodiment, the haloalkyl is a C1-C4 haloalkyl. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (cycloalkyl)(haloalkyl)alkyl groups include: [ka] is.

[0421] The term "(hydroxy)(haloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with one hydroxy group and one haloalkyl group. In one embodiment, the haloalkyl is a C1-C4 haloalkyl. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (hydroxy)(haloalkyl)alkyl groups include: [ka] is.

[0422] The term "(alkoxycarbonyl)(haloalkyl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with one alkoxycarbonyl group and one haloalkyl group. In one embodiment, the haloalkyl is a C1-C4 haloalkyl. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (alkoxycarbonyl)(haloalkyl)alkyl groups include: [ka] is.

[0423] The term "(carboxamido)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with a carboxamido group. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (carboxamido)alkyl groups include -CH2C(=O)NH2, -C(H)(CH3)C(=O)NH2, -CH2C(=O)N(H)CH3, and -CH2C(=O)N(CH3)2.

[0424] The term "(carboxy)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with -C(=O)OH. In one embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. A non-limiting exemplary (carboxy)alkyl group is -CH2CO2H.

[0425] The term "(amino)(hydroxy)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with one hydroxy group and one amino group. In one embodiment, the alkyl is a C1-C4 alkyl. Non-limiting exemplary "(amino)(hydroxy)alkyl groups include: [ka] is.

[0426] The term "(amino)(aryl)alkyl," as used herein, by itself or as part of another group, refers to an alkyl group substituted with one amino group and one optionally substituted aryl group. In one embodiment, the amino group is -NH2, alkylamino, or dialkylamino. In one embodiment, the aryl group is optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting exemplary (amino)(aryl)alkyl groups include: [ka] Includes:

[0427] The term "amino," whether by itself or as part of another group, refers to a group of the formula -NR 55a R 55b where 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.

[0428] In one embodiment, amino is —NH 2 .

[0429] In another embodiment, amino is an "alkylamino", i.e., R 55a C 1~6 alkyl, and R 55b is an amino group where R 55a is C1-C4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0430] In another embodiment, amino is a "dialkylamino", i.e., R 55a and R 55b are each independently C 1~6 In one embodiment, R is an amino group that is alkyl. 55a and R 55b are each independently C1-C4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0431] In another embodiment, amino is "hydroxyalkylamino", i.e., R 55a is (hydroxyl)alkyl, and R 55b is a hydrogen or C1-C4 alkyl amino group.

[0432] In another embodiment, amino is a "cycloalkylamino", i.e., R 55a is optionally substituted cycloalkyl, and R 55b is a hydrogen or C1-C4 alkyl amino group.

[0433] In another embodiment, amino is an "aralkylamino", i.e., R 55a is aralkyl and R 55b is an amino group where R is hydrogen or C1-C4 alkyl. Non-limiting exemplary aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0434] In another embodiment, amino is "(cycloalkyl)alkylamino", i.e., R 55a is (cycloalkyl)alkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary (cycloalkyl)alkylamino groups include: [ka] Includes:

[0435] In another embodiment, amino is "(heterocyclo)alkylamino", i.e., R 55a is (heterocyclo)alkyl, and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary (heterocyclo)alkylamino groups include: [ka] Includes:

[0436] The term "(amino)alkyl," as used herein, by itself or as part of another group, refers to an alkyl substituted with one 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 C1-C6 alkyl. In another embodiment, the alkyl is C1-C4 alkyl. Non-limiting exemplary (amino)alkyl groups include -CHNH, CHCHN(H)CH, -CHCHN(CH), CHN(H)cyclopropyl, -CHN(H)cyclobutyl, and -CHN(H)cyclohexyl, and -CHCHCHN(H)CHPh and -CHCHCHN(H)CH(4-CF-Ph).

[0437] The present disclosure encompasses any of the disclosed compounds 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 isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, 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 36Cl, e.g. 3 H, 11 C and 14 In one embodiment, a composition is provided in which substantially all of the atoms at a position in the compound of the present disclosure are replaced by atoms having a different atomic mass or mass number. In another embodiment, a portion of the atoms at a position in the compound of the present disclosure are replaced, i.e., the compound of the present disclosure is enriched in atoms having a different atomic mass or mass number at a position. The isotopically labeled compounds of the present disclosure can be prepared by methods known in the art.

[0438] The compounds of the present disclosure may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms, and mixtures thereof. Individual enantiomers can be separated by methods known in the art in light of this disclosure. When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, they are intended to include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.

[0439] 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. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0440] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0441] The terms "enantiomer" and "enantiomeric" refer to a molecule that is not superimposable on its mirror image and is therefore optically active, where 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.

[0442] 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.

[0443] 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.

[0444] Stereochemical terms and rules used herein are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0445] 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, the percent enantiomeric excess is |RS| * 100, where R and S are the mole fraction or weight fraction of each of the enantiomers in the mixture, and R + S = 1. Knowing the optical rotation of a chiral substance, the percent enantiomeric excess is calculated by ([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.

[0446] In one embodiment, compounds of the present disclosure having one or more chiral centers are enantiomerically enriched, e.g., the ee is about 5% or greater. In another embodiment, the ee is about 10%. In another embodiment, the ee is about 20%. In another embodiment, the ee is about 30%. In another embodiment, the ee is about 40%. In another embodiment, the ee is about 50%. In another embodiment, the ee is about 60%. In another embodiment, the ee is about 70%. In another embodiment, the ee is about 80% ... In some embodiments, the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.

[0447] The terms "a" and "an" refer to one or more.

[0448] The term "about" as used herein includes the recited number plus or minus 10%. Thus, "about 10" means 9 to 11.

[0449] The terms "treat," "treating," "treatment," and the like, as used herein, refer to eliminating, reducing, or ameliorating a disease or condition and / or its associated symptoms. Treating a disease or condition does not require that the disease, condition, or its associated symptoms be completely eliminated, although not prevented. As used herein, the terms "treat," "treating," "treatment," and the like, can include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition recurring or the recurrence of a previously controlled disease or condition in a subject who does not have the disease or condition but who is at risk of or susceptible to recurrence of the disease or condition or to recurrence of the disease or condition. The term "treat" and cognate terms contemplate administering a therapeutically effective amount of a compound of the present disclosure to an individual in need of such treatment.

[0450] Within the meaning of the present disclosure, "treatment" also includes relapse prevention or phase prevention as well as treatment of acute or chronic signs, symptoms and / or dysfunctions. Treatment may be indicated symptomatically, e.g., to suppress symptoms. Treatment may be short-term, e.g., in the context of maintenance therapy, or may be indicated over the medium term, or may be long-term treatment.

[0451] The term "therapeutically effective amount" or "effective dose," as used herein, refers to an amount of an active ingredient sufficient to effectively deliver the active ingredient to an individual in need thereof for the treatment of a condition or disease of interest when administered by the methods of the present disclosure. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent may reduce (i.e., slow to some extent, and preferably stop) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; inhibit tumor growth to some extent; modulate protein methylation in target cells; 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, this may be cytostatic and / or cytotoxic.

[0452] The term "container" means any receptacle or compartment suitable for storing, transporting, dispensing and / or handling a pharmaceutical product.

[0453] The term "package insert" means the information that accompanies a pharmaceutical product that provides instructions on how to administer the product, along with the safety and effectiveness data needed to enable physicians, pharmacists, and patients to make informed decisions regarding the product's use. Package inserts are commonly considered the "label" for pharmaceutical products.

[0454] The term "disease" or "condition" or "disorder" refers to a condition or disorder that is generally considered to be a pathological state or function and that may manifest itself in the form of specific signs, symptoms and / or dysfunctions. The compounds of the present disclosure inhibit the SETD2 protein and can be used in the treatment of diseases and conditions in which inhibition of the SETD2 protein provides a benefit, such as proliferative diseases. See, e.g., U.S. Provisional Patent Application No. 62 / 545,353.

[0455] In some embodiments, the compounds of the present disclosure can be used to treat "SETD2 protein-mediated disorders." A SETD2 protein-mediated disorder is any pathological condition in which SETD2 protein is known to play a role. In some embodiments, a SETD2-mediated disorder is a proliferative disease.

[0456] In some embodiments, inhibiting the SETD2 protein is inhibiting one or more activities of the SETD2 protein. In some embodiments, the activity of the SETD2 protein is the ability of the SETD2 protein to transfer a methyl group to a target protein, such as a histone. It should be appreciated that the activity of SETD2 can be inhibited in vitro or in vivo. Exemplary levels of inhibition of SETD2 activity include at least 5% inhibition, at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to about 100% inhibition.

[0457] The term "biological sample," as used herein, refers to any tissue or fluid from a subject suitable for detecting chromosomal translocations. Examples of useful biological samples include, but are not limited to, collected tissues and / or cells, such as solid tumors, lymph nodes, inflamed tissues, tissues and / or cells involved in a condition or disease, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebrospinal fluid, etc. Other suitable biological samples are well known to those of skill in the art. Biological samples can be analyzed for chromosomal translocations using any technique known in the art. Such techniques include, but are not limited to, polymerase chain reaction (PCR) methodology, reverse transcription-polymerase chain reaction (RT-PCR) methodology, or cytoplasmic light chain immunofluorescence coupled with fluorescence in situ hybridization (cIg-FISH). Biological samples can be obtained using techniques well within the ordinary skill of a clinician. In one embodiment of the present disclosure, the biological sample comprises blood cells.

[0458] General synthesis of compounds The compounds of the present disclosure are prepared using methods known to those of skill in the art in light of this disclosure, or by exemplary methods shown in the general schemes below. 1d , R 2b , R 2d , R 2e , A 1 , A 2 , R 11a , R 14a , R 14b , R 19 , R 20 , G, Z 4 and q are as defined in relation to formula II, III, IV, V or VI unless otherwise indicated. In any of the general schemes, for example, when Z is (amino)alkyl or any other group that may require protection or when R 8 When is amino, (amino)alkyl, or any other group that may require protection, appropriate protecting groups can be used in the synthesis (see Wuts, PGM; Greene, TW, "Greene's Protective Groups in Organic Synthesis", 4th Ed., J. Wiley & Sons, NY, 2007) unless otherwise indicated.

[0459] In general scheme 1, an arylhydrazine of formula (1) is reacted with ethyl 2-oxopropanoate to give a compound of formula (2). In step 2, the compound of formula (2) is converted to an indole of formula (3) under acidic conditions. In step 3, the compound of formula (3) is hydrolyzed to give an indole-2-carboxylic acid of formula (4). In step 4, the compound of formula (4) can be converted to G under standard coupling conditions. 1 Reaction with NH2 gives compounds of formula II. [ka]

[0460] In General Scheme 2, a compound of formula (5) is reacted with R 2b-H(wherein, R 2b is a heterocyclo, e.g., R 2b -H is piperidine or an amine, e.g., R 2b -H is dimethylamine) to give a compound of formula (6). The nitro group of compound of formula (6) is reduced to give a compound of formula (7). In step 3, compound of formula (7) is reacted with compound of formula (4) (see general scheme 1) under standard coupling conditions to give a compound of formula III (wherein A 1 and A 2 is CH and R 2b is an optionally substituted heterocyclo or amino group. [ka]

[0461] In General Scheme 3, a compound of formula (8) is reacted with R 2b -H(wherein, R 2b is a heterocyclo, e.g., R 2b -H is piperidine or an amine, e.g., R 2b In step 2, the compound of formula (9) is reacted with a compound of formula (10) to give a compound of formula III (wherein A 1 and / or A 2 is N and R 2b is an optionally substituted heterocyclo or amino group). [ka]

[0462] In General Scheme 4, a compound of formula (11) is reacted with R 11a -H(wherein, R 11a is a heterocyclo, e.g., R 11aIn step 2, the Cbz group is removed to give a compound of formula (13). The compound of formula (13) is coupled with a compound of formula (4) to give a compound of formula IV (wherein R 11a is an optionally substituted heterocyclo; Z 5 is -CH2-). [ka]

[0463] In step 1 of general scheme 5, a nitrile of formula (14) is reacted with a Grignard reagent (R 14a —MgBr) and the resulting product is reduced to give a compound of formula (15). The compound of formula (15) is coupled with a compound of formula (4) to give a compound of formula V (wherein p is 0). [ka]

[0464] In General Scheme 6, an aldehyde of formula (16) is reacted with an ester of formula (17) to give a compound of formula (18). In Step 2, the compound of formula (18) is hydrolyzed to give a compound of formula (19). In Step 3, the compound of formula (19) is converted to an isocyanate of formula (20). The compound of formula (20) is reacted with benzyl alcohol to give a compound of formula (21). Hydrogenation of the compound of formula (21) and removal of the Cbz group gives an amine of formula (23). Coupling of the compound of formula (23) with a compound of formula (4) gives a compound of formula V, where p is 1. [ka]

[0465] In general scheme 7, a nitrile of formula (24) is reduced to give an amine of formula (25). The compound of formula (25) is coupled with a compound of formula (4) to give a compound of formula VI. [ka] [Example]

[0466] General synthesis method General methods and experimental procedures for preparing and characterizing compounds of the present disclosure are described in the general schemes above and in the examples below. Reactions were heated, if necessary, using conventional hotplate equipment, heating mantles, or microwave irradiation. Reactions were carried out in open or sealed vessels at atmospheric or elevated pressure, with or without stirring. Reaction progress was monitored using conventional techniques, such as TLC, HPLC, UPLC, or LCMS, using the instrumentation and methods described below. Reactions were quenched, and crude compounds were isolated using conventional methods, as described in the specific examples provided. Solvent removal was achieved using a rotary or centrifugal evaporator at atmospheric or reduced pressure, with or without heating.

[0467] Compound purification was carried out as needed using various traditional methods, including but not limited to, normal-phase or reverse-phase HPLC, or flash column, or preparative TLC plate under acidic, neutral, or basic conditions.Compound purity and mass confirmation was carried out using standard HPLC and / or UPLC and / or MS analyzer and / or LCMS and / or GC equipment (possibly including but not limited to the following instruments: Waters Alliance 2695 with 2996 PDA detector connected to ZQ detector and ESI source; Shimadzu LDMS-2020; Waters Acquity H class with PDA detector connected to SQ detector and ESI source; Agilent 1100 series with PDA detector; Waters Alliance 2695 with 2998 PDA detector; AB SCIEX API2000 with ESI source; Agilent 7890GC). Exemplary compounds were dissolved in MeOH or MeCN to a concentration of approximately 1 mg / mL and analyzed by injection of 0.5-10 μL into a suitable LCMS system using the appropriate method. MS data are presented in Table 1B. In all cases, the mass detection method was ESI.

[0468] Confirmation of compound structure was performed using a standard 300 or 400 MHz NMR spectrometer. Unless otherwise indicated, the LCMS methods used in the examples are as follows:

[0469] Method A Equipment: SHIMADZU LCMS-2010EV Analysis conditions: LC parameters: Column: Shim-pack XR-ODS, 2.2um, 3.0 *50 mm; Mobile phase A: water / 0.05% TFA; Mobile phase B: acetonitrile / 0.05% TFA; Gradient: 5% to 100% B in 2.0 min, 100% B for 0.7 min, 100% to 5% B in 0.05 min, then stop; Flow rate: 1.2 mL / min; Column temperature: 40 °C; Detectors: PDA and ELSD; Sample preparation: 1 mg / mL in methanol; Injection volume: 1 μL; Reported: Area-normalized purity. MS parameters: Interface: ESI (positive); Interface voltage: 4.5kv; Heat block: 250°C; nebulizer gas: 1.50 L / min; scan range: 90-900 (m / z); detector voltage: 1.6 kV.

[0470] Method B Equipment: SHIMADZU LCMS-2020 Analysis conditions: LC parameters: Column: Kinetex EVO C18, 2.6um, 2.1 * 50 mm; Mobile phase A: 6.5 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution; Mobile phase B: acetonitrile; Gradient: 5% to 100% B in 2.0 min, 100% B for 0.7 min, 100% to 5% B in 0.1 min, then stop; Flow rate: 1.0 mL / min; Column temperature: 35 °C; Detectors: PDA and ELSD; Sample preparation: 1 mg / mL in methanol; Injection volume: 1 μL; Report: Area-normalized purity. MS parameters: Interface: ESI (positive and negative); interface voltage: tuning file; heat block: 200°C; nebulizer gas: 1.50 L / min; scan range: 90-900 (m / z); detector voltage: 0.9 kV.

[0471] Method C Equipment: SHIMADZU LCMS-2020 Analysis conditions: LC parameters: Column: CORTECS C18+, 2.7um, 2.1 *50 mm; Mobile phase A: water / 0.1% FA; Mobile phase B: acetonitrile / 0.05% FA; Gradient: 5% to 100% B in 2.0 min, 100% B for 0.7 min, 100% to 5% B in 0.1 min, then stop; Flow rate: 1.0 mL / min; Column temperature: 40 °C; Detectors: PDA and ELSD; Sample preparation: 1 mg / mL in acetonitrile; Injection volume: 1 μL; Reported: Area-normalized purity. MS parameters: Interface: ESI (positive and negative); interface voltage: tuning file; heat block: 200°C; nebulizer gas: 1.50 L / min; scan range: 90-900 (m / z); detector voltage: 1.2 kV.

[0472] Method D Equipment: SHIMADZU LCMS-2020 Analysis conditions: LC parameters: Column: Shim-pack XR-ODS, 2.2um, 3.0 * 50 mm; Mobile phase A: water / 0.05% TFA; Mobile phase B: acetonitrile / 0.05% TFA; Gradient: 5% to 100% B in 2.0 min, 100% B for 0.7 min, 100% to 5% B in 0.05 min, then stop; Flow rate: 1.2 mL / min; Column temperature: 40 °C; Detectors: PDA and ELSD; Sample preparation: 1 mg / mL in acetonitrile; Injection volume: 1 μL; Reported: Area-normalized purity. MS parameters: Interface: ESI (positive); Interface voltage: tuning file; Heat block: 250°C; Nebulizer gas: 1.50 L / min; scan range: 90-900 (m / z); detector voltage: 1.0 kV.

[0473] Method E Equipment: SHIMADZU LCMS-2020 Analysis conditions: LC parameters: Column: Shim-pack XR-ODS, 2.2um, 3.0 *50 mm; Mobile phase A: water / 0.05% TFA; Mobile phase B: acetonitrile / 0.05% TFA; Gradient: 5% to 100% B in 2.0 min, 100% B for 0.7 min, 100% to 5% B in 0.05 min, then stop; Flow rate: 1.2 mL / min; Column temperature: 40 °C; Detectors: PDA and ELSD; Sample preparation: 1 mg / mL in acetonitrile; Injection volume: 1 μL; Reported: Area-normalized purity. MS parameters: Interface: ESI (positive); interface voltage: tuning file; heat block: 300 °C; nebulizer gas: 1.50 L / min; scan range: 90-900 (m / z); detector voltage: 1.1 kV.

[0474] The following abbreviations may be used herein:

[0475] [Table 134]

[0476] Example 1 Synthesis of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide (Compound No. 15) Step 1. Synthesis of ethyl (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazin-1-ylidene]propanoate [ka] A 1000 mL round-bottom flask was charged with a solution of (5-fluoro-2-methylphenyl)hydrazine hydrochloride (100 g, 572.73 mmol, 1.00 equiv.) in ethanol (400 mL), ethyl 2-oxopropanoate (66 g, 1.20 equiv.), and sulfuric acid (10 mL). The resulting solution was stirred at 25° C. for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solid was collected by filtration. This afforded 120 g (yield=88%) of ethyl (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazin-1-ylidene]propanoate as a yellow solid. LCMS (Method A: ESI): RT=1.399 min, m / z=239.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.96(d,J=2.0Hz,1H),7.15(m,2H),6.62(m,1H),4.25(q,J=7.1Hz,2H),2.12(d,J=9.3Hz,6H),1.29(t,J=7.1Hz,3H)ppm.

[0477] Step 2. Synthesis of ethyl 4-fluoro-7-methyl-1H-indole-2-carboxylate [ka] A 1000 mL round-bottom flask was charged with a solution of ethyl (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazin-1-ylidene]propanoate (40 g, 167.89 mmol, 1.00 equiv.) in toluene (400 mL) and 4-methylbenzene-1-sulfonic acid (50 g, 290.36 mmol, 1.70 equiv.). The resulting solution was stirred at 100 °C for 18 h. The reaction progress was monitored by LCMS. The resulting solution was concentrated under vacuum, and the residue was dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 3 × 200 mL of saturated aqueous NaHCO3. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:5). The resulting mixture was concentrated under vacuum. The solid was purified by recrystallization from ethanol. This gave 9.0 g (yield=24%) of ethyl 4-fluoro-7-methyl-1H-indole-2-carboxylate as a yellow solid. LCMS (Method A, ESI): RT=1.354 min: m / z=222.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.07(s,1H),7.17(d,J=2.1Hz,1H),7.00(m,1H),6.77(m,7.8Hz,1H),4.36(q,J=7.1Hz,2H),2.49(d,J=1.0Hz,3H),1.35(t,J=7.1Hz,3H)ppm.

[0478] Step 3. Synthesis of 4-fluoro-7-methyl-1H-indole-2-carboxylic acid [ka] A 500 mL round-bottom flask was charged with a solution of ethyl 4-fluoro-7-methyl-1H-indole-2-carboxylate (9.1 g, 41.13 mmol, 1.00 equiv.) in tetrahydrofuran (150 mL), sodium hydroxide (8 g, 200.00 mmol, 5.00 equiv.), water (50 mL), and methanol (2 mL). The resulting solution was stirred at 25 °C for 6 hours. The resulting mixture was concentrated under vacuum. The residue was diluted with 50 mL of water and then adjusted to pH 5 with hydrogen chloride (3.0 mol / L). The resulting solution was extracted with 3 × 50 mL of ethyl acetate. The solid was collected by filtration. This afforded 8.0 g (yield = 81%) of 4-fluoro-7-methyl-1H-indole-2-carboxylic acid as a brown solid. LCMS (Method C, ESI): RT = 0.989 min, m / z = 192.0 [MH] + . 1 H NMR(300MHz,DMSO-d6)δ 13.10(s,1H),11.94(s,1H),7.09(d,J=2.1Hz,1H),6.96(m,1H),6.73(m,1H),2.46(d,J=1.1Hz,3H)ppm.

[0479] Step 4. Synthesis of tert-butyl N-[3-(4-acetylpiperazin-1-yl)cyclohexyl]carbamate [ka] In a 100 mL round-bottom flask, tert-butyl N-(3-oxocyclohexyl)carbamate (800 mg, 3.75 mmol, 1.00 equiv.), 1-(piperazin-1-yl)ethan-1-one (800 mg, 6.24 mmol, 1.66 equiv.), methanol (10 mL), and Pd / C (0.2 g) were placed, and hydrogen was introduced into the mixture. The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (900 mg) was purified by flash preparative HPLC with the following conditions: column, C18 silica gel; mobile phase; detector, UV 254 / 220 nm. This gave 700 mg (yield=57%) of tert-butyl N-[3-(4-acetylpiperazin-1-yl)cyclohexyl]carbamate as a colorless oil. LCMS (Method A, ESI): RT=1.361 min, m / z=325.9 [M+H] + .

[0480] Step 5. Synthesis of 1-[4-(3-aminocyclohexyl)piperazin-1-yl]ethan-1-one [ka] In a 100 mL round-bottom flask, tert-butyl N-[3-(4-acetylpiperazin-1-yl)cyclohexyl]carbamate (700 mg, 2.15 mmol, 1.00 equiv.) was placed, and dichloromethane (3 mL) and trifluoroacetic acid (2 mL) were added dropwise. The resulting solution was stirred at 25° C. for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. This afforded 700 mg of 1-[4-(3-aminocyclohexyl)piperazin-1-yl]ethan-1-one as a brown oil. LCMS (Method A, ES): RT=0.647 min, m / z=225.95 [M+H] + .

[0481] Step 6. Synthesis of N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide (as TFA salt) [ka] 4-Fluoro-7-methyl-1H-indole-2-carboxylic acid (100 mg, 0.52 mmol, 1.00 equiv.) was placed in a 100 mL round-bottom flask, and 1-[4-(3-aminocyclohexyl)piperazin-1-yl]ethan-1-one (110 mg, 0.49 mmol, 0.94 equiv.), N,N-dimethylformamide (4 mL), DIEA (200 mg, 1.55 mmol, 2.99 equiv.), and HATU (260 mg, 0.68 mmol, 1.32 equiv.) were added batchwise. The resulting solution was stirred at 25 °C for 2 hours. The reaction progress was monitored by LCMS, and the reaction solution was quenched with 10 mL of water. The resulting solution was extracted with 3 × 15 mL of ethyl acetate, and the organic layers were combined and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1). The crude product was purified by chiral preparative HPLC with the following conditions: Column, (R,R)-WHELK-014.6 * 50 mm, 3.5 μm: 1-78220-30056749; mobile phase, hexane (0.1% DEA):EtOH=85:15; detector, UV 254 nm / 220 nm. The product thus obtained was further purified by preparative HPLC with the following conditions: column, XBridge preparative phenyl OBD column, 5 μm, 19 *150 mm; mobile phase, water with 10 mmol TFA and MeCN (20.0% MeCN, to 30.0% in 10 min, to 95.0% in 1 min, hold at 95.0% in 1 min, decrease to 20.0% in 2 min); detector, UV 254 / 220 nm. This gave 30.5 mg (yield = 11%) of N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide trifluoroacetate as a white solid. LCMS (Method B, ES): RT = 1.138 min, m / z = 401.0 [M-TFA] + . 1 H NMR( 300MHz, methanol-d4)δ 7.18(s,1H),6.94-6.92(m,1H),6.64-6.62(m,1H),4.03-3.88(m,1H),3.57-3.55(m,4H),2.65(t,J=16.4Hz,5 H),2.48(t,J=1.0Hz,3H),2.23(d,J=12.0Hz,1H),2.09(s,3H),1.93(d,J=12.2Hz,3H),1.53-1.18(m,4H)ppm.

[0482] Example 2 Synthesis of 4-fluoro-7-methyl-N-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-indole-2-carboxamide (Compound No. 340) [ka] A 100 mL round-bottom flask purged with an inert nitrogen atmosphere was charged with a solution of 4-fluoro-7-methyl-1H-indole-2-carboxamide (632 mg, 3.29 mmol, 1.20 equiv.) in N,N-dimethylformamide (15 mL), 1-(4-bromopyridin-2-yl)-4-methylpiperazine (700 mg, 2.73 mmol, 1.00 equiv.), (1R,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (785 mg, 5.52 mmol, 2.00 equiv.), CuI (522 mg, 2.74 mmol, 1.00 equiv.), and CsCO (2.7 g, 8.29 mmol, 3.00 equiv.). The resulting solution was stirred at 80 °C for 15 hours. The reaction progress was monitored by LCMS. The crude product (100 mg) was purified by preparative HPLC with the following conditions: Column, XSelect CSH preparative C18 OBD column, 5 μm, 19 * 150 mm; mobile phase, water (0.05% TFA) and ACN (15.0% ACN, up to 40.0% in 9 min); detector, UV 254 / 220 nm. This gave 58.8 mg (4%) of 4-fluoro-7-methyl-N-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1H-indole-2-carboxamide as the trifluoroacetate salt as a white solid. LCMS (Method B, ESI): RT = 2.543 min, m / z = 368.0 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.14(dd,J=2.4Hz,4.5Hz,1H),7.88(s,1H),7.51(d,J=1.5Hz,1H),7.38(d,J=5.1Hz,1H),7.08(dd,J=3. 9Hz,5.7Hz,1H),6.72(dd,J=6.0Hz,7.8Hz,1H),3.93(br,4H),3.51(s,4H),3.02(s,3H),2.54(s,3H)ppm.

[0483] Example 3 Synthesis of 4-fluoro-7-methyl-N-((1-(2-(4-methylpiperazin-1-yl)phenyl)cyclopropyl)methyl)-1H-indole-2-carboxamide (Compound No. 392) Step 1. 1-[2-(4-methylpiperazin-1-yl)phenyl]cyclopropane Synthesis of 1-carbonitrile [ka] In a 30 mL microwave tube purged with an inert atmosphere of nitrogen, 1-(2-bromophenyl)cyclopropane-1-carbonitrile (2.0 g, 9.01 mmol, 1.00 equiv.), 1-methylpiperazine (4.5 g, 44.93 mmol, 4.99 equiv.), Pd(dba) (800 mg, 0.87 mmol, 0.10 equiv.), P(t-Bu)BF (0.52 g, 1.79 mmol, 2.00 equiv.), CsCO (8.8 g, 27.01 mmol, 3.00 equiv.), and dioxane (8 mL) were placed. The resulting solution was stirred in an oil bath at 90 °C for 3 h. The reaction progress was monitored by LCMS. The resulting solution was extracted with dichloromethane (30 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum. This gave 0.2 g (yield = 9%) of 1-[2-(4-methylpiperazin-1-yl)phenyl]cyclopropane-1-carbonitrile as a brown oil. LCMS (Method A, ESI): RT = 1.05 min, m / z = 323.0 [M+1] + .

[0484] Step 2. Synthesis of (1-(2-(4-methylpiperazin-1-yl)phenyl)cyclopropyl)methanamine [ka] A 25 mL round-bottom flask was charged with 1-[2-(4-methylpiperazin-1-yl)phenyl]cyclopropane-1-carbonitrile (200 mg, 0.83 mmol, 1.00 equiv.), tetrahydrofuran (4.1 mL), and BH3 / THF (4.1 mL). The resulting solution was stirred under nitrogen atmosphere at 25 °C for 3 h. The reaction progress was monitored by LCMS. The pH value of the solution was adjusted to 8 with sodium bicarbonate (20% aqueous solution). The resulting solution was extracted with dichloromethane (3 × 15 mL), and the organic layers were combined and concentrated under vacuum to give 120 mg (yield = 60%) of (1-(2-(4-methylpiperazin-1-yl)phenyl)cyclopropyl)methanamine. LCMS (Method A, ESI): RT = 0.92 min, m / z = 246.0 [M+1]. + .

[0485] Step 3. Synthesis of 4-fluoro-7-methyl-N-([1-[2-(4-methylpiperazin-1-yl)phenyl]cyclopropyl]methyl)-1H-indole-2-carboxamide [ka] 4-Fluoro-7-methyl-1H-indole-2-carboxylic acid (50 mg, 0.26 mmol, 1.00 equiv.) was placed in a 25 mL round-bottom flask, and 1-[2-(4-methylpiperazin-1-yl)phenyl]cyclopropylmethanamine (82.5 mg, 0.34 mmol, 1.30 equiv.), N,N-dimethylformamide (1 mL), DIEA (166 mg, 1.28 mmol, 4.96 equiv.), and HATU (98 mg, 0.26 mmol, 1.00 equiv.) were added in batches. The resulting solution was stirred at 25 °C for 30 minutes. The crude product (80 mg) was purified by preparative HPLC using the following conditions: Column: Kinetex EVO C18 column, 21.2 *150, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (50.0% ACN, up to 70.0% in 7 min); detector, UV 254 / 220 nm. This gave 23 mg (yield = 21%) of 4-fluoro-7-methyl-N-([1-[2-(4-methylpiperazin-1-yl)phenyl]cyclopropyl]methyl)-1H-indole-2-carboxamide as an off-white solid. LCMS (Method B, ESI): RT = 1.95 min, m / z = 421.1 [M+1] + . 1 H NMR(400MHz, methanol-d4)δ 7.33(dd,J=7.6,1.5Hz,1H),7.29-7.19(m,2H),7.10-7.02(m,2H),6.98-6.91(m,1H),6.65(dd,J=10.4,7.8Hz,1H), 3.82(s,2H),3.09(s,4H),2.72(s,4H),2.46(d,J=1.0Hz,3H),2.41(s,3H),1.08-0.97(m,2H),0.95-0.80(m,2H)ppm.

[0486] Example 4 Synthesis of N-(cyclopropyl(isoquinolin-1-yl)methyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide (Compound No. 507) Step 1. Synthesis of cyclopropyl(isoquinolin-1-yl)methanamine [ka] In a 250 mL three-necked round-bottom flask, isoquinoline-1-carbonitrile (500 mg, 3.24 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL) was placed. The solution was cooled to 0 °C and stirred at this temperature for 30 minutes. After that, bromo(cyclopropyl)magnesium (1 mol / L) (33 mL, 1.00 equiv.) was added dropwise, methanol (10 mL) was added, and NaBH (350 mg, 9.25 mmol, 2.85 equiv.) was added batchwise at 0 °C. The resulting solution was stirred at 25 °C for 4 hours. The reaction progress was monitored by LCMS. The reaction solution was quenched with 10 mL of ice / water. The resulting solution was extracted with 3 × 30 mL of ethyl acetate, and the organic layers were combined and washed with water. The residue was dried over aqueous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane / methanol (10 / 1), which gave 300 mg (yield=60%) of cyclopropyl(isoquinolin-1-yl)methanamine as an off-white solid. LCMS (Method A, ESI): RT=0.865 min, m / z=199.00 [M+H] + .

[0487] Step 2. Synthesis of N-(cyclopropyl(isoquinolin-1-yl)methyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide [ka] A 100 mL round-bottom flask was charged with cyclopropyl(isoquinolin-1-yl)methanamine (300 mg, 1.51 mmol, 1.00 equiv.), TEA (450 mg, 4.45 mmol, 2.94 equiv.), N,N-dimethylformamide (30 mL), 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (300 mg, 1.55 mmol, 1.03 equiv.), and HATU (550 mg, 1.45 mmol, 0.96 equiv.). The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The resulting solution was quenched with 10 mL of ice / water. The resulting solution was extracted with 3 × 50 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC using the following conditions: Column, Kinetex EVO C18 column, 21.2 * 150, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (50.0% ACN, up to 75.0% in 7 min); detector, UV 254 / 220 nm. This gave 60.2 mg (yield = 11%) of N-[cyclopropyl(isoquinolin-1-yl)methyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide as a white solid. LCMS (Method D, ESI): RT = 1.55 min, m / z = 374.00 [M+H] + . 1 H NMR(300MHz, methanol-d4)δ 8.47(t,J=6.5Hz,2H),8.00-7.90(m,1H),7.83-7.65(m,3H),7.24(s,1H),7.00-6.89(m,1H),6 .67-6.61(m,1H),5.65(d,J=8.6Hz,1H),2.48(s,3H),1.72-1.55(m,1H),0.65-0.42(m,4H)ppm.

[0488] Example 5 Synthesis of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide (Compound No. 60) [ka] 3-(1,3,4-Oxadiazol-2-yl)aniline (120 mg, 0.74 mmol, 1.00 equiv.) was placed in a 15 mL vial, and 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (168 mg, 0.87 mmol, 1.17 equiv.), N,N-dimethylformamide (3 mL), DIEA (288 mg, 2.23 mmol, 2.99 equiv.), and HATU (336 mg, 0.88 mmol, 1.19 equiv.) were added batchwise. The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched with 10 mL of ice / water. The resulting solution was extracted with 3 × 12 mL of ethyl acetate, and the organic layers were combined. The organic phase was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:4). The crude product was purified by preparative HPLC with the following conditions: Column, XBridge Preparative Phenyl OBD Column, 5 μm, 19 * 150 mm; mobile phase, water with 10 mmol NH4HCO3 and MeCN (20.0% MeCN, to 30.0% in 10 min, to 95.0% in 1 min, hold at 95.0% in 1 min, decrease to 20.0% in 2 min); detector, UV 254 / 220 nm. This gave 51.1 mg (yield = 20%) of 4-fluoro-7-methyl-N-[3-(1,3,4-oxadiazol-2-yl)phenyl]-1H-indole-2-carboxamide as an off-white solid. LCMS (Method E, ESI): RT = 0.924 min, m / z = 337.1 [M+H] + . 1 H-NMR(300MHz,DMSO-d6):δ 11.98(s,1H);10.55(s,1H);9.38(s,1H);8.59(s,1H);8.14-8.11(d,J=12.0Hz ,1H);7.78-7.76(m,1H);7.01-6.97(m,1H);6.81-6.75(m,1H);2.51(s,3H)ppm.

[0489] Example 6 Synthesis of N-((5-((1H-imidazol-1-yl)methyl)-3-methylpyridin-2-yl)(cyclopropyl)methyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide (Compound No. 161) Step 1. Synthesis of (5-bromo-3-methylpyridin-2-yl)(cyclopropyl)methanamine [ka] In a 100 mL three-necked round-bottom flask maintained under an inert nitrogen purging atmosphere, 5-bromo-3-methylpyridine-2-carbonitrile (1 g, 5.10 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL) was added dropwise at 0 °C to bromo(cyclopropyl)magnesium (1 mol / L) (5.1 mL, 5.10 mmol, 1.00 equiv.). The resulting solution was stirred at this temperature for 30 minutes, and then methanol (10 mL) was added. NaBH (0.58 g, 15.30 mmol, 3.00 equiv.) was added batchwise at 0 °C. The resulting solution was stirred at 25 °C for 12 hours. The reaction progress was monitored by LCMS. The reaction solution was quenched with 10 mL of ice / water. The resulting solution was extracted with 3 × 30 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane / methanol (10 / 1). This gave 600 mg (yield = 60%) of (5-bromo-3-methylpyridin-2-yl)(cyclopropyl)methanamine as an orange oil. LCMS (Method A, ESI): RT = 1.109 min, m / z = 241.0 [M+H] + .

[0490] Step 2. tert-Butyl N-[(5-bromo-3-methylpyridin-2-yl)( Synthesis of cyclopropylmethylcarbamate [ka] In a 250 mL round-bottom flask was placed (5-bromo-3-methylpyridin-2-yl)(cyclopropyl)methanamine (5 g, 20.74 mmol, 1.00 equiv.), TEA (10.37 g, 103.7 mmol, 5.00 equiv.) in dichloromethane (150 mL), and di-tert-butyl dicarbonate (8.8 g, 40.32 mmol, 2.00 equiv.) in 10 mL of dichloromethane was added dropwise at 0 °C. The resulting solution was stirred at 25 °C for 12 h. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3 × 100 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:3). This gave 6.00 g (yield=85%) of tert-butyl N-[(5-bromo-3-methylpyridin-2-yl)(cyclopropyl)methyl]carbamate as a yellow solid. LCMS (Method C, ESI): RT=1.356 min, m / z=341.0 [M+H] + .

[0491] Step 3. Synthesis of 6-([[(tert-butoxy)carbonyl]amino](cyclopropyl)methyl)-5-methylpyridine-3-carboxylate [ka] In a 100 mL round-bottom flask purged with an inert atmosphere of nitrogen, tert-butyl N-[(5-bromo-3-methylpyridin-2-yl)(cyclopropyl)methyl]carbamate (5.0 g, 14.65 mmol, 1.00 equiv.), Pd(dppf)Cl2 (1.8 g, 2.46 mmol, 0.17 equiv.), and TEA (5.0 g, 49.41 mmol, 3.37 equiv.) in 30 mL of methanol were placed. Carbon monoxide was introduced into the mixture. The resulting solution was stirred in an oil bath at 80 °C for 16 hours. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:2). This gave 4.3 g (yield=80%) of methyl 6-([[(tert-butoxy)carbonyl]amino](cyclopropyl)methyl)-5-methylpyridine-3-carboxylate as a yellow oil. LCMS (Method A, ESI): RT=1.263 min, m / z=321.0 [M+H] + . 1 H NMR (300 MHz, methanol-d4) δ 8.95 (s, 1H), 8.15 (s, 1H), 3.95 (s, 3H), 3.36-3.30 (m, 1H), 2.50 (s, 3H), 2.46-2.38 (m, 1H), 1.52 (s, 9H), 0.53-0.48 (m, 4H)

[0492] Step 4. Synthesis of tert-butyl N-[(5-carbamoyl-3-methylpyridin-2-yl)(cyclopropyl)methyl]carbamate [ka] A 100 mL round-bottom flask was charged with methyl 6-([[(tert-butoxy)carbonyl]amino](cyclopropyl)methyl)-5-methylpyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv.) and NH3 / MeOH (10 mL). The resulting solution was stirred in an oil bath at 80 °C for 16 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. This afforded 450 mg (yield = 79%) of tert-butyl N-[(5-carbamoyl-3-methylpyridin-2-yl)(cyclopropyl)methyl]carbamate as a yellow oil. LCMS (Method A, ESI): RT = 0.978 min, m / z = 306.0 [M+H] + .

[0493] Step 5. Synthesis of tert-butyl N-[[5-(aminomethyl)-3-methylpyridin-2-yl](cyclopropyl)methyl]carbamate [ka] In a 100 mL round-bottom flask maintained under an inert nitrogen purging atmosphere, tert-butyl N-[(5-carbamoyl-3-methylpyridin-2-yl)(cyclopropyl)methyl]carbamate (400 mg, 1.31 mmol, 1.00 equiv.) was placed, and tetrahydrofuran (2 mL) and NaBH (250 mg, 6.61 mmol, 5.05 equiv.) were added batchwise at 0 °C. The resulting solution was stirred for 1 h, and BF-EtO (1.5 mL) was added dropwise at 0 °C. The resulting solution was stirred at 25 °C for 3 h. The reaction progress was monitored by LCMS. The reaction solution was quenched with 5 mL of methanol, the resulting mixture was concentrated, and the residue was dissolved with 20 mL of dichloromethane. The solution was washed with water (3 × 10 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. This gave 300 mg (yield=79%) of tert-butyl N-[[5-(aminomethyl)-3-methylpyridin-2-yl](cyclopropyl)methyl]carbamate as a yellow oil, which was used directly for the next step. LCMS (Method A, ESI): RT=0.837 min, m / z=292.0 [M+H] + .

[0494] Step 6. Synthesis of tert-butyl N-[cyclopropyl[5-(1H-imidazol-1-ylmethyl)-3-methylpyridin-2-yl]methyl]carbamate [ka] A 100 mL round-bottom flask was charged with tert-butyl N-[[5-(aminomethyl)-3-methylpyridin-2-yl](cyclopropyl)methyl]carbamate (300 mg, 1.03 mmol, 1.00 equiv.), HCHO (40% in water) (2 mL), NH3 / MeOH (7 mol / L) (3 mL), and oxaldehyde (2 mL). The resulting solution was stirred in an oil bath at 60 °C for 4 h. The reaction progress was monitored by LCMS, and the resulting solution was concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane / methanol (10:1). This afforded 300 mg (85% yield) of tert-butyl N-[cyclopropyl[5-(1H-imidazol-1-ylmethyl)-3-methylpyridin-2-yl]methyl]carbamate as a yellow oil. LCMS (Method A, ESI): RT=1.291 min, m / z=343.0[M+H] + .

[0495] Step 7. Synthesis of (5-((1H-imidazol-1-yl)methyl)-3-methylpyridin-2-yl)(cyclopropyl)methanamine hydrochloride [ka] Into a 25 mL round-bottom flask was placed tert-butyl (5-((1H-imidazol-1-yl)methyl)-3-methylpyridin-2-yl)(cyclopropyl)methylcarbamate (300.00 mg, 0.87 mmol, 1.00 equiv), HCl (g) / dioxane (2 mol / L) (4.00 mL), and the resulting solution was stirred at 25° C. for 30 min. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. This afforded 260.00 mg (crude) of (5-((1H-imidazol-1-yl)methyl)-3-methylpyridin-2-yl)(cyclopropyl)methanamine hydrochloride as an off-white solid. LCMS (Method A, ESI): RT=0.861 min, m / z=243.0 [M+H] + .

[0496] Step 8. Synthesis of N-((5-((1H-imidazol-1-yl)methyl)-3-methylpyridin-2-yl)(cyclopropyl)methyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide [ka] Cyclopropyl[5-(1H-imidazol-1-ylmethyl)-3-methylpyridin-2-yl]methanamine (260 mg, 0.95 mmol, 1.00 equiv.) was placed in a 100 mL round-bottom flask, and TEA (375 mg, 3.71 mmol, 2.99 equiv.), N,N-dimethylformamide (2 mL), 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (263 mg, 1.36 mmol, 1.10 equiv.), and HATU (565 mg, 1.49 mmol, 1.20 equiv.) were added batchwise. The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The reaction solution was quenched with 5 mL of water, and the solid was collected by filtration. The crude product was purified by preparative HPLC using the following conditions: Column, X-bridge Shield RP18, 5 μm, 19 * 150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (10.0% CH3CN, to 28.0% in 2 min, to 46.0% in 10 min, to 100.0% in 1 min, decreasing to 10.0% in 1 min); detector, UV 254 / 220 nm. This gave 11.5 mg (yield = 2%) of N-((5-((1H-imidazol-1-yl)methyl)-3-methylpyridin-2-yl)(cyclopropyl)methyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide as a white solid. LCMS (Method B, ESI): RT = 1.27 min, m / z = 418.0 [M+H] + . 1H NMR(400MHz, methanol-d4)δ 8.37(s,1H),7.81(s,1H),7.52(s,1H),7.22(s,1H),7.17(s,1H),7.04(s,1H),7.01-6.92(m,1H),6.66(t,J=10.3Hz,1H),5.27 (s,2H),4.93(d,J=8.9Hz,1H),2.50(s,6H),1.51-1.45(m,1H),0.72-0.62(m,1H),0.60-0.47(m,1H),0.47(t,J=5.3Hz,2H)ppm.

[0497] Example 7 Synthesis of N-(1-((1r,4r)-4-(dimethylamino)cyclohexyl)-1H-indazol-4-yl)-4-fluoro-7-methyl-1H-indole-2-carboxamide (Compound No. 213) Step 1. Synthesis of tert-butyl N-[(1r,4r)-4-(4-nitro-1H-indazol-1-yl)cyclohexyl]carbamate [ka] Into a 25 mL two-necked round-bottom flask maintained under an inert atmosphere of nitrogen was added a solution of 4-nitro-1H-indazole (500 mg, 3.06 mmol, 1.00 equiv.) in tetrahydrofuran (12 mL), tert-butyl N-[(1s,4s)-4-hydroxycyclohexyl]carbamate (700 mg, 3.25 mmol, 1.20 equiv.), P Ph3 (700 mg, 2.67 mmol, 1.20 equiv.) was added. After this, DIAD (700 mg, 3.46 mmol, 1.20 equiv.) was added dropwise over 10 min at 0 °C with stirring. The resulting solution was stirred at 25 °C for 12 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:6). This gave 260 mg (yield = 24%) of tert-butyl N-[(1r,4r)-4-(4-nitro-1H-indazol-1-yl)cyclohexyl]carbamate as a pale yellow solid. LCMS (Method A, ESI): m / z = 361.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.91(s,1H),8.21-8.19(dd,J=8.1,4.8Hz,2H),7.51-7.47(t,J=8.1Hz,1H),6.88-6.86(d,J=7.7Hz,1H),4.6 8-4.62(m,1H),3.46-3.34(m,1H),2.12-2.07(m,4H),2.03-1.96(m,2H),1.52-1.44(m,2H),1.40(s,9H)ppm.

[0498] Step 2. Synthesis of tert-butyl N-[(1r,4r)-4-(4-amino-1H-indazol-1-yl)cyclohexyl]carbamate [ka] A 40 mL vial was charged with a solution of tert-butyl N-[(1r,4r)-4-(4-nitro-1H-indazol-1-yl)cyclohexyl]carbamate (100 mg, 0.28 mmol, 1.00 equiv.) in ethanol (20 mL), Fe powder (100 mg, 5.00 equiv.) in water (3 mL), and NH4Cl (100 mg, 1.87 mmol, 5.00 equiv.). The resulting solution was stirred at 80 °C for 2 h. The reaction progress was monitored by LCMS. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane / methanol (10 / 1). This gave 80 mg (yield=87%) of tert-butyl N-[(1r,4r)-4-(4-amino-1H-indazol-1-yl)cyclohexyl]carbamate as a pale yellow solid. LCMS (Method A, ESI): RT=0.753 min, m / z=331.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.05(s,1H),7.01-6.97(dd,J=8.3,7.4Hz,1H),6.85-6.83(d,J=7.8Hz,1H),6.73-6.71(d,J=8.3Hz,1H),6.14-6.12(d, J=7.4Hz,1H),5.71(s,2H),4.36-4.33(m,1H),3.38-3.35(m,1H),1.99-1.89(m,6H),1.48-1.41(m,2H),1.40(s,9H)ppm.

[0499] Step 3. Synthesis of tert-butyl N-[(1r,4r)-4-[4-(4-fluoro-7-methyl-1H-indole-2-amido-1H-indazol-1-yl]cyclohexyl]carbamate [ka] A 40 mL round-bottom flask was charged with a solution of tert-butyl N-[(1r,4r)-4-(4-amino-1H-indazol-1-yl)cyclohexyl]carbamate (200 mg, 0.61 mmol, 1.00 equiv.) in N,N-dimethylformamide (10 mL), and 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (160 mg, 0.83 mmol, 1.20 equiv.), TEA (260 mg, 2.57 mmol, 3.00 equiv.), and HATU (423 mg, 1.11 mmol, 1.30 equiv.) were added batchwise. The resulting solution was stirred at 25 °C for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was quenched with 30 mL of water. The resulting solution was extracted with 3 × 10 mL of ethyl acetate, and the organic layers were combined. The filtrate was concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1). This gave 190 mg (yield=62%) of tert-butyl N-[(1r,4r)-4-[4-(4-fluoro-7-methyl-1H-indole-2-amido)-1H-indazol-1-yl]cyclohexyl]carbamate as a pale yellow oil. LCMS (Method D, ESI): RT=1.253 min, m / z=506.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.95(s,1H),10.39(s,1H),8.26(s,1H),7.60-7.59(d,J=2.1Hz,1H),7.56-7.50(dd,J =18.3,7.9Hz,2H),7.40-7.36(dd,J=8.4,7.5Hz,1H),7.01-6.97(dd,J=7.8,5.2,1.0Hz, 1H),6.89-6.87(d,J=7.7Hz,1H),6.80-6.75(dd,J=10.4,7.8Hz,1H),4.60-4.57(m,1H), 3.17(s,1H),2.52(s,3H),2.05-1.93(m,6H),1.56-1.46(m,5.9Hz,2H),1.41(s,9H)ppm.

[0500] Step 4. Synthesis of 4-fluoro-7-methyl-N-[1-[(1r,4r)-4-aminocyclohexyl]-1H-indazol-4-yl]-1H-indole-2-carboxamide [ka] In an 8 mL vial, tert-butyl N-[(1r,4r)-4-[4-(4-fluoro-7-methyl-1H-indole-2-amido)-1H-indazol-1-yl]cyclohexyl]carbamate (200 mg, 0.40 mmol, 1.00 equiv.) and hydrogen chloride in 1,4-dioxane (2 mol / L) (10 mL) were placed. The resulting solution was stirred at 25° C. for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum to give 150 mg (yield=94%) of the product. 4-Fluoro-7-methyl-N-[1-[(1r,4r)-4-aminocyclohexyl]-1H-indazol-4-yl]-1H-indole-2-carboxamide was obtained as a pale yellow oil. LCMS (Method A, ESI): RT = 1.423 min, m / z = 406.2 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.22(s,1H),10.64(s,1H),8.33(s,1H),7.59-7.53(m,3H),7.41-7.36 (dd,J=8.3,7.6Hz,1H),7.00-6.97(dd,J=7.7,5.2Hz,1H),6.79-6.75(d d,J=10.4,7.8Hz,1H),4.67-4.58(d,J=8.0Hz,1H),3.63-3.60(m,1H),2 .54(s,3H),2.17-2.10(m,6H),2.08-1.99(m.2H),1.72-1.59(m,2H)ppm.

[0501] Step 5. Synthesis of N-(1-((1r,4r)-4-(dimethylamino)cyclohexyl)-1H-indazol-4-yl)-4-fluoro-7-methyl-1H-indole-2-carboxamide [ka] A 40 mL round-bottom flask was charged with a solution of 4-fluoro-7-methyl-N-[1-[(1r,4r)-4-aminocyclohexyl]-1H-indazol-4-yl]-1H-indole-2-carboxamide (350 mg, 0.86 mmol, 1.00 equiv.) in methanol (10 mL). Subsequently, CHO (40% in water) (3 mL) was added. To this was added NaBHCN (160 mg, 2.5 mmol, 3.00 equiv.) in a batchwise manner. The resulting solution was stirred at 25 °C for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was quenched with 30 mL of water. The resulting solution was extracted with 3 × 10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was concentrated under vacuum. The crude product (180 mg) was purified by preparative HPLC using the following conditions: Column, XSelect CSH Preparative C18 OBD Column, 5 μm, 19 * 150 mm; mobile phase, water (0.05% TFA) and ACN (22.0% ACN, up to 45.0% in 7 min); detector, UV 220 / 254 nm. This gave 36.2 mg (yield = 9.6%) of 4-fluoro-7-methyl-N-[1-[(1r,4r)-4-(dimethylamino)cyclohexyl]-1H-indazol-4-yl]-1H-indole-2-carboxamide trifluoroacetate as a white solid. LCMS (Method D, ESI): RT = 1.510 min, m / z = 434.2 [M+H] + . 1 H NMR(300MHz, methanol-d4)δ 8.22(s,1H),7.47-7.43(m,4H),7.02-6.97(m,1H),6.74-6.64(m,1H),4.72-4.62(m,1H) ,3.43-3.41(m,1H),2.93(s,6H),2.53(s,3H),2.32-2.15(m,6H),1.98-1.80(m,2H)ppm.

[0502] Example 8 Synthesis of 4-fluoro-N-(7-fluoroisoquinolin-5-yl)-7-methyl-1H-indole-2-carboxamide (Compound No. 82) [ka] A 40 mL vial purged with an inert nitrogen atmosphere was charged with a solution of 4-fluoro-7-methyl-1H-indole-2-carboxamide (100 mg, 0.52 mmol, 1.00 equiv.) in N,N-dimethylformamide (10 mL), 7-fluoroisoquinolin-5-amine (100 mg, 0.62 mmol, 1.20 equiv.), CuI (110 mg, 0.58 mmol, 1.00 equiv.), CsCO (537 mg, 1.65 mmol, 3.00 equiv.), and (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (100 mg, 0.70 mmol, 1.40 equiv.). The resulting solution was stirred at 80 °C for 2 h. The reaction progress was monitored by LCMS. The resulting solution was quenched with 20 mL of water / ice. The resulting solution was extracted with 3 x 10 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3 x 10 mL of HO. The crude product (300 mg) was purified by preparative HPLC with the following conditions: Column, XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (39% ACN, up to 61% in 7 min); detector, UV 254 / 220 nm. This gave 31.8 mg (yield = 18%) of 4-fluoro-N-(7-fluoroisoquinolin-5-yl)-7-methyl-1H-indole-2-carboxamide as a white solid. LCMS (Method B, ESI): m / z = 337.9 [M + H] + . 1 H NMR(300MHz,DMSO-d6)δ 12.03(s,1H),10.69(s,1H),9.37(s,1H),8.58(d,J=6.0Hz,1H),8.03(t,J=4.5Hz,6.0Hz,2H),7.9 1(d,J=9.0Hz,1H),7.68(s,1H),7.01(t,J=6.9Hz,5.7Hz,1H),6.85-6.75(m,1H),3.30(s,3H)ppm.

[0503] Example 9 Synthesis of 4-fluoro-7-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethyl)-1H-indole-2-carboxamide (Compound No. 85) Step 1. Synthesis of 1-methyl-1H-pyrazole-4-carbaldehyde [ka] An 8 mL vial was charged with a solution of 1H-pyrazole-4-carbaldehyde (50 mg, 0.52 mmol, 1.00 equiv.) in N,N-dimethylformamide (1 mL), CHCl (96 mg, 0.68 mmol, 1.30 equiv.), and CsCO (510 mg, 1.57 mmol, 3.00 equiv.). The resulting solution was stirred at 60° C. for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched with 10 mL of water. The resulting solution was extracted with 3×12 mL of ethyl acetate, and the organic layers were combined. The organic phase was concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:4). This gave 40 mg (yield = 80%) of 1-methyl-1H-pyrazole-4-carbaldehyde as a white solid. LCMS (Method A, ESI): RT = 0.699 min, m / z = 111.1 [M+H] + .

[0504] Step 2. Synthesis of E)-ethyl 3-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylpyridin-2-yl)acrylate [ka] A 40 mL vial purged with an inert nitrogen atmosphere was charged with a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (465 mg, 4.22 mmol, 1.50 equiv.) in ethanol (20 mL), ethyl 2-(3-methylpyridin-2-yl)acetate (500 mg, 2.79 mmol, 1.00 equiv.), acetic acid (840 mg, 13.99 mmol, 5.00 equiv.), and piperidine (1.2 g, 14.09 mmol, 5.00 equiv.). The resulting solution was stirred at 80 °C for 48 h. The reaction progress was monitored by LCMS. The resulting solution was concentrated under vacuum, and the residue was dissolved in 20 mL of dichloromethane. The resulting mixture was washed with 3 × 15 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column with dichloromethane / methanol (10:1). This gave 620.00 mg (yield=75%) of (E)-ethyl 3-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylpyridin-2-yl)acrylate as a white solid. LCMS (Method A, ESI): RT=0.842 min, m / z=272.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.48(t,J=3.0Hz,1H),7.75(s,2H),7.37(t,J=6.0Hz,1H),7.30(s,1H),6.44(s,1H) ),4.14(q,J=6.0Hz,15Hz,2H),3.72(s,3H),2.06(s,3H),1.17(t,J=6.0Hz,3H)ppm.

[0505] Step 3. Synthesis of E)-3-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylpyridin-2-yl)acrylic acid [ka] A 40 mL vial was charged with a solution of ethyl (2E)-3-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylpyridin-2-yl)prop-2-enoate (620 mg, 2.29 mmol, 1.00 equiv.) in 20 mL of hydrogen chloride (6 mol / L). The resulting solution was stirred at 80° C. for 15 hours. The reaction progress was monitored by LCMS. The resulting solution was concentrated under vacuum to give 500.00 mg (yield=80%) of (E)-3-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylpyridin-2-yl)acrylic acid as a white solid, which was used for the next step without further purification. LCMS (Method A, ESI): RT=0.745 min, m / z=244.0 [M+H] + .

[0506] Step 4. Synthesis of (E)-2-(1-isocyanato-2-(1-methyl-1H-pyrazol-4-yl)vinyl)-3-methylpyridine [ka] A solution of (2E)-3-(1-methyl-1H-pyrazol-4-yl)-2-(3-methylpyridin-2-yl)prop-2-enoic acid (500 mg, 2.06 mmol, 1.00 equiv.) in N,N-dimethylformamide (20 mL), DPPA (850 mg, 3.09 mmol, 1.50 equiv.), and TEA (1.05 g, 10.38 mmol, 5.00 equiv.) was placed in a 40 mL vial purged with an inert atmosphere of nitrogen. The resulting solution was stirred at 80 °C for 2 hours. The reaction progress was monitored by LCMS. The resulting solution was quenched with 30 mL of water, and the resulting mixture was extracted with 3 × 35 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column with dichloromethane / methanol (20:1). This gave 170.00 mg (yield=34%) of (E)-2-(1-isocyanato-2-(1-methyl-1H-pyrazol-4-yl)vinyl)-3-methylpyridine as a solid. LCMS (ESI): RT=0.736 min, m / z=241.0 [M+H] + .

[0507] Step 5. Synthesis of (E)-benzyl 2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)vinylcarbamate [ka] A 20 mL vial was charged with a solution of 2-[(E)-1-isocyanato-2-(1-methyl-1H-pyrazol-4-yl)ethenyl]-3-methylpyridine (170 mg, 0.71 mmol, 1.00 equiv.) in benzyl alcohol (2 mL). The resulting solution was stirred at 100 °C for 15 h. The reaction progress was monitored by LCMS. The resulting solution was quenched with 30 mL of water, and the resulting mixture was extracted with 3 × 20 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column with dichloromethane / methanol (15:1). This afforded 80.00 mg (yield = 46%) of (E)-benzyl 2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)vinylcarbamate as a white solid. LCMS (Method, ESI): RT=0.859 min, m / z=349.0[M+H] + .

[0508] Step 6. Synthesis of 2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethanamine [ka] A 50 mL round-bottom flask was charged with a solution of benzyl N-[(E)-2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethenyl]carbamate (80 mg, 0.23 mmol, 1.00 equiv.) in MeOH (5 mL) and PtO2 (20 mg). Hydrogen was introduced into the mixture. The resulting solution was stirred at 25 °C for 20 min. The reaction progress was monitored by LCMS. The solids were removed by filtration, and the resulting mixture was concentrated under vacuum to give 70 mg (yield = 85%) of 2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethanamine. LCMS (Method A, ESI): RT = 0.326 min, m / z = 216.0 [M+H] + .

[0509] Step 7. Synthesis of 4-fluoro-7-methyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethyl)-1H-indole-2-carboxamide [ka] A solution of 2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethan-1-amine (80 mg, 0.37 mmol, 1.00 equiv.) in N,N-dimethylformamide (3 mL) was placed in a 100 mL round-bottom flask, and 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (80 mg, 0.41 mmol, 1.10 equiv.), TEA (113 mg, 1.12 mmol, 3.00 equiv.), and HATU (183 mg, 0.48 mmol, 1.30 equiv.) were added batchwise. The resulting solution was stirred at 25 °C for 1 hour. The crude product (100 mg) was purified by preparative HPLC using the following conditions: Column: XSelect CSH preparative C18 OBD column, 5 μm, 19 * 150 mm; mobile phase, water (0.05% TFA) and ACN (16.0% ACN, up to 42.0% in 7 min); detector, UV 220 / 254 nm. This gave 37.5 mg (yield = 20%) of 4-fluoro-7-methyl-N-[2-(1-methyl-1H-pyrazol-4-yl)-1-(3-methylpyridin-2-yl)ethyl]-1H-indole-2-carboxamide as the trifluoroacetate salt as a white solid. LCMS (Method A, ESI): m / z = 391.9 [M + H] + . 1 H NMR(400MHz, methanol-d4)δ 8.56(s,1H),8.16(s,1H),7.68(s,1H),7.41(d,J=2.7Hz,1H),7.32(d,J=1.1Hz,1H),7.20(d,J=4.7Hz,1H),6.99-6.96 (m,1H),6.73-6.63(m,1H),5.56(t,J=7.6Hz,1H),4.86(s,3H),3.36(s,1H),3.27-3.17(m,1H),2.53-2.45(m,6H)ppm.

[0510] Example 10 Synthesis of 4-fluoro-N-(3-fluoro-5-(3-(N-methylacetamido)pyrrolidin-1-yl)phenyl)-7-methyl-1H-indole-2-carboxamide (Compound No. 1) Step 1. Synthesis of tert-butyl N-[1-(3-fluoro-5-nitrophenyl)pyrrolidin-3-yl]-N-methylcarbamate [ka] A 250 mL round-bottom flask was charged with 1,3-difluoro-5-nitrobenzene (2 g, 12.57 mmol, 1.00 equiv.), CsCO (13 g, 39.90 mmol, 3.17 equiv.), DMSO (30 mL), and tert-butyl N-methyl-N-(pyrrolidin-3-yl)carbamate (2.6 g, 12.98 mmol, 1.03 equiv.). The resulting solution was stirred at 100 °C for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This afforded 680 mg (yield = 16%) of tert-butyl N-[1-(3-fluoro-5-nitrophenyl)pyrrolidin-3-yl]-N-methylcarbamate as a pale yellow solid. LCMS (Method A, ESI): RT=2.876 min, m / z=340.00[M+H] + .

[0511] Step 2. Synthesis of 1-(3-fluoro-5-nitrophenyl)-N-methylpyrrolidin-3-amine [ka] In a 40 mL vial, tert-butyl N-[1-(3-fluoro-5-nitrophenyl)pyrrolidin-3-yl]-N-methylcarbamate (650 mg, 1.92 mmol, 1.00 equiv.) and trifluoroacetic acid (3 mL) were placed in dichloromethane (7 mL). The resulting solution was stirred at 25° C. for 1 hour, and the reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. This afforded 350 mg (yield=76%) of 1-(3-fluoro-5-nitrophenyl)-N-methylpyrrolidin-3-amine as a pale yellow solid. LCMS (Method A, ES): RT=0.900 min, m / z=240.00 [M+H] + .

[0512] Step 3. Synthesis of N-[1-(3-fluoro-5-nitrophenyl)pyrrolidin-3-yl]-N-methylacetamide [ka] 1-(3-Fluoro-5-nitrophenyl)-N-methylpyrrolidin-3-amine (1 g, 4.18 mmol, 1.00 equiv.) was placed in a 40 mL vial, and TEA (2 g, 19.76 mmol, 4.73 equiv.) and acetylacetate (750 mg, 7.35 mmol, 1.76 equiv.) in dichloromethane (10 mL) were added dropwise at 0 °C. The resulting solution was stirred at 25 °C for 2 hours. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This gave 900 mg (yield = 77%) of N-[1-(3-fluoro-5-nitrophenyl)pyrrolidin-3-yl]-N-methylacetamide as a pale yellow solid. LCMS (Method A, ES): RT=1.188 min, m / z=282.00[M+H] + .

[0513] Step 4. Synthesis of N-[1-(3-amino-5-fluorophenyl)pyrrolidin-3-yl]-N-methylacetamide [ka] A 100 mL round-bottom flask was charged with N-[1-(3-fluoro-5-nitrophenyl)pyrrolidin-3-yl]-N-methylacetamide (300 mg, 1.07 mmol, 1.00 equiv.) and Raney nickel (100 mg) in methanol (10 mL). Hydrogen was introduced into the mixture. The resulting solution was stirred at 25° C. for 1 hour. The reaction progress was monitored by LCMS. The solid was filtered off. The resulting mixture was concentrated under vacuum. This afforded 220 mg (yield=82%) of N-[1-(3-amino-5-fluorophenyl)pyrrolidin-3-yl]-N-methylacetamide as an off-white solid. LCMS (Method A, ESI): RT=0.834 min, m / z=252.00 [M+H] + .

[0514] Step 5. Synthesis of 4-fluoro-N-(3-fluoro-5-(3-(N-methylacetamido)pyrrolidin-1-yl)phenyl)-7-methyl-1H-indole-2-carboxamide [ka] N-[1-(3-amino-5-fluorophenyl)pyrrolidin-3-yl]-N-methylacetamide (330 mg, 1.31 mmol, 1.00 equiv.) was placed in a 40 mL vial, and TEA (700 mg, 6.92 mmol, 5.27 equiv.), 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (250 mg, 1.29 mmol, 0.99 equiv.), and HATU (649 mg, 1.71 mmol, 1.30 equiv.) in N,N-dimethylformamide (10 mL) were added batchwise. The resulting solution was stirred at 25 °C for 2 hours. The resulting mixture was concentrated in vacuo. The reaction progress was monitored by LCMS, and the reaction solution was quenched with 20 mL of water. The resulting solution was extracted with 3 × 20 mL of ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:1). The crude product (200 mg) was purified by preparative HPLC with the following conditions: Column, XBridge Shield RP18OBD column, 5 μm, 19 * 150 mm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (40.0% ACN, up to 68.0% in 7 min); detector, UV 220 / 254 nm. This gave 47.4 mg (yield = 8%) of 4-fluoro-N-(3-fluoro-5-(3-(N-methylacetamido)pyrrolidin-1-yl)phenyl)-7-methyl-1H-indole-2-carboxamide as a pale yellow solid. LCMS (Method B, ES): RT = 3.206 min, m / z = 427 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.19(s,1H),7.51(s,1H),7.19-7.08(m,1H),7.03-6.93(m,1H),6.87(d,J=2.1Hz,1H),6.86-6.73(m,1H) ,6.17-6.13(m,1H),5.23-4.63(m,1H),3.54-3.33(m,2H),3.26-3.16(m, 2H),2.90(s,2H),2.76(s,1H),2.61-2.51(s,3H),2.24-2.00(m,5H)ppm.

[0515] Example 11 In-cell Western (ICW) assay for SETD2 inhibitors (A549 assay) Representative compounds of the present disclosure were tested in the A549 assay according to the following protocol: The A549 assay results are provided in Table 1B.

[0516] protocol: 1. Reagents and Consumables:

[0517] [Table 135]

[0518] 2. Tools and equipment:

[0519] [Table 136]

[0520] 3. Screening Method Prepare compound-bearing plates. Seed A549 cells into compound-bearing plates (4,000 cells / well, 50 μL / well). Place plates on a non-vibrating surface at room temperature for 20 minutes, then place in an incubator. Incubate plates at 37°C in a CO2 incubator for 3 days. Remove plates from incubator and allow to come to room temperature. Remove medium from plates and add 50 μL of ice-cold 100% methanol. Incubate at room temperature for 30 minutes. Remove methanol by aspiration. Wash 3 times with PBST. Add 50 μL of blocking buffer + 0.1% Tween 20. Incubate for 1 hour. Remove blocking buffer and wash 3 times with PBST. Add 20 μL of H3K36me3 (1:1000 dilution) (Cell Signaling Technologies mAb#4909). Incubate overnight at 4°C. Wash plates 5 times with PBS-T. Add 20 μL of DRAQ5 (1:1000) and IRDye800CW goat anti-rabbit IgG (1:500). Incubate in the dark for 1 hour. Wash plate 5 times with PBS-T. Wash plate 3 times with water. Blot dry on paper towels, then centrifuge plate upside down on a thin layer of paper towels at 1000 rpm for 1 minute to remove excess reagent. Allow plate to sit uncovered without direct light for approximately 10 minutes before reading. Read on a Licor instrument.

[0521] 4. Licor Equipment Setup: Preset: Plate; Resolution: 84 μm; Quality: Low; Focus Offset: 4.0; 700 Channel Intensity: 2; and 800 Channel Intensity: 3.

[0522] Example 12 SETD2(1434-1711) assay Representative compounds of the present disclosure were tested in the SETD2(1434-1711) assay using the following protocol: The SETD2(1434-1711) assay results are presented in Table 1B.

[0523] 1. Reagents

[0524] [Table 137]

[0525] 2. Tools / Equipment List

[0526] [Table 138]

[0527] 3. Reagent Formulation

[0528] [Table 139]

[0529] 4. Procedure Description

[0530] [Table 140]

[0531] Example 13 14-day KMS-34 long-term proliferation (LTP) assay Representative compounds of the present disclosure were tested in a 14-day KMS-34 LTP assay using the following protocol. The assay results for the 14-day KMS-34 LTP assay are provided in Table 5 and Figure 2. Figure 3 compares the KMS-34 LTP activity and A549H3K36me3 activity of compound numbers 7, 11, 15, 22, 31, 32, 34, 64, 65, 66, 76, 115, 134, 151, 194, and 221 (see Example 11).

[0532] 1. Reagents, consumables and equipment:

[0533] [Table 141]

[0534] 2. Screening Method Day 0: 1.25 x 10 in a flat-bottom 96-well plate 5 Add 100 μl of cells per well at a density of cells / ml (Note: inner wells only. Fill all outer wells with PBS to avoid evaporation of inner wells). Add 50 μl of compound to each well. The final volume in each well is 150 μl. Incubate the plate for 96 hours. Days 1, 2, and 3: Wait

[0535] Day 4: Pipette cells up and down to mix in each well. Aspirate 20 μl of cell suspension in the V-bottom plate and add to a poly-D-lysine coated 96-well plate. Add 30 μl of HBSS and 50 μl of HBSS containing 2 μM Calcein-AM. Final concentration is 1 μM. Let cells sit for 10 minutes at RT, followed by a quick spin to sediment the cells to the bottom of the well. Incubate plate for another 40 minutes in the incubator (to fill with Calcein AM and give cells more time to adhere). Remove plate and read in Acumen. Calculate cell number taking into account the dilution factor. Divide the master plate by calculating the total viable cell number. Pipette cells up and down to mix in each well. 1.1 * 100 μl of the calculated cell suspension is aspirated from each well and added to a V-bottom plate. The plate is spun at 1100 rpm for 5 minutes. Following the spin, the medium is removed, being careful not to disturb the cell pellet. The pellet is resuspended in 110 μl of fresh medium. The cells are mixed in each well by pipetting up and down. 100 μl of cell suspension is aspirated from each well and added to a new 96-well flat-bottom plate. 50 μl of compound solution is added. The plate is incubated for 72 hours.

[0536] Day 7: Pipette the cells up and down to mix in each well. Aspirate 20 μl of cell suspension from the V-bottom plate and add to a poly-D-lysine-coated 96-well plate. Add 30 μl of HBSS and 50 μl of HBSS containing 2 μM calcein-AM. The final concentration is 1 μM. Let the cells sit for 10 minutes at RT, followed by a quick spin to settle the cells to the bottom of the wells. Incubate the plate for another 40 minutes in the incubator (to fill with Calcein AM and give the cells more time to attach). Remove the plate and read it in the Acumen. Calculate the cell number taking into account the dilution factor. Split the master plate by calculating the total viable cell number. Pipette the cells up and down to mix in each well. 1.1 * Aspirate the calculated volume of cell suspension from each well and add to a V-bottom plate. Spin the plate at 1100 rpm for 5 minutes. Following the spin, remove the medium carefully so as not to disturb the cell pellet. Resuspend the pellet in 110 uL of fresh medium. Pipette the cells up and down to mix in each well. Aspirate 100 μl of cell suspension from each well and add to a new 96-well flat-bottom plate. Add 50 μl of compound solution. Incubate the plate for 96 hours.

[0537] Day 11: Pipette cells up and down to mix in each well. Aspirate 20 μl of cell suspension from the V-bottom plate and add to a poly-D-lysine-coated 96-well plate. Add 30 μl of HBSS and 50 μl of HBSS containing 2 μM calcein-AM. The final concentration is 1 μM. Allow cells to sit at RT for 10 minutes, followed by a quick spin to settle the cells to the bottom of the well. Incubate the plate in the incubator for an additional 40 minutes (to fill with calcein AM and give the cells more time to attach). Remove plate and read in Acumen. Calculate cell number taking into account the dilution factor. Divide the master plate by calculating the total viable cell count. Pipette cells up and down to mix in each well to reduce variations that may be introduced by pipetting. Aspirate all cell suspensions from B1-2, C1-2, and D1-2 and add to the V-bottom plate. 1.1 * Aspirate the calculated cell suspension from the other wells and add to the V-bottom plate. Spin the plate at 1100 rpm for 5 minutes. Following the spin, remove the medium carefully so as not to disturb the cell pellet. Resuspend the pellets in B1-2, C1-2, and D1-2 in 100 uL of fresh medium. Pipette the cells up and down to mix in each well. Resuspend the pellets in the other wells in 110 μl of fresh medium. Pipette the cells up and down to mix in each well. Aspirate 100 μl of cell suspension from each well and add to a new 96-well flat-bottom plate.

[0538] Day 14: Pipette cells up and down to mix in each well. Aspirate 20 μl of cell suspension in the V-bottom plate and add to a poly-D-lysine coated 96-well plate. Add 30 μl of HBSS and 50 μl of HBSS containing 2 μM calcein-AM. Final concentration is 1 μM. Let cells sit for 10 minutes at RT, followed by a quick spin to sediment the cells to the bottom of the well. Incubate plate for a further 40 minutes in the incubator (to fill with calcein AM and give the cells more time to adhere). Remove plate and read in Acumen. Calculate cell number taking into account the dilution factor.

[0539] To calculate growth for days 4, 7, 11 and 14: 1. Calculate the division coefficients for days 4-7, days 7-11, and days 11-14. The division coefficient is the quotient of viable cells / mL on day X (day 4, day 7, or day 11) divided by the density at which cells divide. 2. For cell growth from days 4 to 7, multiply the viable cells / mL density on day 7 by the division factor from day 4. 3. For cell growth from days 7 to 11, multiply the viable cells / mL density on day 11 by the division factors on days 4 and 7. 4. For cell growth from days 11 to 14, multiply the viable cells / mL density on day 14 by the division factors for days 4, 7, and 11. 5. Plot growth on a semi-log chart (viable cells / mL in logarithm on the Y-axis and days on the X-axis).

[0540] Compound preparation: Compounds were dissolved in DMSO at 10 mM and stored at -20°C. Compounds were diluted in 3-fold serial dilutions with DMSO from 5 mM to 0.25 μM. 1.2 μl of compound from the compound plate was transferred and added to a 96-well plate with 200 μl of medium in each well. The wells were mixed by pipetting up and down. 50 μl of compound-containing medium was transferred to the cell plate.

[0541] [Table 142]

[0542] Example 14 14-day LTP assay in multiple myeloma cells Compound No. 15 was tested in several multiple myeloma cell lines in the LTP assay described in Example 13. The results are presented in Table 6 and Figure 1.

[0543] [Table 143]

[0544] Example 15 Evaluation of the antitumor activity of Compound No. 15 as a single agent in NOD SCID mice bearing human myeloma KMS-11 tumors animal Species and strain: NOD SCID mice; Age: 6-8 weeks; Total number: 75 mice including spares, 50 mice were used in the study; Gender: Female; Weight: 18-22 g

[0545] Groups and treatments The average tumor volume was approximately 118 mm 3 Groups and treatments were initiated when tumor volume reached 100 μg / kg. Mice were assigned to respective groups based on tumor volume and body weight so that the average starting tumor size and body weight were the same for each treatment group. The study groups and number of animals per group are shown in Table 7.

[0546] [Table 144]

[0547] Cell culture methods The KMS-11 tumor cell line was cultured at 37°C in an atmosphere of 5% CO2 in air at RPM Tumor cells were maintained in vitro as monolayer cultures in I-1640 + 10% FBS. Tumor cells were routinely passaged before confluence, but not for more than 4-5 passages. Cells growing in exponential growth phase were harvested and counted for tumor seeding.

[0548] Methods of tumor seeding For tumor development, each mouse was inoculated with KMS-11 tumor cells (1 × 10) in 0.1 ml of RPMI-1640 subcutaneously on the right flank. 7 ) and Matrigel mixture (1:1 ratio). The average tumor size was 118 mm 3 Treatment began when tumor volume reached 100 mg / kg / day. Mice were then assigned to groups so that the mean tumor volume was the same for each treatment group and time point. Treatments were administered to tumor-bearing mice according to the study design shown in Table 7.

[0549] Tumor measurements Tumor size measurements were taken twice weekly with calipers and tumor volume (mm3) was estimated using the formula: TV = a x b x b / 2, where "a" and "b" are the long and short diameters of the tumor, respectively. TV is used to calculate tumor growth inhibition and tumor growth delay. The value for tumor growth inhibition (TGI) was calculated using the formula: a. %ΔT / ΔC = (treated TV final - treated TV initial) / (vehicle TV final - vehicle TV initial) * 100 b. %TGI = [1 - (treated TV last - treated VT first) / (vehicle TV last - vehicle TV first)] * 100.

[0550] "TV last" and "TV first" are the mean tumor volumes on the last and first days of dosing.

[0551] After removing five mice from G2 to G5 after the last dose, the remaining mice were maintained for monitoring tumor growth twice a week.

[0552] Criteria for determining the end Continually worsening conditions were observed or their tumor size exceeded 3,000 mm3 (individual tumor or group mean > 3,000 mm3). 3 ) were euthanized before death or before reaching coma. Animals showing obvious signs of severe distress and / or pain were humanely sacrificed by carbon dioxide followed by cervical dislocation to ensure death.

[0553] Sample collection Tumor samples and plasma were collected on the indicated days.

[0554] Data collection and statistical analysis Data collection: Measurements and observations required by the protocol were recorded manually on appropriate forms or directly on a computerized database.

[0555] Statistical analysis: All statistical tests were performed with a significance level of 5% or P<0.05. Group means and standard deviations were calculated for all measured parameters as per the study design. Two-way RM ANOVA was performed, followed by Tukey's post-hoc comparison of means.

[0556] Tumor volume The therapeutic effect of the compound as a single agent in a KMS-11 subcutaneous xenograft model was evaluated. The tumor sizes in different groups at different time points during the treatment period are shown in Tables 8 and 9 and Figure 4.

[0557] [Table 145]

[0558] [Table 146]

[0559] Inhibition rate of tumor growth The inhibition rate for tumor growth in each group is shown in Table 10.

[0560] [Table 147]

[0561] Compound No. 15 was also tested in the MM.1S non-t(4;14) multiple myeloma xenograft model using similar methods and BID dosing. The results are provided in Figure 5.

[0562] Although the present invention has been fully described above, those skilled in the art will recognize that the present invention can be practiced within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof.

[0563] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the description and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0564] All patents and publications cited herein are hereby incorporated by reference in their entirety.

[0565] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula I: [ka] (In the formula, R 1a is selected from the group consisting of halogen, alkyl, alkoxy, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl; Q 1 is -C(R 1b )= and -N=; Q 2 is -C(R 1c )= and -N=; Q 3 is -C(R1d )= and -N=; However, Q 1 、Q 2 or Q 3 At least one of each is -C(R 1b )=, -C(R 1c )= or -C(R 1d )=and; R 1b 、R 1c and R 1d are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; R 1e is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

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Claims

1. Formula III: 【Chemistry 1】 (In the formula, R 1d is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; A 1 is selected from the group consisting of -N= and -C(R 2a )=; R 2a is selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl; R 2b is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclo, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, (carboxamido)alkyl, -OR 10c , amino, (heterocyclo)alkyl, (amino)alkyl, (hydroxy)alkyl, carboxamido, (heteroaryl)alkyl, -S(=O)R 9b , -S(=O) 2 R 9b and -C(=O)R 9c ; A 2 is selected from the group consisting of -N= and -C(R 2c )=; R 2c is selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl; R 2d is selected from the group consisting of hydrogen, alkyl, halogen, cyano, and haloalkyl; R 2e is selected from the group consisting of hydrogen, alkyl, halogen, and haloalkyl; R 9b is selected from the group consisting of amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl; R 9c is selected from the group consisting of amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl; and R 10c is selected from the group consisting of alkyl, (hydroxy)alkyl, and (amino)alkyl. or a pharma- ceutically acceptable salt or solvate thereof.

2. Formula III-A: 【Chemistry 2】 2. The compound of claim 1, having the formula:

3. R 2a is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, halogen, and C 1 -C 4 haloalkyl; R 2b is (A) unsubstituted 4- to 10-membered heterocyclo; (B) (i) -N(R 3a )C(═O)R 4a ; (ii) -NR 5a R 5b ; (iii) unsubstituted 4-10 membered heterocyclo; (iv) substituted 4-10 membered heterocyclo having one, two or three substituents independently selected from the group consisting of hydroxy, -NR 5c R 5d , C 1 -C 4 alkyl, C 1 -C 6 alkoxy, -C(R 6a )(R 6b )C(═O)NR 5e R 5f , -C(═O)R 4b , (hydroxy)C 1 -C 4 alkyl and halo; (v) unsubstituted C 3 -C 6 cycloalkyl; (vi) (hydroxy)C 1 -C 4 alkyl; (vii) C 1 -C 6 alkyl; (viii) -C(═O)NR 5g R 5h ; (ix) halo; (x) -C(=O)R 4c ; (xi) C 1 -C 6 haloalkyl; (xii) hydroxy; (xiii) (amino)C 1 -C 4 alkyl; (xiv) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (xv) -S(=O) 2 R 9a ; (xvi) (3-8 membered heterocyclo)C 1 -C 4 alkyl; (xvii) C 1 -C 6 alkoxy; (xviii) (C 3 -C 6 cycloalkyl)C 1 -4 alkyl; (xix) (C 6-10 aryl)C 1 -C 4 alkyl; and (xxii) -OR 10b a substituted 4-10 membered heterocyclo having 1, 2, 3 or 4 substituents independently selected from the group consisting of: (C) unsubstituted C3-C8 cycloalkyl; (D) (i) unsubstituted 4-10 membered heterocyclo; (ii) substituted 4-10 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of amino and C 1 -C 4 alkyl; (iii) unsubstituted 5- or 6-membered heteroaryl; (iv) substituted 5- or 6-membered heteroaryl having 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, (3- to 8-membered heterocyclo)alkyl, hydroxy and amino; (v) -NR 5i R 5j ; (vi) cyano; (vii) -N(R 3d )C(═O)R 4f ; (viii) hydroxy; and (ix) substituted C 3 -C 8 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 4 alkyl; (E) unsubstituted 5-10 membered heteroaryl; (F) (i) halo; (ii) C 1 -C 4 alkyl; (iii) (C 1 -C 4 alkoxy) C 1 -C 4 alkyl; (iv) (hydroxy) C 1 -C 4 alkyl; (v) C 3 -C 6 cycloalkyl; (vi) (amino) C 1 -C 4 alkyl; (vii) unsubstituted C 3 -C 6 cycloalkyl; (viii) substituted C 3 -C 6 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from the group consisting of -NR 5g R 5h ; (xi) unsubstituted 4-14 membered heterocyclo; (xii) substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C 1 -C 4 alkyl; (xiii) -NR 5q R 5r and (ix) a substituted 5-10 membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of (3-8 membered heterocyclo)C 1 -C 4 alkyl; (G) unsubstituted C 6 -C 10 aryl; (H) substituted C 6 -C 10 aryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of (i) halo; (ii) C 1 -C 4 alkyl; (iii) -CH 2 N(H)S(═O) 2 R 8 ; (iv) (5-9 membered heteroaryl)C 1 -C 4 alkyl; (v) -OR 10a ; (vi) -N(R 3b )C(═O)R 4b ; (vii) (amino)C 1 -C 4 alkyl; and (viii) (hydroxy)C 1 -C 4 alkyl; (I) (carboxamido)C 1 -C 4 alkyl; (J)-OR 10c; (K)-NR 5o R 5p; (L) (3- to 8-membered heterocyclo)C 1 -C 4 alkyl; (M) (amino)C 1 -C 4 alkyl; (N)(hydroxy)C 1 -C 4 alkyl; (O)-C(=O)NR 5s R 5t; (P)(5- to 9-membered heteroaryl)C 1 -C 4 alkyl; and (Q)-S(=O) 2 R 9b selected from the group consisting of: R 2c is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, halogen, and C 1 -C 4 haloalkyl; R 2d is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, halogen, cyano, and C 1 -C 4 haloalkyl; R 2e is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, halogen, and C 1 -C 4 haloalkyl; R 3a , R 3b , R 3c and R 3d are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl and optionally substituted 4-14 membered heterocyclo; R 4a , R 4b , R 4c , R 4d , R 4e and R 4f are selected from the group consisting of C 1 -C 6 alkyl; C 1 -C 6 haloalkyl; C 3 -C 6 cycloalkyl; C 1 -C 6 alkoxy; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (C 6-10 aryl)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (hydroxy)C 1 -C 4 alkyl; (cyano)C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted C 6 -C 10 aryl; halo and C 1 -C 4 substituted C 6 -C 10 aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl; unsubstituted 5- or 6-membered heteroaryl; and substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; R 5a and R 5b are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; R 5c and R 5d are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5c and R 5d together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5e and R 5f are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5e and R 5f together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5g and R 5h are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5g and R 5h together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5i and R 5j are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5i and R 5j together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5k and R 5l are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5k and R 5l together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5m and R 5n are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5m and R 5n together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5o and R 5p are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; or R 5o and R 5p together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 5q and R 5r are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; R 5s and R 5t are independently selected from the group consisting of hydrogen; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; (hydroxy)C 1 -C 4 alkyl; (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (5-9 membered heteroaryl)C 1 -C 4 alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; and substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C 1 -C 4 alkyl; R 6a , R 6b , R 6c and R 6d are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; R 8 is C 1 -C 6 alkyl; R 9a is selected from the group consisting of C 1 -C 6 alkyl; unsubstituted C 3 -C 8 cycloalkyl; and substituted C 3 -C 8 cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; R 9b is selected from the group consisting of C 1 -C 6 alkyl and amino; R 10a is selected from the group consisting of alkyl, (hydroxy)C 1 -C 4 alkyl, and (amino)C 1 -C 4 alkyl; R 10b is (amino)C 1 -C 4 alkyl; and R 10c is (amino)C 1 -C 4 alkyl; 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof.

4. The compound according to any one of claims 1 to 3, wherein A 1 and A 2 are -C(H)=; R 2e is hydrogen; and R 2d is selected from the group consisting of hydrogen and halogen, or a pharma- ceutically acceptable salt or solvate thereof.

5. R 2b is 【Chemistry 5-1】 【Chemistry 5-2】 selected from the group consisting of: R a1 is selected from the group consisting of -N(R 3a )C(═O)R 4a ; -NR 5a R 5b ; unsubstituted 4-10 membered heterocyclo; and substituted 4-10 membered heterocyclo having 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, -NR 5c R 5d , C 1 -C 4 alkyl, C 1 -C 6 alkoxy, -C(R 6a )(R 6b )C(═O)NR 5e R 5f , -C(═O)R 4b , (hydroxy)C 1 -C 4 alkyl and halo; R a2 and R a3 are each hydrogen; or R a2 and R a3 together with the carbon atom to which they are attached form a C(═O) group; R a4 is selected from the group consisting of hydrogen, halo, and hydroxy; R a5 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; R b1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; R c1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 4c ; R c2 and R c3 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl; or R c2 and R c3 together with the carbon atom to which they are attached form a C(═O) group; R c4 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; m is 1 or 2; R d1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R d2 and R d3 are each independently selected from the group consisting of hydrogen and fluoro; R e1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 4c ; R f1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 4c ; R g1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, —C(═O)R 4c , C 1 -C 4 haloalkyl, and (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; R h1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and -C(=O)R 4c ; R h2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; R h3 and R h4 are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; or R h3 and R h4 together with the carbon atom to which they are attached form a C(═O) group; R i1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (hydroxy)C 1 -C 4 alkyl, —N(R 3a )C(═O)R 4a and (amino)C 1 -C 4 alkyl; Z 1 is selected from the group consisting of -CH 2 - and -O-; R j1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and -C(=O)R 4c ; R k1 is selected from the group consisting of C 1 -C 4 alkyl, unsubstituted 4-14 membered heterocyclo, and -NR 5a R 5b ; R k2 is selected from the group consisting of hydrogen, hydroxy, and C 1 -C 4 alkyl; r is 0, 1 or 2; Z 2 is selected from the group consisting of -O- and -N(R m3 )-; R m3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl; R n1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R o1 is selected from the group consisting of hydroxy, (hydroxy)C 1 -C 4 alkyl, (amino)C 1 -C 4 alkyl, (C 1 -C 4 alkoxy)C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -NR 5a R 5b , unsubstituted 4-14 membered heterocyclo, and substituted 4-14 membered heterocyclo having 1, 2, or 3 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy; R o2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; R o3 is selected from the group consisting of hydrogen, fluoro, and C 1 -C 4 alkyl; R p1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; Z 3 is selected from the group consisting of -O- and -N(R q1 )-; R q1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R r1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R s1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R t1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R u1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and -C(=O)R 4c ; R v1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R w1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R x1 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and —C(═O)R 4c ; R y1 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and R z1 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt or solvate thereof.

6. R 2b is 【Chemistry 6-1】 【Chemistry 6-2】 6. The compound of claim 5, selected from the group consisting of: or a pharma- ceutically acceptable salt or solvate thereof.

7. The compound according to claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is selected from the group consisting of R2b-1A, R2b-1B, R2b-1C and R2b-1D.

8. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is selected from the group consisting of R2b-2A and R2b-2B; and Rb1 is C1-C4 alkyl.

9. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is selected from the group consisting of R2b-5A and R2b-5B; and Re1 is -C(=O)R4c.

10. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is selected from the group consisting of R2b-6A and R2b-6B; and Rf1 is -C(=O)R4c.

11. The compound according to claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is selected from the group consisting of R2b-10A, R2b-10B, R2b-10C and R2b-10d.

12. The compound according to claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is selected from the group consisting of R2b-11A and R2b-11B.

13. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2b is R2b-4; Rd1 is -C(=O)R4c; and Rd2 and Rd3 are each hydrogen or fluoro.

14. R 2b is R 2b -3; R c1 is selected from the group consisting of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 4c ; R c2 and R c3 are each hydrogen; or R c2 and R c3 together with the carbon atom to which they are attached form a C(═O) group; R c4 is hydrogen; and m is 1; 6. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof.

15. The compound of claim 5, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2b is R 2b -8; R h1 is -C(=O)R 4c; and R h2 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl.

16. The compound according to claim 5, wherein R 2b is R 2b -12; and R j1 is -C(=O)R 4c , or a pharma- ceutically acceptable salt or solvate thereof.

17. The compound according to any one of claims 5, 6, 9, 10, or 13 to 16, or a pharma- ceutically acceptable salt or solvate thereof, wherein R4c is C1-C4 alkyl.

18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt or solvate thereof, wherein R2d is selected from the group consisting of hydrogen, fluoro and chloro.

19. Formula V: 【Chemistry 19】 (In the formula, R 1d is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; R 14a is selected from the group consisting of optionally substituted alkyl and optionally substituted heteroaryl; R 14b is selected from the group consisting of optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted cycloalkyl, and carboxamido; and p is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt or solvate thereof.

20. R 14a is (A) unsubstituted 5-10 membered heteroaryl; (B) (i) halo; (ii) C 1 -C 4 alkyl; (iii) C 1 -C 4 alkoxy; (iv) (3-8 membered heterocyclo)C 1 -C 4 alkyl; (v) (5-9 membered heteroaryl)C 1 -C 4 alkyl; (vi) -C(=O)NR 15a R 15b ; (vii) unsubstituted 5-10 membered heteroaryl; (viii) substituted 5-10 membered heteroaryl having 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, (3-8 membered heterocyclo)C 1 -C 4 alkyl, 5-9 membered heteroaryl and -NR 15e R 15f ; (ix) -OR 16 ; (x) unsubstituted C 3 -C 6 cycloalkyl; (xi) C 1 -C 4 (xii) cyano; (xiii) unsubstituted 4-14 membered heterocyclo; (xiv) substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, (5-9 membered heteroaryl)C 1 -C 4 alkyl; (xv) (carboxy)C 1 -C 4 alkyl; (xvi) (carboxamido)C 1 -C 4 alkyl; and (xvii) substituted 5-10 membered heteroaryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of carboxy; and (C) C1-C6 alkyl selected from the group consisting of: R 14b is (A) unsubstituted 5-10 membered heteroaryl; (B) a substituted 5- or 10-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, and (C 3 -C 6 cycloalkyl)C 1 -C 4 alkyl; (C) unsubstituted C 6 -C 10 aryl; (D) substituted C 6 -C 10 aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, and (3- to 8-membered heterocyclo)C 1 -C 4 alkyl; (E) unsubstituted 4- to 14-membered heterocyclo; (F) a substituted 4-14 membered heterocyclo having 1, 2, 3 or 4 substituents independently selected from the group consisting of hydroxy, amino and C 1 -C 4 alkyl; (G)-C(=O)NR 15c R 15d; (H) unsubstituted C 3 -C 6 cycloalkyl; and (I) C 1 -C 6 alkyl selected from the group consisting of: p is 0, 1, 2 or 3; R 15a and R 15b are (A) hydrogen; (B) C 1 -C 6 alkyl; (C) C 1 -C 6 haloalkyl; (D) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (E) (hydroxy)C 1 -C 4 alkyl; (F) (cyano)alkyl; (G) unsubstituted C 6 -C 10 aryl; (H) substituted C 6 -C 10 aryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (K) unsubstituted 4-14 membered heterocyclo; (L) amino, hydroxy and C 1 (M) unsubstituted C 3 -C 8 cycloalkyl; and (N) substituted C 3 -C 8 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl and -NR 15g R 15h ; or R 15a and R 15b together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 15c and R 15d are (A) hydrogen; (B) C 1 -C 6 alkyl; (C) C 1 -C 6 haloalkyl; (D) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (E) (hydroxy)C 1 -C 4 alkyl; (F) (cyano)alkyl; (G) unsubstituted C 6 -C 10 aryl; (H) substituted C 6 -C 10 aryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (K) unsubstituted 4-14 membered heterocyclo; (L) amino, hydroxy and C 1 (M) unsubstituted C 3 -C 8 cycloalkyl; and (N) substituted C 3 -C 8 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl and -NR 15g R 15h ; or R 15c and R 15d together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 15e and R 15f are (A) hydrogen, (B) C 1 -C 6 alkyl; (C) C 1 -C 6 haloalkyl; (D) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (E) (hydroxy)C 1 -C 4 alkyl; (F) (cyano)alkyl; (G) unsubstituted C 6 -C 10 aryl, (G') substituted C 6 -C 10 aryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (K) unsubstituted 4-14 membered heterocyclo; (L) amino, hydroxy and C (M) unsubstituted C 3 -C 8 cycloalkyl; and (N) substituted C 3 -C 8 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl and -NR 15g R 15h ; or R 15e and R 15f together with the nitrogen atom to which they are attached form an optionally substituted 4-14 membered heterocyclo; R 15g and R 15h are (A) hydrogen; (B) C 1 -C 6 alkyl; (C) C 1 -C 6 haloalkyl; (D) C 1 -C 6 alkoxy; (E) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (F) (hydroxy)C 1 -C 4 alkyl; (G) (cyano)alkyl; (H) unsubstituted C 6 -C 10 aryl; (I) substituted C 6 -C 10 aryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (J) unsubstituted 5- or 6-membered heteroaryl; (K) halo, amino, hydroxy and C 1 -C 4 alkyl. (L) unsubstituted 4-14 membered heterocyclo; (M) substituted 4-14 membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl; (N) unsubstituted C 3 -C 8 cycloalkyl; and (O) substituted C 3 -C 8 cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1 -C 6 alkyl and -NR 15g R 15h ; or R 15g and R 15g together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclo; R 16 is (amino)(hydroxy)C 1 -C 4 alkyl; R 17a is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and R 18a is (A) C 1 -C 6 alkyl; (B) C 1 -C 6 haloalkyl; (C) C 1 -C 6 alkoxy; (D) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (E) (hydroxy)C 1 -C 4 alkyl; (F) (cyano)alkyl; (G) unsubstituted C 6 -C 10 aryl; (H) substituted C 6 -C 10 aryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having 1, 2, 3 or 4 substituents independently selected from the group consisting of halo, amino, hydroxy and C 1 -C 4 alkyl; (K) unsubstituted 4-14 membered heterocyclo; (L) amino, hydroxy and C (M) unsubstituted C 3 -C 8 cycloalkyl; and (N) substituted C 3 -C 8 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from the group consisting of amino, hydroxy and C 1 -C 4 alkyl.

20. The compound of claim 19, or a pharma- ceutically acceptable salt or solvate thereof.

21. R 14a is selected from the group consisting of unsubstituted 5-10 membered heteroaryl; and substituted 5-10 membered heteroaryl having 1, 2 or 3 substituents independently selected from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkoxy; (3- to 8-membered heterocyclo)C 1 -C 4 alkyl; (5- to 9-membered heteroaryl)C 1 -C 4 alkyl; -C(═O)NR 15a R 15b ; unsubstituted 5- to 10 membered heteroaryl; substituted 5- to 10 membered heteroaryl having 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, (3- to 8-membered heterocyclo)C 1 -C 4 alkyl, 5- to 9-membered heteroaryl and -NR 15e R 15f ; unsubstituted C 3 -C 6 cycloalkyl; and C 1 -C 4 alkyl and -N(R 17a 21. The compound of claim 19 or 20, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of substituted C3-C6 cycloalkyl having 1, 2 or 3 substituents independently selected from the group consisting of: C(=O)R18a;

22. R 14a is selected from the group consisting of C 1 -C 4 alkyl; C 1 -C 4 alkoxy; (3- to 8-membered heterocyclo)C 1 -C 4 alkyl; (5- to 9-membered heteroaryl)C 1 -C 4 alkyl; -C(═O)NR 15a R 15b , substituted pyridyl having one, two or three substituents independently selected from the group consisting of: unsubstituted 5- to 10-membered heteroaryl; substituted 5- to 10-membered heteroaryl having one, two or three substituents independently selected from the group consisting of halo, C 1 -C 4 alkyl, (3- to 8-membered heterocyclo)C 1 -C 4 alkyl, 5- to 9-membered heteroaryl and -NR 15e R 15f ; unsubstituted C 3 -C 6 cycloalkyl; and C 1 -C 4 alkyl and -N(R 17a )C(═O)R 18a or a pharma- ceutically acceptable salt or solvate thereof. The compound of any one of claims 19 to 21, which is a substituted C3-C6 cycloalkyl having 1, 2 or 3 substituents independently selected from the group consisting of:

23. The compound according to any one of claims 19 to 22, wherein R 14b is selected from the group consisting of unsubstituted 5-10 membered heteroaryl; substituted 5-10 membered heteroaryl having one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl and (C 3 -C 6 cycloalkyl) C 1 -C 4 alkyl; unsubstituted C 6 -C 10 aryl; substituted C 6 -C 10 aryl having one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl and (3-8 membered heterocyclo) C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of hydroxy, amino and C 1 -C 4 alkyl; and unsubstituted C 3 -C 6 cycloalkyl, or a pharma- ceutically acceptable salt or solvate thereof.

24. The compound of any one of claims 19 to 23, or a pharma- ceutically acceptable salt or solvate thereof, wherein R14b is selected from the group consisting of unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having one or two substituents independently selected from the group consisting of C1-C4 alkyl and (C3-C6 cycloalkyl)C1-C4 alkyl; unsubstituted phenyl; substituted phenyl having one or two substituents independently selected from the group consisting of C1-C4 alkyl and (3-8 membered heterocyclo)C1-C4 alkyl; and unsubstituted C3-C6 cycloalkyl.

25. The compound according to any one of claims 19 to 24, or a pharma- ceutically acceptable salt or solvate thereof, wherein p is 0.

26. The compound according to any one of claims 19 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein p is 1.

27. ​​Formula VI: 【Chemical 27】 (In the formula, R 1d is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; R19 is unsubstituted 4- to 14-membered heterocyclo; and A substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl. selected from the group consisting of: R 20 is selected from the group consisting of hydrogen, halo, and C 1 -C 4 alkyl; and q is 1, 2 or 3. or a pharma- ceutically acceptable salt or solvate thereof.

28. Formula VII: 【Chemistry 28】 (In the formula, R 1d is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; R 11a is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, and -N(R 12b )C(=O)R 13c ; R 12b is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclo, (C 1 -C 4 alkoxy)C 1 -C 4 alkyl, and (hydroxy)C 1 -C 4 alkyl; R 13c is selected from the group consisting of alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycle, amino, (amino)alkyl, (C 3 -C 6 cycloalkyl)oxy, and (4-8 membered heterocyclo)oxy; and R 11b is selected from the group consisting of C 1 -C 4 alkyl, halo, and C 1 -C 4 haloalkyl. or a pharma- ceutically acceptable salt or solvate thereof.

29. Formula VIII: 【Chemical 29】 (In the formula, R 1d is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy; R 30 is selected from the group consisting of hydrogen; C 1 -C 6 alkyl; unsubstituted C 3 -C 6 cycloalkyl; substituted C 3 -C 6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl; -C(=O)R 13b and -S(=O) 2 R 24 ; R 13b is selected from the group consisting of C 1 -C 4 alkyl; amino; C 1 -C 4 haloalkyl; C 1 -C 4 alkoxy; (hydroxy)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (amino)alkyl; unsubstituted C 3 -C 6 cycloalkyl; substituted C 3 -C 6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; unsubstituted 4-14 membered heterocyclo; substituted 4-14 membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl; (C 3 -C 6 cycloalkyl)oxy; and (4-8 membered heterocyclo)oxy; R 24 is selected from the group consisting of C 1 -C 4 alkyl and (hydroxy)C 1 -C 4 alkyl; and u is 0, 1, 2 or 3. or a pharma- ceutically acceptable salt or solvate thereof.

30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1d is fluoro.

31. The compound according to any one of claims 1 to 30, selected from the group consisting of the compounds in Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

33. A composition comprising a compound according to any one of claims 1 to 31 or a pharma- ceutically acceptable salt or solvate thereof for use in the treatment of cancer.

34. The composition described in claim 33, wherein the cancer is a blood cancer.

35. The composition of claim 34, wherein the blood cancer is t(4;14) multiple myeloma.

36. A method for providing an indication for identifying whether a subject having multiple myeloma is a candidate for treatment with a compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt or solvate thereof, the indication being the presence or absence of a chromosomal translocation in a biological sample taken from the subject, the method comprising determining the presence or absence of the chromosomal translocation in the biological sample taken from the subject, wherein the presence of the chromosomal translocation in the biological sample indicates that the subject is a candidate for treatment; or the absence of the chromosomal translocation in the biological sample indicates that the subject is not a candidate for treatment.

37. A method of providing an index for predicting treatment outcome in a subject having multiple myeloma, the index being the presence or absence of a chromosomal translocation in a biological sample taken from the subject, the method comprising determining the presence or absence of the chromosomal translocation in a biological sample taken from the subject, wherein (a) the presence of the chromosomal translocation in the biological sample indicates that administering to the subject a compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, is likely to result in a favorable therapeutic response; and (b) the absence of the chromosomal translocation in the biological sample indicates that administering to the subject a compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, is likely to result in an unfavorable therapeutic response.

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