Setd2 inhibitors and related methods and uses, including combination therapy

Abstract

The present invention provides SETD2 protein inhibitors, and methods of using SETD2 protein inhibitors and optionally a second therapeutic agent in the treatment of a disease, disorder, or condition in a subject, wherein the second therapeutic agent comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPOl inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or combinations thereof.

Description

BACKGROUND TECHNICAL FIELD

[0002] The present disclosure provides SETD2 protein inhibitors, and methods of using the SETD2 protein inhibitors for treating a disease, disorder, or condition in a subject, compositions, and kits. In some embodiments, the methods of treating a disease, disorder, or condition, compositions, and kits further comprise a second therapeutic agent, wherein the second therapeutic agent comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPOl inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or a combination thereof. BACKGROUND

[0004] The selective addition of methyl groups to specific amino acid sites of histones is controlled by the action of a family of enzymes known as histone methyltransferases (HMTs). The expression level of a particular gene is influenced by the presence or absence of one or more methyl groups at the relevant histone site. The specific effects of a methyl group at a particular histone site persist 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 classes of enzymes can modify DNA and histones with other chemical species, while other enzymes can remove these species to provide control over gene expression.

[0005] SETD2 is a human histone methyltransferase located at cytogenetic band p21.31 (3p21.31) of chromosome 3. The acronym "SETD2" stands for Suppressor of variegation, zeste enhancer, and Trithorax domain-containing protein 2. The SETD2 protein contains three conserved functional domains: (1) a tripartite 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 believed to be the sole human gene responsible for the trimethylation (H3K36me3) of lysine 36 (Lys-36) of histone H3 using dimethylated Lys-36 (H3K36me2) as a substrate. Edmunds, J.W. et al., The EMBO Journal 27:406-420 (2008).

[0006] 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). Also, it has been reported that the expression level of SETD2 in breast cancer samples was significantly lower than the expression level in adjacent non-cancerous tissue (ANCT) samples. Newbold, R.F. and Mokbel, K., Anticancer Research 30:3309-3311 (2010). In addition, biallelic mutations and loss-of-function point mutations in SETD2 were reported in patients with acute leukemia. Zhu, X. et al., Nature Genetics 46:287-293 (2014). Mutations in SETD2 have been reported in pediatric high-grade gliomas. Fontebasso, A.M. et al., Acta Neuropathol. 125:659-669 (2013). SUMMARY

[0007] The present invention generally provides SETD2 protein inhibitors, and methods, compositions, and kits for using the SETD2 protein inhibitors and optionally a second therapeutic agent in treating a disease, disorder, or condition in a subject, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor, or a combination thereof.

[0008] In one aspect, the present invention provides a method for treating a disease, disorder, or condition, e.g., cancer, in a subject in need thereof, using:

[0009] (1) a therapeutically effective amount of a substituted indole represented by any one of the following formulae I, II, II-A, III, III-A, IV, IV-A, IV-B, IV-C, IV-D, V, V-A, V-B, VI, VII, VII-A, VII-B, VII-C, VII-D, VII-E, VII-F, VII-G, VII-H, VIII, VIII-A, or VIII-B, or a compound of Table 1, or any one of the compounds of Table IB, and pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "the compounds of the disclosure"; and

[0010] (2) a therapeutically effective amount of a second therapeutic agent,

[0011] wherein the second therapeutic agent comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more multi- effector pathway modulators, one or more XPOl inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or combinations thereof.

[0012] In another aspect, the present application provides a compound of the present disclosure for use in treating cancer, e.g., multiple myeloma, in a subject in need thereof, wherein the compound of the present disclosure is administered to the subject in combination with a second therapeutic agent.

[0013] In another aspect, the present application provides a compound of the present disclosure for use in the preparation of a medicament for treating cancer in a subject, wherein the compound of the present disclosure is administered to the subject in combination with a second therapeutic agent.

[0014] In another aspect, the present application provides a kit comprising a compound of the present disclosure and a second therapeutic agent.

[0015] In another aspect, the present application provides a compound of the present disclosure, i.e., a substituted indole represented by any one of Formula I, II, II-A, III, III-A, IV, IV-A, IV-B, IV-C, IV-D, V, V-A, V-B, VI, VII, VII-A, VII-B, VII-C, VII-D, VII-E, VII-F, VII-G, VII-H, VIII, VIII-A, or VIII-B, or a compound of Table 1, or a compound of Table IB.

[0016] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0017] In one aspect, the present application provides a method of treating a disease, disorder, or condition, e.g., cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0018] In another aspect, the present application provides a compound of the present disclosure for use in treating cancer, e.g., multiple myeloma, in a subject in need thereof.

[0019] In another aspect, the present application provides a compound of the present disclosure for use in the preparation of a medicament for treating cancer in a subject.

[0020] Additional embodiments and advantages of the disclosure will be set forth in part in the description that follows, and in part will be obvious from the description, or can 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.

[0021] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application claimed. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is a line graph showing the anti-proliferative activity of Compound No. 15, tazemetostat (Taz), and lenalidomide (Len), and combinations thereof, in KMS-11 cells over the course of a 14-day co-treatment study.

[0024] Figure 2 is a bar graph showing the anti-proliferative activity of Compound No. 15, tazemetostat (Taz), and lenalidomide (Len), and combinations thereof, in KMS-11 cells over the course of a 14-day co-treatment study.

[0025] Figure 3 is a line graph showing the synergistic anti-proliferative activity of Compound No. 15 in combination with pomalidomide in KMS-11 cells in a 7-day co-treatment study.

[0026] Figure 4 is a table showing the Loewe Excess model analysis of the combination of Compound No. 15 + pomalidomide in KMS-11 cells in a 7-day co-treatment study. DETAILED DESCRIPTION

[0028] I. Compounds of the Disclosure

[0029] Certain compounds of the disclosure are disclosed as SETD2 inhibitors in PCT / US2019 / 046569. PCT / US2019 / 046569 is incorporated by reference in its entirety. Certain other compounds of the disclosure are an embodiment of the disclosure described herein.

[0030] In one embodiment, the compound of the disclosure is a compound of Formula I:

[0031]

[0032] wherein:

[0033] R 1a is selected from halo, alkyl, alkoxy, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0034] Q1is selected from -C(R 1b )= and -N=;

[0035] Q2is selected from -C(R 1c )= and -N=.

[0036] Q3is selected from -C(R 1d ) = and -N =;

[0037] provided that at least one of Q 1 , Q 2 or Q 3 is -C(R 1b ) =, -C(R 1c ) = or -C(R 1d ) =, respectively;

[0038] R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy;

[0039] R 1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0040] is a single or double bond;

[0041] G1is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, (aryl)alkyl, (heteroaryl)alkyl, (heterocyclyl)alkyl, (amino)(aryl)alkyl, (heteroaryl)(aryl)alkyl, (heteroaryl)(heterocyclyl)alkyl, (heteroaryl)(carboxamido)alkyl, (heteroaryl)(cycloalkyl)alkyl, (aryl)(alkoxycarbonyl)alkyl, (cycloalkyl)alkyl, (heteroaryl)(amino)alkyl, (cycloalkyl)(alkoxycarbonyl)alkyl, (heteroaryl)(alkoxycarbonyl)alkyl, (heterocyclyl)(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

[0042] G 2 is selected from hydrogen and alkyl; or

[0043] G 1 and G 2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl,

[0044] or a pharmaceutically acceptable salt or solvate thereof.

[0045] In another embodiment, the compound of Formula I is not N-(1-(1-(L-alanyl)piperidin-4- yl)ethyl)-7-methyl-1H-indole-2-carboxamide, N-((1r,4r)-4-(3-aminopropionamido)cyclohexyl)-7- methyl-1H-indole-2-carboxamide, or N-((1r,4r)-4-aminocyclohexyl)-7-methyl-1H-indole-2- carboxamide.

[0046] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein:

[0047] R 1a is selected from halogen, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, (hydroxy)C 1-6 alkyl, and (C3-C6cycloalkyl)C 1-6 alkyl;

[0048] R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, (hydroxy)C1-C6alkyl, and C1-C6alkoxy;

[0049] R 1e is selected from hydrogen and C1-C6alkyl;

[0050] G 1 is selected from optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 10-membered heterocyclo, optionally substituted C3-C8cycloalkyl, (C6-C 10 aryl)C1-C6alkyl, (5- to 10-membered heteroaryl)C1-C6alkyl, (3- to 10-membered heterocyclo)C1-C6alkyl, (amino)(C6-C 10 aryl)C1-C6alkyl, (5- to 14-membered heteroaryl)(C6-C 10 aryl)C1-C6alkyl, (5- to 10-membered heteroaryl)(3- to 10-membered heterocyclo)C1-C6alkyl, (5- to 10-membered heteroaryl)(carboxamido)C1-C6alkyl, (5- to 10-membered heteroaryl)(C3-C6cycloalkyl)C1-C6alkyl, (C6-C 10 aryl)(alkoxycarbonyl)C1-C6alkyl, (C3-C6cycloalkyl)C1-C6alkyl, (5- to 10-membered heteroaryl)(amino)C1-C6alkyl, (C3-C6cycloalkyl)(alkoxycarbonyl)C1-C6alkyl, (5- to 14-membered heteroaryl)(alkoxycarbonyl)C1-C6alkyl, (3- to 14-membered heterocyclo)(C3-C8cycloalkyl)C1-C6alkyl, (C6-10 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

[0051] G 2 Selected from hydrogen and C1-C6 alkyl; or

[0052] G 1 and G 2 Together with the nitrogen atoms attached to them, they form 5- to 10-membered, optionally substituted heterocycles.

[0053] Or its pharmaceutically acceptable salts or solvates.

[0054] In another embodiment, the compound disclosed herein is a compound having formula I, wherein:

[0055] R 1a Selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkyl groups, and (hydroxy)C 1-4 Alkyl and (C3-C6 cycloalkyl)C 1-4 alkyl;

[0056] R 1b R 1c and R 1d Each is independently selected from hydrogen, halogen, C1-C3 alkyl, C2-C4 alkenyl, (hydroxy)C1-C4 alkyl, and C1-C3 alkoxy;

[0057] R 1e Selected from hydrogen and C1-C3 alkyl groups;

[0058] G 1 Selected from optional C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 10-membered heterocyclic, optionally substituted C3-C8 cycloalkyl, (C6-C 10 (aryl)C1-C4 alkyl, (5- to 10-membered heteroaryl)C1-C6 alkyl, (3- to 10-membered heterocyclic)C1-C4 alkyl, (amino)(C6-C 10 (aryl)C1-C6 alkyl, (5- to 14-membered heteroaryl)(C6-C 10(aryl)C1-C4 alkyl, (5- to 10-membered heteroaryl) (3- to 10-membered heterocyclic)C1-C4 alkyl, (5- to 10-membered heteroaryl) (formamido)C1-C4 alkyl, (5- to 10-membered heteroaryl) (C3-C6 cycloalkyl)C1-C4 alkyl, (C6-C 10 aryl)(alkoxycarbonyl)C1-C4 alkyl, (C3-C6 cycloalkyl)C1-C4 alkyl, (5- to 10-membered heteroaryl)(amino)C1-C4 alkyl, (C3-C6 cycloalkyl)(alkoxycarbonyl)C1-C4 alkyl, (5- to 14-membered heteroaryl)(alkoxycarbonyl)C1-C4 alkyl, (3- to 14-membered heterocyclic)(C3-C6 cycloalkyl)C1-C4 alkyl, (C 6-10 Aryl (C3-C6 cycloalkyl) C1-C4 alkyl, (C6-C 10 Aryl (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

[0059] G 2 Selected from hydrogen and C1-C4 alkyl; or

[0060] G 1 and G 2 Together with the nitrogen atoms attached to them, they form 5- to 10-membered optionally substituted heterocycles, or pharmaceutically acceptable salts or solvates thereof.

[0061] In another embodiment, the compound disclosed herein is a compound having formula I, wherein It is a double bond, or a pharmaceutically acceptable salt or solvate thereof.

[0062] In another embodiment, the compound disclosed herein is a compound having formula I, wherein Q 1 and Q 2 It is -C(H)=, or a pharmaceutically acceptable salt or solvate thereof.

[0063] In another embodiment, the compound disclosed herein is a compound having formula I, wherein Q 3 -C(R) 1d = ; and R 1d Selected from hydrogen and halogens, or pharmaceutically acceptable salts or solvates thereof.

[0064] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein R 1e is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0065] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein R 1a is C1-C3 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0066] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein G 2 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0067] In another embodiment, the compound of the present disclosure is a compound of Formula II:

[0068]

[0069] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1d and G 1 are as described in Formula I.

[0070] In another embodiment, the compound of the present disclosure is a compound of Formula I or II, wherein R 1d is selected from hydrogen and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

[0071] In another embodiment, the compound of the present disclosure is a compound of Formula II-A:

[0072]

[0073] or a pharmaceutically acceptable salt or solvate thereof, wherein G 1 is as described in Formula II.

[0074] In another embodiment, the compound of the present disclosure is a compound of Formula I, II, or II-A, wherein G 1 is selected from optionally substituted C6-C 10 aryl, optionally substituted 5- to 9-membered heteroaryl, optionally substituted 3- to 10-membered heterocycle, 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 heteroaryl heteroaryl)(C3-C6 cycloalkyl)C1-C4 alkyl, and (C3-C6 cycloalkyl)C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0075] In another embodiment, the compound of the present disclosure is a compound of Formula III:

[0076]

[0077] wherein:

[0078] A 1 is selected from -N= and -C(R 2a )=;

[0079] R 2a is selected from hydrogen, alkyl, halo, and haloalkyl;

[0080] R 2b is selected from optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, (formylamido)alkyl, -OR 10c , amino, (heterocyclyl)alkyl, (amino)alkyl, (hydroxy)alkyl, formylamido, (heteroaryl)alkyl, -S(=O)R 9b , -S(=O)2R 9b , and -C(=O)R 9c ;

[0081] A 2 is selected from -N= and -C(R 2c )=;

[0082] R 2c is selected from hydrogen, alkyl, halo, and haloalkyl;

[0083] R 2d is selected from hydrogen, alkyl, halo, cyano, and haloalkyl;

[0084] R 2e is selected from hydrogen, alkyl, halo, and haloalkyl;

[0085] R 9b is selected from amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycle, and optionally substituted heteroaryl;

[0086] R 9c is selected from amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycle, and optionally substituted heteroaryl; and

[0087] R 10c is selected from alkyl, (hydroxy)alkyl, and (amino)alkyl; and

[0088] R 1d is as described in Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0089] In another embodiment, the compound of the present disclosure is a compound of Formula III-A:

[0090]

[0091] Where R 1d R 2a R 2b R 2c R 2d and R 2e As defined in Formula III, or a pharmaceutically acceptable salt or solvate thereof.

[0092] In another embodiment, the compound disclosed herein is a compound having formula III or formula III-A, wherein:

[0093] R 2a Selected from hydrogen, C1-C4 alkyl, halogen, and C1-C4 haloalkyl;

[0094] R 2b Selected from:

[0095] (A) Unsubstituted 4- to 10-membered heterocycles;

[0096] (B) A substituted 4- to 10-membered heterocycle having 1, 2, 3 or 4 independent substituents selected from the following: (i) -N(R 3a )C(=O)R 4a (ii)-NR 5a R 5b (iii) Unsubstituted 4- to 10-membered heterocycles; (iv) Substituted 4- to 10-membered heterocycles having one, two, or three independent substituents selected from: hydroxyl, -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) (hydroxy) C1-C4 alkyl and halogen; (vi) (hydroxy) C1-C4 alkyl; (vii) C1-C6 alkyl; (viii) -C(=O)NR 5g R 5h ;(ix)halogen;(x)-C(=O)R 4c ;(xi)C1-C6 haloalkyl; (xii) hydroxyl; (xiii) (amino)C1-C4 alkyl; (xiv) (C1-C4 alkoxy)C1-C4 alkyl; (xv)-S(=O)2R 9a ;(xvi)(3-to-8-membered heterocyclic)C1-C4 alkyl; (xvii)C1-C6 alkoxy; (xviii)(C3-C6 cycloalkyl)C1-4 Alkyl group; (xix)(C 6-10 (aryl)C1-C4 alkyl; and (xxii)-OR 10b ;

[0097] (C) Unsubstituted C3-C8 cycloalkyl groups;

[0098] (D) A substituted C3-C8 cycloalkyl group having 1, 2, 3, or 4 independent substituents selected from the following: (i) an unsubstituted 4- to 10-membered heterocycle; (ii) a substituted 4- to 10-membered heterocycle having 1 or 2 independent substituents selected from the following: amino and C1-C4 alkyl; (iii) an unsubstituted 5- or 6-membered heteroaryl; (iv) a substituted 5- or 6-membered heteroaryl group having 1, 2, or 3 independent substituents selected from the following: halogen, C1-C4 alkyl, (3- to 8-membered heterocyclic) alkyl, hydroxyl, and amino; (v) -NR 5i R 5j ;(vi)cyano;(vii)-N(R) 3d )C(=O)R 4f ;(viii) hydroxyl; and (ix) C1-C4 alkyl;

[0099] (E) Unsubstituted 5- to 10-membered heteroaryl groups;

[0100] (F) Substituted 5- to 10-membered heteroaryl groups having 1, 2, 3, or 4 independent substituents selected from the following: (i) halogen; (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; substituted C3-C6 cycloalkyl groups having 1, 2, 3, or 4 independent substituents selected from the following: -NR 5g R 5h Unsubstituted 4- to 14-membered heterocyclic group; substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: hydroxyl, amino, and C1-C4 alkyl; -NR 5q R 5r ; and (ix) (3- to 8-membered heterocyclic) C1-C4 alkyl;

[0101] (G) Unsubstituted C6-C 10 Aryl;

[0102] (H)-substituted C6-C 10 aryl group having 1, 2, 3 or 4 independently selected substituents from: (i) halogen; (ii) C1-C4 alkyl; (iii) -CH-2N(H)S(=O)2R 8(iv) (5- to 9-membered heteroaryl)Ci-C4alkyl; (v) -OR 10a (vi) -N(R 3b )C(=0)R 4b (vii) (amino)Ci-C4alkyl; and (viii) (hydroxy)Ci-C4alkyl;

[0103] (I) (carboxamido)Ci-C4alkyl;

[0104] (J) -OR 10c ;

[0105] (K) -NR 5o R 5p ;

[0106] (L) (3- to 8-membered heterocyclo)Ci-C4alkyl;

[0107] (M) (amino)Ci-C4alkyl;

[0108] (N) (hydroxy)Ci-C4alkyl;

[0109] (O) -C(=0)NR 5s R 5t ;

[0110] (P) (5- to 9-membered heteroaryl)Ci-C4alkyl; and

[0111] (Q) -S(=0)2R 9b ;

[0112] R2c is selected from hydrogen, Ci-C4alkyl, halogen, and Ci-C4haloalkyl;

[0113] R 2d is selected from hydrogen, Ci-C4alkyl, halogen, cyano and Ci-C4haloalkyl;

[0114] R 2e is selected from hydrogen, Ci-C4alkyl, halogen and Ci-C4haloalkyl;

[0115] R 3a , R 3b , R 3c , and R 3d are each independently selected from hydrogen, Ci-C4alkyl, optionally substituted C3-C6cycloalkyl and optionally substituted 4- to 14-membered heterocyclyl;

[0116] R 4a , R 4b , R 4c , R 4d , R 4e , and R 4feach independently is selected from the group consisting of C1-C6alkyl; C1-C6haloalkyl; C3-C6cycloalkyl; C1-C6alkoxy; (C1-C4alkoxy)C1-C4alkyl; (C 6-10 aryl; substituted C6-C 10 aryl; substituted C6-C 10 aryl; substituted C6-C

[0117] R 5a and R 5b are independently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl;

[0118] R 5c and R 5d are independently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl; or

[0119] R 5c and R 5d form, together with the nitrogen atom to which they are attached, an optionally substituted 4- to 14-membered heterocyclyl;

[0120] R 5e and R 5findependently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl; or

[0121] R 5e and R 5f together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0122] R 5g and R 5h independently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl; or

[0123] R 5g and R 5h together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0124] R 5i and R 5j independently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl; or

[0125] R 5i and R 5j together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0126] R5k and R 5l are independently selected from the group consisting of hydrogen; Ci-C4alkyl; Ci-C4haloalkyl; (hydroxy)Ci-C4alkyl; (amino)Ci-C4alkyl; (Ci-C4alkoxy)Ci-C4alkyl; (5- to 9-membered heteroaryl)Ci-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and Ci-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and Ci-C4alkyl; or

[0127] R 5k and R 5l together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0128] R 5m and R 5n are independently selected from the group consisting of hydrogen; Ci-C4alkyl; Ci-C4haloalkyl; (hydroxy)Ci-C4alkyl; (amino)Ci-C4alkyl; (Ci-C4alkoxy)Ci-C4alkyl; (5- to 9-membered heteroaryl)Ci-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and Ci-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and Ci-C4alkyl; or

[0129] R 5m and R 5n together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0130] R 5o and R 5p are independently selected from the group consisting of hydrogen; Ci-C4alkyl; Ci-C4haloalkyl; (hydroxy)Ci-C4alkyl; (amino)Ci-C4alkyl; (Ci-C4alkoxy)Ci-C4alkyl; (5- to 9-membered heteroaryl)Ci-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and Ci-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and Ci-C4alkyl; or

[0131] R 5o and R 5p together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0132] R 5q and R 5r are each independently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl;

[0133] R 5s and R 5t are each independently selected from the group consisting of hydrogen; C1-C4alkyl; C1-C4haloalkyl; (hydroxy)C1-C4alkyl; (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of hydroxy, amino and C1-C4alkyl;

[0134] R 6a , R 6b , R 6c , and R 6d are each independently selected from the group consisting of hydrogen and C1-C4alkyl;

[0135] R 8 is C1-C6alkyl;

[0136] R 9a is selected from the group consisting of C1-C6alkyl; unsubstituted C3-C8cycloalkyl; and substituted C3-C8cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, C1-C4alkyl, amino and (amino)C1-C4alkyl;

[0137] R 9b is selected from the group consisting of C1-C6alkyl and amino;

[0138] R 10a is selected from the group consisting of alkyl, (hydroxy)C1-C4alkyl and (amino)C1-C4alkyl;

[0139] R 10b is (amino)C1-C4alkyl; and

[0140] R 10cis (amino)C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0141] In another embodiment, the compound of the present disclosure is a compound of Formula III or Formula III-A, wherein R 2b is an optionally substituted 3- to 10-membered heterocycle which is attached to the rest of the molecule through a nitrogen atom, for example, R 2b is:

[0142] and the like.

[0143] In another embodiment, the compound of the present disclosure is a compound of Formula III or Formula III-A, wherein:

[0144] R 2b is selected from:

[0145]

[0146]

[0147] R a1 is selected from -N(R 3a )C(=O)R 4a ; -NR 5a R 5b ; an unsubstituted 4- to 10-membered heterocycle; a substituted 4- to 10-membered heterocycle having 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, -NR 5c R 5d , C1-C4alkyl, C1-C6alkoxy, -C(R 6a )(R 6b )C(=O)NR 5e R 5f , -C(=O)R 4b , (hydroxy)C1-C4alkyl, and halogen;

[0148] R a2 and R a3 are each hydrogen; or

[0149] R a2 and R a3 together with the carbon atom to which they are attached form a C(=O) group;

[0150] R a4 is selected from hydrogen, halogen, and hydroxy;

[0151] R a5 is selected from hydrogen, C1-C4alkyl, and C3-C6cycloalkyl;

[0152] R b1selected from hydrogen, C1-C4alkyl and C3-C6cycloalkyl;

[0153] R c1 selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=O)R 4c ;

[0154] R c2 and R c3 are each independently selected from hydrogen, C1-C4alkyl and C1-C4haloalkyl; or

[0155] R c2 and R c3 together with the carbon atom to which they are attached form a C(=O) group;

[0156] R c4 selected from hydrogen and C1-C4alkyl;

[0157] m is 1 or 2;

[0158] R d1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ,

[0159] R d2 and R d3 are each independently selected from hydrogen and fluorine;

[0160] R e1 selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=O)R 4c ;

[0161] R f1 selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=O)R 4c ,

[0162] R g1 selected from hydrogen, C1-C4alkyl, -C(=O)R 4c , C1-C4haloalkyl, (C1-C4alkoxy)C1-C4alkyl,

[0163] R h1 selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=O)R 4c ;

[0164] R h2 selected from hydrogen and C1-C4alkyl;

[0165] R h3 and R h4 are each independently selected from hydrogen and C1-C4alkyl; or

[0166] R h3 and Rh4 together with the carbon atom to which they are attached form a C(=O) group;

[0167] R i1 is selected from the group consisting of hydrogen, C1-C4alkyl, C3-C6cycloalkyl, (hydroxy)C1-C4alkyl, -N(R 3a )C(=O)R 4a and (amino)C1-C4alkyl;

[0168] Z 1 is selected from the group consisting of -CH2- and -O-;

[0169] R j1 is selected from the group consisting of hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=O)R 4c ;

[0170] R k1 is selected from the group consisting of C1-C4alkyl, unsubstituted 4- to 14-membered heterocyclyl and -NR 5a R 5b ;

[0171] R k2 is selected from the group consisting of hydrogen, hydroxy and C1-C4alkyl;

[0172] r is 0, 1 or 2;

[0173] Z 2 is selected from the group consisting of -O- and -N(R m3 )-;

[0174] R m3 is selected from the group consisting of hydrogen, C1-C4alkyl and C1-C4haloalkyl;

[0175] R n3 is selected from the group consisting of hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0176] R o1 is selected from the group consisting of hydroxy, (hydroxy)C1-C4alkyl, (amino)C1-C4alkyl, (C1-C4alkoxy)C1-C4alkyl, C1-C4alkoxy, -NR 5a R 5b , unsubstituted 4- to 14-membered heterocyclyl, 4- to 14-membered heterocyclyl having 1, 2 or 3 substituents independently selected from the group consisting of halogen, C1-C4alkyl and C1-C4alkoxy;

[0177] R o2 is selected from the group consisting of hydrogen, C1-C4alkyl and (C1-C4alkoxy)C1-C4alkyl,

[0178] R o3 is selected from the group consisting of hydrogen, fluorine, and C1-C4alkyl;

[0179] R p1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0180] Z 3 selected from -O- and -N(R q1 )-;

[0181] R q1 selected from hydrogen and C1-C4alkyl;

[0182] R r1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0183] R s1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0184] R t1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0185] R u1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0186] R v1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0187] R w1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0188] R x1 selected from hydrogen, C1-C4alkyl and -C(=O)R 4c ;

[0189] R y1 selected from hydrogen and C1-C4alkyl; and

[0190] R z1 selected from hydrogen and C1-C4alkyl,

[0191] or a pharmaceutically acceptable salt or solvate thereof.

[0192] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein:

[0193] R 2b is selected from:

[0194]

[0195]

[0196] or a pharmaceutically acceptable salt or solvate thereof.

[0197] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein 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. In another embodiment, R 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 hydrogen and C1-C4alkyl. In another embodiment, R a1 is an optionally substituted 4- to 10-membered heterocyclic ring.

[0198] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -2, R 2b -2A, or R 2b -2B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R b1 is C1-C4alkyl.

[0199] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -3, R 2b -3A, or R 2b -3B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R c1 is selected from C1-C4alkyl, C3-C6cycloalkyl, and -C(=O)R 4c . In another embodiment, R c2 and R c3 are each hydrogen. In another embodiment, R c2 and R c3together 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.

[0200] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R d1 is C(=O)R 4c . In another embodiment, R d2 and R d3 are each hydrogen or fluoro.

[0201] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -5, R 2b -5A, or R 2b -5B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R e1 is -C(=O)R 4c .

[0202] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -6, R 2b -6A, or R 2b -6B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R f1 is C(=O)R 4c .

[0203] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -7, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R g1 is C(=O)R 4c .

[0204] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein 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. In another embodiment, Rh1 -C(=O)R 4c In another embodiment, R h2 is selected from hydrogen and C1-C3 alkyl. In another embodiment, R h3 is hydrogen.

[0205] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -9, or a pharmaceutically acceptable salt or solvate thereof.

[0206] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -10, R 2b -10A, R 2b -10B, R 2b -10C, and R 2b -10d, or a pharmaceutically acceptable salt or solvate thereof.

[0207] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -11, R 2b -11A, and R 2b -11B, or a pharmaceutically acceptable salt or solvate thereof.

[0208] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -12, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R j1 is -C(=O)R 4c .

[0209] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from 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.

[0210] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b R 2b -14, or a pharmaceutically acceptable salt or solvate thereof.

[0211] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b R 2b -15, or a pharmaceutically acceptable salt or solvate thereof.

[0212] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -16, R 2b -16A, and R 2b -16B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R n3 is -C(=O)R 4c .

[0213] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b R 2b -17, or a pharmaceutically acceptable salt or solvate thereof.

[0214] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b R 2b -18, or a pharmaceutically acceptable salt or solvate thereof.

[0215] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b R 2b -19, or a pharmaceutically acceptable salt or solvate thereof.

[0216] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b R 2b -20, or a pharmaceutically acceptable salt or solvate thereof.

[0217] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -21, R 2b -21A, and R 2b -21B, or a pharmaceutically acceptable salt or solvate thereof.

[0218] In another embodiment, the compound of the disclosure is a compound of Formula III, wherein R 2b is selected from R 2b -22, R 2b -22A, and R 2b -22B, or a pharmaceutically acceptable salt or solvate thereof.

[0219] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -23, or a pharmaceutically acceptable salt or solvate thereof.

[0220] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -24, or a pharmaceutically acceptable salt or solvate thereof.

[0221] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -25, or a pharmaceutically acceptable salt or solvate thereof.

[0222] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -26, R 2b -26A, and R 2b -26B, or a pharmaceutically acceptable salt or solvate thereof.

[0223] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -27, R 2b -27A, and R 2b -27B, or a pharmaceutically acceptable salt or solvate thereof.

[0224] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is selected from R 2b -28, R 2b -28A, and R 2b -28B, or a pharmaceutically acceptable salt or solvate thereof.

[0225] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b-29, or a pharmaceutically acceptable salt or solvate thereof.

[0226] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is R 2b -30, R 2b -30A, or R 2b -30B, or a pharmaceutically acceptable salt or solvate thereof.

[0227] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2b is any one or more of the R 11a groups provided in relation to Formula IV, see below, or a pharmaceutically acceptable salt or solvate thereof.

[0228] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 4c is C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0229] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2d is selected from hydrogen, fluoro and chloro, or a pharmaceutically acceptable salt or solvate thereof.

[0230] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2d is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0231] In another embodiment, the compound of the disclosure is a compound of Formula III in any of the above embodiments, wherein A 1 and A 2 is -C(H)=; R 2e is hydrogen; and R 2d is selected from hydrogen and halo, or a pharmaceutically acceptable salt or solvate thereof.

[0232] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R 2d is fluoro, or a pharmaceutically acceptable salt or solvate thereof.

[0233] In another embodiment, the compound of the disclosure is a compound of Formula IV:

[0234]

[0235] wherein:

[0236] Z 4 is selected from -0-, -C(R 28a )(R 28b )- and -N(R 23 )-; or Z 4 is absent;

[0237] Z 5 is selected from -CH2- and -CH2CH2-;

[0238] R 11a is selected from optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl and -N(R 12b )C(=0)R 13c ;

[0239] R 12b is selected from hydrogen, alkyl, cycloalkyl and heterocycle;

[0240] R 13c is selected from alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclyl, amino, (amino)alkyl, (C3-C6cycloalkyl)oxy and (4- to 8-membered heterocyclyl)oxy;

[0241] R 23 is selected from hydrogen and C1-C4alkyl;

[0242] R 28a and R 28b are independently selected from hydrogen, alkyl and halogen; and

[0243] R 1d is as defined in Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0244] In another embodiment, the compound of the present disclosure is a compound of Formula IV, wherein Z 4 is selected from -0- and -CH2-; or Z 4 is absent, or a pharmaceutically acceptable salt or solvate thereof.

[0245] In another embodiment, the compound of the present disclosure is a compound of Formula IV, wherein:

[0246] Z 4 is selected from -0- and -CH2-; or Z 4 is absent;

[0247] Z 5 is selected from -CH2- and -CH2CH2-;

[0248] R 13cis selected from alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycle, and

[0249] R 1d is as defined in Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0250] In another embodiment, the compound of the disclosure is a compound of Formula IV-A:

[0251]

[0252] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1d , R 11a , and Z 4 are as defined in Formula IV.

[0253] In another embodiment, the compound of the disclosure is a compound of Formula IV-B:

[0254]

[0255] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1d , R 11a , and Z 4 are as defined in Formula IV.

[0256] In another embodiment, the compound of the disclosure is a compound of Formula IV-C:

[0257]

[0258] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1d , R 11a , and Z 4 are as defined in Formula IV.

[0259] In another embodiment, the compound of the disclosure is a compound of Formula IV-D:

[0260]

[0261] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1d , R 11a , and Z 4 are as defined in Formula IV.

[0262] In another embodiment, the compound of the disclosure is a compound of any of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein:

[0263] R 11a is selected from the group consisting of: (A) unsubstituted 4- to 14-membered heterocyclyl; (B) substituted 4- to 14-membered heterocyclyl having 1, 2, or 3 substituents independently selected from the group consisting of -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 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4 alkyl; (C) unsubstituted 5- to 10-membered heteroaryl; (D) substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, and (amino)alkyl; (E) C1-C6 alkyl; and (F) -N(R 12b )C(=O)R 13c ;

[0264] 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;

[0265] R 13a , R 13b , and R 13c are each independently selected from the group consisting of 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 10aryl, substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, amino, hydroxyl, and C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; 5- or 6-membered heteroaryl substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, amino, hydroxyl, and C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; 4- to 14-membered heterocyclyl substituted with 1 or 2 substituents independently selected from the group consisting of amino, hydroxyl, and C1-C4alkyl; amino; (amino)alkyl; (C3-C6cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy; and

[0266] R 24 is selected from the group consisting of C1-C4alkyl and (hydroxy)C1-C4alkyl.

[0267] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, 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-C4alkyl, and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

[0268] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein Z 4 is -C(R 28a )(R 28b )-; R 28a is hydrogen; and R 28b is selected from the group consisting of C1-C4alkyl and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

[0269] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein Z 4 is -C(R 28a )(R 28b )-; and R 28a and R 28b are independently C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0270] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein Z 4 is selected from the group consisting of -O-, -CH2-, and -N(R 23 ), or Z 4 is absent, or a pharmaceutically acceptable salt or solvate thereof.

[0271] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein Z 4 is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[0272] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is an optionally substituted 3- to 10-membered heterocyclyl ring attached to the remainder of the molecule through a nitrogen atom, for example, R 11a is

[0273] and the like.

[0274] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais a substituted 4- to 14-membered heterocyclyl group selected from:

[0275]

[0276] R 12a is selected from hydrogen, C1-C3alkyl, (C1-C4alkoxy)C1-C4alkyl; and (hydroxy)C1-C4alkyl;

[0277] R 13a is selected from C1-C4alkyl; amino; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, amino, and (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (hydroxy)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxyl, and C1-C4alkyl;

[0278] R 13b is selected from C1-C4alkyl; amino; C1-C4haloalkyl; C1-C4alkoxy; (hydroxy)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (amino)alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxyl, and C1-C4alkyl; (C3-C6cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy;

[0279] R 21 selected from hydrogen, -C(=O)R 13b , C1-C4alkyl, C1-C4haloalkyl, unsubstituted 4- to 14-membered heterocyclyl, and -S(=O)2R 24 ;

[0280] R 22 is C1-C4alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxyl, and C1-C4alkyl;

[0281] R 24 is selected from C1-C4alkyl and (hydroxyl)C1-C4alkyl;

[0282] R 25 is selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl;

[0283] R 25b and R 25c are independently selected from C1-C4alkyl and C1-C4haloalkyl;

[0284] R 26 is selected from unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxyl, and C1-C4alkyl; and

[0285] R 21a and R 25a together with the atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclyl, or a pharmaceutically acceptable salt or solvate thereof.

[0286] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from:

[0287]

[0288]

[0289] wherein:

[0290] R 27a and R 27beach independently is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, (C1-C4alkoxy)C1-C4alkyl; and (hydroxy)C1-C4alkyl;

[0291] R 27c is selected from hydrogen; -C(=O)R 13b ; C1-C4alkyl; C1-C4haloalkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; and -S(=O)2R 24 ;

[0292] R 27d is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl;

[0293] R 13b is selected from C1-C4alkyl; amino C1-C4haloalkyl; C1-C4alkoxy; (hydroxy)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (amino)alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having one or two substituents independently selected from the group consisting of halogen, hydroxy, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; substituted 4- to 14-membered heterocyclyl having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (C3-C6cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy; and

[0294] R 24 is selected from C1-C4alkyl and (hydroxy)C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0295] In another embodiment, the compound of the present disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from:

[0296]

[0297]

[0298] or a pharmaceutically acceptable salt or solvate thereof

[0299] In another embodiment, the compound of the present disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from unsubstituted 4- to 14-membered heterocyclyl; substituted 4- to 14-membered heterocyclyl having one or two substituents independently selected from the group consisting of -N(R12a )C(=O)R 13a , -C(=O)R 13b and C1-C4alkyl; 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 halogen and C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0300] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is a substituted 4- to 14-membered heterocycle selected from the group consisting of:

[0301]

[0302] or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R 12a is selected from the group consisting of hydrogen and C1-C3alkyl; R 13a is C1-C4alkyl; and R 13b is C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R 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.

[0303] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is any one or more of the R 2b groups provided with respect to Formula III, see above, or a pharmaceutically acceptable salt or solvate thereof.

[0304] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein:

[0305] R 11a is selected from the group consisting of:

[0306]

[0307] and R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R c1 , R c2 , R c3 , R c4 , m, Rd1 , 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 , R w1 , R x1 , R y1 , and R z1 are as defined in Formula III; or a pharmaceutically acceptable salt or solvate thereof.

[0308] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D:

[0309] R 11a is selected from:

[0310]

[0311]

[0312] 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 are as defined in Formula III; or a pharmaceutically acceptable salt or solvate thereof.

[0313] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein 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. In another embodiment, R 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 hydrogen and C1-C4alkyl. In another embodiment, R a1 is an optionally substituted 4- to 10-membered heterocyclic ring.

[0314] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -2, R 11a -2A, or R 11a -2b, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R b1 is C1-C4alkyl.

[0315] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -3, R 11a -3A, or R 11a -3B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R c1 is selected from C1-C4alkyl, C3-C6cycloalkyl, and -C(=O)R 4c . In another embodiment, R c2 and R c3 are each hydrogen. In another embodiment, R c2 and R c3 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.

[0316] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R d1 is C(=O)R 4c . In another embodiment, R d2 and R d3 are each hydrogen or fluoro.

[0317] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -5, R 11a -5A, or R 11a -5B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R e1 is C(=O)R 4c .

[0318] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -6, R 11a -6A, or R 11a -6B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R f1 is C(=O)R 4c .

[0319] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -7, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R g1 is C(=O)R 4c .

[0320] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein 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. In another embodiment, R h1-C(=O)R 4c In another embodiment, R h2 is selected from hydrogen and C1-C3alkyl. In another embodiment, R h3 is hydrogen.

[0321] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -9, or a pharmaceutically acceptable salt or solvate thereof.

[0322] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -10, R 11a -10A, R 11a -10B, R 11a -10C, and R 11a -10d, or a pharmaceutically acceptable salt or solvate thereof.

[0323] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -11, R 11a -11A, and R 11a -11B, or a pharmaceutically acceptable salt or solvate thereof.

[0324] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -12, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R j1 is -C(=O)R 4c .

[0325] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -13, R 11a -13A, R 11a -13B, R 11a -13C, R 11a -13D, R 11a -13E, and R 11a -13F, or a pharmaceutically acceptable salt or solvate thereof.

[0326] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -14, or a pharmaceutically acceptable salt or solvate thereof.

[0327] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -15, or a pharmaceutically acceptable salt or solvate thereof.

[0328] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -16, R 11a -16A, and R 11a -16B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R n3 is -C(=O)R 4c .

[0329] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -17, or a pharmaceutically acceptable salt or solvate thereof.

[0330] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -18, or a pharmaceutically acceptable salt or solvate thereof.

[0331] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -19, or a pharmaceutically acceptable salt or solvate thereof.

[0332] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -20, or a pharmaceutically acceptable salt or solvate thereof.

[0333] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -21, R 11a -21A, and R 11a -21B, or a pharmaceutically acceptable salt or solvate thereof.

[0334] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -22, R 11a -22A, and R 11a -22B, or a pharmaceutically acceptable salt or solvate thereof.

[0335] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -23, or a pharmaceutically acceptable salt or solvate thereof.

[0336] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -24, or a pharmaceutically acceptable salt or solvate thereof.

[0337] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a -25, or a pharmaceutically acceptable salt or solvate thereof.

[0338] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -26, R 11a -26A, and R 11a -26B, or a pharmaceutically acceptable salt or solvate thereof.

[0339] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a -27, R 11a -27A, and R 11a- 27B, or a pharmaceutically acceptable salt or solvate thereof.

[0340] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is selected from R 11a - 28, R 11a - 28A, and R 11a - 28B, or a pharmaceutically acceptable salt or solvate thereof.

[0341] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a - 29, or a pharmaceutically acceptable salt or solvate thereof.

[0342] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R 11a is R 11a - 30, R 11a - 30A, or R 11a - 30B, or a pharmaceutically acceptable salt or solvate thereof.

[0343] In another embodiment, the compound of the disclosure is a compound of any one of Formula IV-A, IV-B, IV-C, or IV-D, wherein:

[0344] Z 4 is -CH2-;

[0345] R 11a is selected from:

[0346]

[0347] R 12a is selected from hydrogen and C1-C3 alkyl;

[0348] R 21 is -C(=O)R 13b ;

[0349] R 27c is -C(=O)R 13b ;

[0350] R 13b is selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[0351] R 24 is C1-C4 alkyl;

[0352] R25 selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; and

[0353] R 25b and R 25c are independently selected from C1-C4alkyl and C1-C4haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0354] In another embodiment, the compound of the disclosure is a compound of any one of Formulae IV-A, IV-B, IV-C, or IV-D:

[0355] Z 4 is -CH2-; and

[0356] R 11a is selected from:

[0357]

[0358] or a pharmaceutically acceptable salt or solvate thereof.

[0359] In another embodiment, the compound of the disclosure is a compound of any one of Formulae IV-A, IV-B, IV-C, or IV-D:

[0360] Z 4 is -CH2-; and

[0361] R 11a is selected from:

[0362]

[0363] or a pharmaceutically acceptable salt or solvate thereof.

[0364] In another embodiment, the compound of the disclosure is a compound of any one of Formulae IV-A, IV-B, IV-C, or IV-D:

[0365] Z 4 is -CH2-;

[0366] R 11a is:

[0367] and

[0368] R 27a is selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, (C1-C4alkoxy)C1-C4alkyl, and (hydroxy)C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R 27a is methyl.

[0369] In another embodiment, the compound of the present disclosure is a compound of Formula V:

[0370]

[0371] wherein:

[0372] R 14a is selected from the group consisting of optionally substituted alkyl and optionally substituted heteroaryl;

[0373] R 14b is selected from the group consisting of optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and carboxamide; and

[0374] p is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

[0375] In another embodiment, the compound of the present disclosure is a compound of Formula V-A:

[0376]

[0377] wherein R 1d , R 14a , R 14d , and p are as defined in Formula V, or a pharmaceutically acceptable salt or solvate thereof.

[0378] In another embodiment, the compound of the present disclosure is a compound of Formula V-B:

[0379]

[0380] wherein R 1d , R 14a , R 14d , and p are as defined in Formula V, or a pharmaceutically acceptable salt or solvate thereof.

[0381] In another embodiment, the compound of the present disclosure is a compound of any one of Formula V, V-A, or V-B, wherein:

[0382] R 14a is selected from the group consisting of (A) an unsubstituted 5- to 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 (i) halogen; (ii) C1-C4 alkyl; (iii) C1-C4 alkoxy; (iv) (3- to 8-membered heterocyclo)C1-C4 alkyl; (v) (5- to 9-membered heteroaryl)C1-C4 alkyl; (vi) -C(=O)NR 15a R 15b; (vii) unsubstituted 5- to 10-membered heteroaryl; (viii) substituted 5- or 10-membered heteroaryl having 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4alkyl, (3- to 8-membered heterocyclo)C1-C4alkyl, 5- to 9-membered heteroaryl, and -NR 15e R 15f ; (ix) -OR 16 (x) unsubstituted C3-C6cycloalkyl; (xi) substituted C3-C6cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C4alkyl and -N(R 17a )C(=O)R 18a ; (xii) cyano; (xiii) unsubstituted 4- to 14-membered heterocyclyl; (xiv) substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of C1-C4alkyl, (5- to 9-membered heteroaryl)C1-C4alkyl; (xv) (carboxyl)C1-C4alkyl; (xvi) (carboxamide)C1-C4alkyl; and (xvii) carboxyl; and (C) C1-C6alkyl;

[0383] R 14b is selected from the group consisting of: (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 halogen, C1-C4alkyl, and (C3-C6cycloalkyl)C1-C4alkyl; (C) unsubstituted C6-C 10 aryl; (D) substituted C6-C 10 aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C1-C4alkyl, and (3- to 8-membered heterocyclo)C1-C4alkyl; (E) unsubstituted 4- to 14-membered heterocyclyl; (F) substituted 4- to 14-membered heterocyclyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of hydroxy, amino, and C1-C4alkyl; (G) -C(=O)NR 15c R 15d ; (H) unsubstituted C3-C6cycloalkyl; and (I) C1-C6alkyl;

[0384] p is 0, 1, 2, or 3;

[0385] R 15a and R 15b are independently selected from the group consisting of: (A) hydrogen; (B) C1-C6alkyl; (C) C1-C6haloalkyl; (D) (C1-C4alkoxy)C1-C4alkyl; (E) (hydroxy)C1-C4alkyl; (F) (cyano)alkyl; (G) unsubstituted C6-C 10 aryl; (H) substituted C6-C 10substituted C6-C10aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, amino, hydroxy, and C1-C4alkyl; (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 halogen, amino, hydroxy, and C1-C4alkyl; (K) unsubstituted 4- to 14-membered heterocyclyl; (L) substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (M) unsubstituted C3-C8cycloalkyl; and (N) substituted C3-C8cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C6alkyl and -NR 15g R 15h ; or

[0386] R 15a and R 15b together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0387] R 15c and R 15d are independently selected from the group consisting of: (A) hydrogen; (B) C1-C6alkyl; (C) C1-C6haloalkyl; (D) (C1-C4alkoxy)C1-C4alkyl; (E) (hydroxy)C1-C4alkyl; (F) (cyano)alkyl; (G) unsubstituted C6-C10aryl; (H) substituted C6-C10aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, amino, hydroxy, and C1-C4alkyl; (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 halogen, amino, hydroxy, and C1-C4alkyl; (K) unsubstituted 4- to 14-membered heterocyclyl; (L) substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (M) unsubstituted C3-C8cycloalkyl; and (N) substituted C3-C8cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C6alkyl and -NR 10 aryl; (H) substituted C6-C 10 aryl; (H) substituted C6-C 15g R 15h ; or

[0388] R 15c and R 15d together with the nitrogen atom to which they are attached form an optionally substituted 4- to 14-membered heterocyclyl;

[0389] R 15e and R 15fIndependently selected from: (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 10 aryl group having 1, 2, 3, or 4 independent substituents selected from: halogen, amino, hydroxyl, and C1-C4 alkyl; (I) unsubstituted 5- or 6-membered heteroaryl; (J) substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 independent substituents selected from: halogen, amino, hydroxyl, and C1-C4 alkyl; (K) unsubstituted 4- to 14-membered heterocyclic group; (L) substituted 4- to 14-membered heterocyclic group having 1 or 2 independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; (M) unsubstituted C3- to C8 cycloalkyl; and (N) substituted C3- to C8 cycloalkyl group having 1, 2, 3, or 4 independent substituents selected from: C1-C6 alkyl and -NR 15g R 15h ;or

[0390] R 15e and R 15f Together with the nitrogen atoms attached to them, they form optionally substituted 4- to 14-membered heterocyclic groups;

[0391] R 15g and R 15h Independently selected from: (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)-substituted C6-C 10 aryl group having 1, 2, 3, or 4 independent substituents selected from: halogen, amino, hydroxyl, and C1-C4 alkyl; (J) unsubstituted 5- or 6-membered heteroaryl; (K) substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 independent substituents selected from: halogen, amino, hydroxyl, and C1-C4 alkyl; (L) unsubstituted 4- to 14-membered heterocyclic group; (M) substituted 4- to 14-membered heterocyclic group having 1 or 2 independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; (N) unsubstituted C3- to C8 cycloalkyl; and (O) substituted C3- to C8 cycloalkyl group having 1, 2, 3, or 4 independent substituents selected from: C1-C6 alkyl and -NR 15g R 15h ;or

[0392] R 15g and R15g together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 14-membered heterocyclyl group;

[0393] R 16 is (amino)(hydroxy)C1-C4alkyl;

[0394] R 17a is selected from hydrogen and C1-C4alkyl;

[0395] R 18a is selected from: (A) C1-C6alkyl; (B) C1-C6haloalkyl; (C) C1-C6alkoxy; (D) (C1-C4alkoxy)C1-C4alkyl; (E) (hydroxy)C1-C4alkyl; (F) (cyano)alkyl; (G) unsubstituted C6-C10aryl; (H) substituted C6-C10aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, amino, hydroxy, and C1-C4alkyl; (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 halogen, amino, hydroxy, and C1-C4alkyl; (K) unsubstituted 4- to 14-membered heterocyclyl; (L) substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (M) unsubstituted C3-C8cycloalkyl; and (N) substituted C3-C8cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl, 10 aryl; (H) substituted C6-C 10 aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, amino, hydroxy, and C1-C4alkyl; (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 halogen, amino, hydroxy, and C1-C4alkyl; (K) unsubstituted 4- to 14-membered heterocyclyl; (L) substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (M) unsubstituted C3-C8cycloalkyl; and (N) substituted C3-C8cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl,

[0396] or a pharmaceutically acceptable salt or solvate thereof.

[0397] In another embodiment, the compound of the present disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R 14a is selected from unsubstituted 5- to 10-membered heteroaryl; and substituted 5- or 10-membered heteroaryl having 1, 2, or 3 substituents independently selected from the group consisting of C1-C4alkyl; C1-C4alkoxy; (3- to 8-membered heterocyclyl)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; -C(=O)NR 15a R 15b unsubstituted 5- to 10-membered heteroaryl; substituted 5- or 10-membered heteroaryl having 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4alkyl, (3- to 8-membered heterocyclyl)C1-C4alkyl, 5- to 9-membered heteroaryl, and -NR 15e R 15fsubstituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, (3- to 8-membered heterocyclo)C1-C4alkyl, (5- to 9-membered heteroaryl)C1-C4alkyl, -C(=O)NR 17a )C(=O)R 18a , or a pharmaceutically acceptable salt or solvate thereof.

[0398] In another embodiment, the compound of the disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R 14a is substituted pyridyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-C4alkyl; C1-C4alkoxy; (3- to 8-membered heterocyclo)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; -C(=O)NR 15a R 15b ; unsubstituted 5- to 10-membered heteroaryl; substituted 5- to 10-membered heteroaryl substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4alkyl, (3- to 8-membered heterocyclo)C1-C4alkyl, 5- to 9-membered heteroaryl, and -NR 15e R 15f ; unsubstituted C3-C6cycloalkyl; and substituted C3-C6cycloalkyl substituted by 1, 2, or 3 substituents independently selected from the group consisting of C1-C4alkyl and -N(R 17a )C(=O)R 18a , or a pharmaceutically acceptable salt or solvate thereof.

[0399] In another embodiment, the compound of the disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R 14b is selected from the group consisting of unsubstituted 5- to 10-membered heteroaryl; substituted 5- to 10-membered heteroaryl substituted by 1 or 2 substituents independently selected from the group consisting of C1-C4alkyl and (C3-C6cycloalkyl)C1-C4alkyl; unsubstituted C6-C 10 aryl; substituted C6-C 10 aryl substituted by 1 or 2 substituents independently selected from the group consisting of C1-C4alkyl and (3- to 8-membered heterocyclo)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; substituted 4- to 14-membered heterocyclyl substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, and C1-C4alkyl; and unsubstituted C3-C6cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0400] In another embodiment, the compound of the disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R 14bsubstituted 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of C1-C4alkyl and (C3-C6cycloalkyl)C1-C4alkyl; unsubstituted phenyl; substituted phenyl having 1 or 2 substituents independently selected from the group consisting of C1-C4alkyl and (3- to 8-membered heterocyclo)C1-C4alkyl; and unsubstituted C3-C6cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0401] In another embodiment, the compound of the disclosure is a compound of any one of Formula V, V-A, or V-B, wherein p is 0, or a pharmaceutically acceptable salt or solvate thereof.

[0402] In another embodiment, the compound of the disclosure is a compound of any one of Formula V, V-A, or V-B, wherein p is 1, or a pharmaceutically acceptable salt or solvate thereof.

[0403] In another embodiment, the compound of the disclosure is a compound of Formula VI:

[0404]

[0405] wherein:

[0406] R 19 selected from the group consisting of unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl;

[0407] R 20 selected from the group consisting of hydrogen, halogen, and C1-C4alkyl; and

[0408] q is 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

[0409] In another embodiment, the compound of the disclosure is a compound of Formula VI, wherein q is 1.

[0410] In another embodiment, the compound of the disclosure is a compound of Formula VII:

[0411]

[0412] wherein:

[0413] R 11b selected from the group consisting of C1-C4alkyl, halogen, and C1-C4haloalkyl; and

[0414] R 1d and R 11a as described for Formula IV, or a pharmaceutically acceptable salt or solvate thereof.

[0415] In another embodiment, a compound of the disclosure is a compound of Formula VII-A:

[0416]

[0417] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0418] In another embodiment, a compound of the disclosure is a compound of Formula VII-B:

[0419]

[0420] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0421] In another embodiment, a compound of the disclosure is a compound of Formula VII-C:

[0422]

[0423] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0424] In another embodiment, a compound of the disclosure is a compound of Formula VII-D:

[0425]

[0426] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0427] In another embodiment, a compound of the disclosure is a compound of Formula VII-E:

[0428]

[0429] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0430] In another embodiment, a compound of the disclosure is a compound of Formula VII-F:

[0431]

[0432] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0433] In another embodiment, a compound of the disclosure is a compound of Formula VII-G:

[0434]

[0435] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0436] In another embodiment, a compound of the disclosure is a compound of Formula VII-H:

[0437]

[0438] wherein R 1d , R 11a , and R 11b are as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0439] In another embodiment, a compound of the disclosure is a compound of Formula VIII:

[0440]

[0441] wherein:

[0442] R 30 is selected from hydrogen; C1-C6alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from halogen, hydroxyl, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from amino, hydroxyl, and C1-C4alkyl; -C(=O)R 13b , and -S(=O)2R 24 ;

[0443] R 13bselected from C1-C4alkyl; amino; C1-C4haloalkyl; C1-C4alkoxy; (hydroxy)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (amino)alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (C3-C6cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy;

[0444] R 24 selected from C1-C4alkyl and (hydroxy)C1-C4alkyl;

[0445] u is 0, 1, 2, or 3; and

[0446] R 1d as described in Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0447] In another embodiment, the compounds of the present disclosure are compounds of Formula VIII-A:

[0448]

[0449] wherein R 1d , R 30 and u are as defined in Formula VII I, or a pharmaceutically acceptable salt or solvate thereof.

[0450] In another embodiment, the compounds of the present disclosure are compounds of Formula VIII-B:

[0451]

[0452] wherein R 1d , R 30 and u are as defined in Formula VII I, or a pharmaceutically acceptable salt or solvate thereof.

[0453] In another embodiment, the compounds of the present disclosure are compounds of Table 1, and pharmaceutically acceptable salts or solvates thereof. The chemical names of the compounds in Table 1 are derived from ChemDraw Ultra 12.0.2 (CambridgeSoft®). Professional version 17.0.0.206 was used for the generation of the mass spectrometry and biological data of representative compounds of the present disclosure. Mass spectrometry and biological data of representative compounds of the present disclosure are provided in Table 1B and / or PCT / US2019 / 046569. In another embodiment, a compound of the present disclosure is a compound of Table 1B, and pharmaceutically acceptable salts or solvates thereof. The biological data in Table 1B was generated following the protocols described in Examples 11 and 12 of PCT / US2019 / 046569.

[0454] In another embodiment, a compound of the present disclosure is selected from Compound Nos. 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, a compound of the present disclosure is selected from Compound Nos. 15, 922, 930, 942, 1055, 1070, 1117, 1180, 1184, and 1192, and pharmaceutically acceptable salts or solvates thereof. In another embodiment, a compound of the present disclosure is selected from Compound Nos. 1228, 1229, 1230, 1231, 1232, 1233, 1234, and 1235, and pharmaceutically acceptable salts or solvates thereof.

[0455] In another embodiment, a compound of the present disclosure is selected from Compound Nos. 15, 942, 1184, and 1232, and pharmaceutically acceptable salts or solvates thereof.

[0456] In non-limiting embodiments, the compound of the disclosure is Compound No. 15. In non-limiting embodiments, the compound of the disclosure is Compound No. 1228. In non-limiting embodiments, the compound of the disclosure is Compound No. 1229. In non-limiting embodiments, the compound of the disclosure is Compound No. 1230. In non-limiting embodiments, the compound of the disclosure is Compound No. 1231. In non-limiting embodiments, the compound of the disclosure is Compound No. 1232. In non-limiting embodiments, the compound of the disclosure is Compound No. 1233. In non-limiting embodiments, the compound of the disclosure is Compound No. 1234. In non-limiting embodiments, the compound of the disclosure is Compound No. 1235. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 15. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1228. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1229. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1230. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1231. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1232. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1233. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1234. In non-limiting embodiments, the compound of the disclosure is a pharmaceutically acceptable salt or solvate of Compound No. 1235.

[0457] Table 1

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514] Table 1B

[0515]

[0516]

[0517] The present disclosure includes the preparation and use of salts of the compounds of the present disclosure, including nontoxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, and basic salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metals such as calcium salt, magnesium salt, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate, and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, and the like; sulfonic acid salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; and amino acid salts such as arginate, asparaginate, glutamate, and the like. The term "pharmaceutically acceptable salt" as used herein refers to a compound of the present disclosure that is physiologically tolerable in the subject (e.g., a mammal, e.g., a human).

[0518] Acid addition salts can be formed by mixing a solution of the particular compound of this 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, and the like. Basic salts can be formed by mixing a solution of the compound of this disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.

[0519] The present disclosure includes the preparation and use of solvates of the compounds of the present disclosure. Solvates typically do not significantly modify the physiological activity or toxicity of the compounds and thus can be used as pharmacological equivalents. The term "solvate" as used herein refers to a combination or a physical association and / or solvation of a compound of the present disclosure with a solvent molecule, such as, for example, a disolvate, monosolvate, or hemisolvate, wherein the ratio of solvent molecules to compounds of the present disclosure is about 2: 1, about 1: 1, or about 1:2, respectively. Such physical associations involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated in the crystalline solid state of the lattice. Thus, "solvate" encompasses both solution- phase and isolatable solvates. The compounds of the present disclosure can exist as solvated forms with pharmaceutically acceptable solvents such as water, methanol, ethanol, and the like, and the present disclosure is intended to include both solvated and unsolvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates where the solvent molecule is water. Solvates typically can be used as pharmacological equivalents. The preparation of solvates is known in the art. See, e.g., M. Caira et al., J. Pharmaceut. Sci. 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and water. Similar preparations of solvates, hemisolvates, hydrates and the like are described by E. C. van Tonder et al., AAPS PharmSci. Tech., 5(1): Article 12 (2004) and A. L. Bingham et al., Chem. Commun 603-604 (2001). A typical, non-limiting process of preparing a solvate would involve dissolving the compound of the present disclosure in a desired solvent (organic, water or a mixture thereof) at a temperature above 20 °C to about 25 °C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of a solvent as a crystalline form of a solvate.

[0520] II. Second Therapeutic Agent

[0521] In some embodiments, the treatment methods of the present application comprise administering a therapeutically effective amount of a compound of the present disclosure in combination with a therapeutically effective amount of a second therapeutic agent.

[0522] The term "second therapeutic agent" as used herein includes one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more multi- effector pathway modulators, one or more XPOl inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or combinations thereof. In one embodiment, the second therapeutic agent includes one compound from a drug class, i.e., a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. In another embodiment, the second therapeutic agent includes two different compounds from a drug class, e.g., two different glucocorticoid receptor agonists, e.g., dexamethasone and prednisone, two different immunomodulatory drugs, two different proteasome inhibitors, two different Bcl-2 inhibitors, two different multi- effector pathway modulators, two different XPOl inhibitors, two different histone deacetylase inhibitors, or two different EZH2 inhibitors. In another embodiment, the second therapeutic agent includes three different compounds from a drug class, e.g., three different glucocorticoid receptor agonists, e.g., dexamethasone, prednisone, and methylprednisolone, three different immunomodulatory drugs, three different proteasome inhibitors, three different Bcl-2 inhibitors, three different multi- effector pathway modulators, three different XPOl inhibitors, three different histone deacetylase inhibitors, or three different EZH2 inhibitors. In another embodiment, the second therapeutic agent includes three different compounds from two drug classes, e.g., two different glucocorticoid receptor agonists, e.g., dexamethasone and prednisone, and one immunomodulatory drug; two different glucocorticoid receptor agonists and one proteasome inhibitor; and so forth.

[0523] In another embodiment, the second therapeutic agent includes compounds from different drug classes, e.g., a first compound from a first drug class and a second compound from a second drug class, wherein the first drug class and the second drug class are different. As a specific, non-limiting example, the second therapeutic agent includes an EZH2 inhibitor, e.g., tazemetostat, and an immunomodulatory drug, e.g., lenalidomide. The following table provides non-limiting examples of drug class combinations:

[0524]

[0525]

[0526] In another embodiment, the second therapeutic agent comprises three compounds from three different drug classes. For example, in one embodiment, the second therapeutic agent comprises a first compound from a first drug class, a second compound from a second drug class, and a third compound from a third drug class, wherein the first drug class, the second drug class, and the third drug class are different. The following table provides non-limiting examples of drug class combinations:

[0527]

[0528]

[0529]

[0530] The term "glucocorticoid receptor agonist" or "GR agonist" as used herein refers to a compound that activates the glucocorticoid receptor. Glucocorticoid receptor agonists and methods of administering a glucocorticoid receptor agonist to a subject are known in the art. See, e.g., Pufall, M. A., Adv Exp Med Biol. 872:315-333 (2015). Exemplary glucocorticoid receptor agonists include, but are not limited to, dexamethasone, hydrocortisone, corticosterone, prednisolone, methylprednisolone, prednisone, triamcinolone, mapracorat, ciclesonide, and (20S)-protopanaxatriol. In one embodiment, the glucocorticoid receptor agonist is prednisone. In another embodiment, the glucocorticoid receptor agonist is dexamethasone.

[0531] The term "immunomodulatory drug" or "IMiD" as used herein refers to a compound that suppresses the production of tumor necrosis factor, interleukin 6, immunoglobulin G, and / or VEGF, and / or costimulates T cells and NK cells, and / or increases interferon gamma and interleukin 2 production. Immunomodulatory drugs and methods of administering an immunomodulatory drug to a subject are known in the art. Exemplary immunomodulatory drugs include, but are not limited to, thalidomide, lenalidomide, and pomalidomide. In one embodiment, the immunomodulatory drug is pomalidomide.

[0532] The term "proteasome inhibitor" as used herein refers to a compound that blocks the action of the proteasome, thereby preventing the degradation of pro-apoptotic factors such as the p53 protein. Proteasome inhibitors and methods of administering a proteasome inhibitor to a subject are known in the art. Exemplary proteasome inhibitors include, but are not limited to, bortezomib, carfilzomib, and ixazomib. In one embodiment, the proteasome inhibitor is bortezomib.

[0533] The term "Bcl-2 inhibitor" as used herein refers to a compound that inhibits anti-apoptotic Bcl-2 proteins. Bcl-2 inhibitors and methods of administering Bcl-2 inhibitors to a subject are known in the art. Exemplary Bcl-2 inhibitors include, but are not limited to, navitoclax (ABT-263), ABT-737, Sabutoclax, AT-1019 (Gossypol), TW-37, venetoclax (ABT-199), obatoclax, HA14-1, A-1155463, A-1331852, and WEHI-539. In one embodiment, the Bcl-2 inhibitor is venetoclax.

[0534] The term "pleiotropic pathway modulator" as used herein refers to a compound that binds to cereblon to promote protein degradation. Pleiotropic pathway modulators and methods of administering pleiotropic pathway modulators to a subject are known in the art. See, e.g., Hagner et al., Blood 126:779-789 (2017). A non-limiting exemplary pleiotropic pathway modulator is CC-122.

[0535] The term "XPOl inhibitor" as used herein refers to an inhibitor of exportin-1 (also known as chromosome region maintenance protein 1 homolog; CRMl). XPOl inhibitors and methods of administering XPOl inhibitors to a subject are known in the art. See, e.g., Wang and Liu, Stem Cell Invest 6:6 (2019). A non-limiting exemplary XPOl inhibitor is selinexor.

[0536] The term "histone deacetylase inhibitor" or "HDAC inhibitor" as used herein refers to a compound that inhibits histone deacetylases. Histone deacetylase inhibitors and methods of administering histone deacetylase inhibitors to a subject are known in the art. See, e.g., Eckschlager et al., Int. J. Mol. Sci. 18:1414 (2017) doi: 10.3390 / ijms18071414. Exemplary histone deacetylase inhibitors include, but are not limited to, romidepsin, belinostat, panobinostat, and vorinostat. In one embodiment, the histone deacetylase inhibitor is panobinostat.

[0537] As used herein, the term "EZH2 inhibitor" refers to a compound that inhibits Enhancer of Zeste Homolog 2 enzyme. EZH2 inhibitors and methods of administering an EZH2 inhibitor to a subject are known in the art. See, e.g., Lue and Amengual, Curr Hematol Malig Rep 13:369-382 (2018). Exemplary EZH2 inhibitors include, but are not limited to, talazoparib, EPZ011989, EPZ005687, GSK126, PF-06821497, and valemetostat. In one embodiment, the EZH2 inhibitor is talazoparib.

[0538] The present application provides the following specific embodiments relating to combination therapy (CT):

[0539] CT Embodiment I. A method of treating a subject in need thereof, the method comprising administering to the subject: (a) a therapeutically effective amount of a compound of the present disclosure; and (b) a therapeutically effective amount of a second therapeutic agent, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor, or a combination thereof; and the subject has a cancer.

[0540] CT Embodiment II. The method of CT Embodiment I, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist.

[0541] CT Embodiment III. The method of CT Embodiment II, wherein the glucocorticoid receptor agonist is dexamethasone.

[0542] CT Embodiment IV. The method of any one of CT Embodiments I-III, wherein the second therapeutic agent comprises an immunomodulatory drug.

[0543] CT Embodiment V. The method of CT Embodiment IV, wherein the immunomodulatory drug is pomalidomide or lenalidomide.

[0544] CT Embodiment VI. The method of any one of CT Embodiments I-V, wherein the second therapeutic agent comprises a proteasome inhibitor.

[0545] CT Embodiment VII. The method of CT Embodiment VI, wherein the proteasome inhibitor is bortezomib.

[0546] CT Embodiment VIII. The method of any one of CT Embodiments I-VII, wherein the second therapeutic agent comprises a Bcl-2 inhibitor.

[0547] CT Embodiment IX. The method of CT Embodiment VIII, wherein the Bcl-2 inhibitor is venetoclax.

[0548] CT Embodiment X. The method of any one of CT Embodiments I-IX, wherein the second therapeutic agent comprises a pleiotropic pathway modulator.

[0549] CT Embodiment XI. The method of CT Embodiment X, wherein the pleiotropic pathway modulator is CC-122.

[0550] CT Embodiment XII. The method of any one of CT Embodiments I-XI, wherein the second therapeutic agent comprises an XPOl inhibitor.

[0551] CT Embodiment XIII. The method of CT Embodiment XII, wherein the XPOl inhibitor is selinexor.

[0552] CT Embodiment XIV. The method of any one of CT Embodiments I-XIII, wherein the second therapeutic agent comprises a histone deacetylase inhibitor.

[0553] CT Embodiment XV. The method of CT Embodiment XIV, wherein the histone deacetylase inhibitor is panobinostat.

[0554] CT Embodiment XVI. The method of any one of CT Embodiments I-XV, wherein the second therapeutic agent is an EZH2 inhibitor.

[0555] CT Embodiment XVII. The method of CT Embodiment XVI, wherein the EZH2 inhibitor is tazemetostat.

[0556] III. Methods of Treatment

[0557] The present disclosure relates generally to methods for treating a disease, condition, or disorder in a subject having or likely to have the disease, condition, or disorder, the method comprising administering to the subject an effective amount of a compound of the present disclosure and an optional second therapeutic agent. In one embodiment, the disease, condition, or disorder is responsive to or mediated by inhibition of a SETD2 protein by a compound of the present disclosure.

[0558] In the methods of treatment provided herein, a compound of the present disclosure can be administered to a subject having cancer as a single agent. A compound of the present disclosure can also be administered to a subject having cancer in combination with a second therapeutic agent. The compound of the present disclosure and the second therapeutic agent can be administered in combination under one or more of the following conditions: as separate pharmaceutical compositions, in different cycles, e.g., simultaneously or sequentially, for different durations, at different concentrations, by different routes of administration, etc. An additional optional therapeutic agent, e.g., an anti-cancer agent, can also be administered to the cancer patient.

[0559] The present disclosure also relates to a method of inhibiting a SETD2 protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0560] In one aspect, the present 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 present disclosure.

[0561] In another aspect, the present 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 present disclosure in combination with a second therapeutic agent.

[0562] In another aspect, the present disclosure provides a method of treating a cancer in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure. In another aspect, the present disclosure provides a method of treating a cancer in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure in combination with a second therapeutic agent. While not limited to a particular mechanism, in some embodiments, the compounds of the present disclosure treat cancer by inhibiting a SETD2 protein. Examples of treatable cancers include, but are not limited to, the cancers listed in Table 2.

[0563] Table 2

[0564]

[0565]

[0566]

[0567]

[0568] In another embodiment, the cancer is pancreatic cancer or esophageal cancer.

[0569] 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 / urologic cancer, head and neck cancer, prostate cancer, hematological cancer, pancreatic cancer, skin cancer, endometrial cancer, ovarian cancer, and colorectal cancer.

[0570] In another embodiment, the cancer or cancer cell is a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3.

[0571] Table 3

[0572]

[0573] In another embodiment, the cancer is multiple myeloma.

[0574] In another embodiment, the multiple myeloma is characterized by having a chromosomal translocation at 14q32 involving the immunoglobulin heavy chain locus. In another embodiment, the chromosomal translocation is a t(4; 14) translocation, i.e., the multiple myeloma is a t(4; 14) multiple myeloma.

[0575] In another embodiment, the cancer is mantle cell lymphoma.

[0576] In another embodiment, the cancer is diffuse large B-cell lymphoma.

[0577] In another embodiment, the present application provides a method of treating a cancer in vivo by modulating protein methylation, gene expression, cell proliferation, cell differentiation, and / or apoptosis by administering to a subject in need of such treatment and optionally a second therapeutic agent, a therapeutically effective amount of a compound of the present disclosure.

[0578] The present application provides the following specific embodiments, which relate to compounds of the present application, methods of treating cancer with compounds of the present application, and methods of treating cancer with compounds of the present application in combination with a second therapeutic agent.

[0579] Embodiment I. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure and optionally, a second therapeutic agent, wherein the subject has a cancer, and the second therapeutic agent is selected from the group consisting of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, and an EZH2 inhibitor, or a combination thereof.

[0580] Embodiment II. The method of embodiment I, wherein the cancer is any one or more of the cancers of Table 2.

[0581] Embodiment III. The method of embodiment I, wherein the cancer is a hematological cancer.

[0582] Embodiment IV. The method of embodiment III, wherein the hematological cancer is any one or more of the cancers of Table 3, e.g., multiple myeloma.

[0583] Embodiment V. The method of embodiment IV, wherein the hematological cancer is a t(4; 14) multiple myeloma.

[0584] Embodiment VI. The method of any one of embodiments I-V, further comprising administering a therapeutically effective amount of a second therapeutic agent.

[0585] Embodiment VII. A pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier for use in treating cancer, wherein the pharmaceutical composition comprising a compound of the disclosure is optionally administered in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, and an EZH2 inhibitor, or a combination thereof.

[0586] Embodiment VIII. The pharmaceutical composition of Embodiment VII, wherein the cancer is any one or more of the cancers of Table 2.

[0587] Embodiment IX. The pharmaceutical composition of Embodiment VII, wherein the cancer is a hematological cancer.

[0588] Embodiment X. The pharmaceutical composition of Embodiment IX, wherein the hematological cancer is any one or more of the cancers of Table 3, e.g., multiple myeloma.

[0589] Embodiment XI. The pharmaceutical composition of Embodiment X, wherein the hematological cancer is t(4; 14) multiple myeloma.

[0590] Embodiment XII. A compound of the disclosure for use in treating cancer, wherein a compound of the disclosure is optionally administered in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, and an EZH2 inhibitor, or a combination thereof.

[0591] Embodiment XIII. The compound for use of Embodiment XII, wherein the cancer is any one or more of the cancers of Table 2.

[0592] Embodiment XIV. The compound for use of Embodiment XII, wherein the cancer is a hematological cancer.

[0593] Embodiment XV. The compound for use of Embodiment XIV, wherein the hematological cancer is any one or more of the cancers of Table 3, e.g., multiple myeloma.

[0594] Embodiment XVI. The compound for use of Embodiment XV, wherein the hematological cancer is t(4; 14) multiple myeloma.

[0595] Embodiment XVII. Use of a compound of the disclosure in the manufacture of a medicament for the treatment of cancer, wherein the medicament is optionally administered in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, and an EZH2 inhibitor, or a combination thereof.

[0596] Embodiment XVIII. The use of embodiment XVII, wherein the cancer is any one or more of the cancers of Table 2.

[0597] Embodiment XVIII. The use of embodiment XVII, wherein the cancer is a hematological cancer.

[0598] Embodiment XIX. The use of embodiment XVII, wherein the hematological cancer is any one or more of the cancers of Table 3, e.g., multiple myeloma.

[0599] Embodiment XX. The use of embodiment XIX, wherein the hematological cancer is t(4; 14) multiple myeloma.

[0600] Embodiment XXI The use of any one of embodiments XVII-XX, comprising a second therapeutic agent.

[0601] Embodiment XXII. A kit comprising a compound of the disclosure and optionally a second therapeutic agent, and instructions for administering a compound of the disclosure to a subject having a cancer.

[0602] Embodiment XXIII. The kit of embodiment XXII, wherein the cancer is any one or more of the cancers of Table 2.

[0603] Embodiment XXIV. The kit of embodiment XXII, wherein the cancer is a hematological cancer.

[0604] Embodiment XXV. The kit of embodiment XXIV, wherein the hematological cancer is any one or more of the cancers of Table 3, e.g., multiple myeloma.

[0605] Embodiment XXVI. The kit of embodiment XXV, wherein the hematological cancer is t(4; 14) multiple myeloma.

[0606] Embodiment XXVII. The kit of any one of embodiments XXII-XXVI, further comprising a second therapeutic agent.

[0607] Embodiment XXVIII. The method of embodiment VI, wherein the compound of the disclosure and the second therapeutic agent are administered simultaneously.

[0608] Embodiment XXIX. The method of embodiment VI, wherein the compound of the disclosure and the second therapeutic agent are administered sequentially.

[0609] Embodiment XXX. The pharmaceutical composition of any one of embodiments VII-XI, wherein the pharmaceutical composition is formulated for simultaneous administration of the compound of the disclosure and the second therapeutic agent.

[0610] Embodiment XXXI. The pharmaceutical composition of any one of embodiments VII-XI, wherein the pharmaceutical composition is formulated for sequential administration of the compound of the disclosure and the second therapeutic agent.

[0611] Embodiment XXXII. The compound for use of any one of embodiments XII-XVI, wherein the combination of the compound of the disclosure and the second therapeutic agent is administered simultaneously.

[0612] Embodiment XXXIII. The compound for use of any one of embodiments XII-XVI, wherein the combination of the compound of the disclosure and the second therapeutic agent is administered sequentially.

[0613] Embodiment XXXIV. The use of any one of embodiments XVII-XX, wherein the combination of the compound of the disclosure and the second therapeutic agent is administered simultaneously.

[0614] Embodiment XXXV. The use of any one of embodiments XVII-XX, wherein the combination of the compound of the disclosure and the second therapeutic agent is administered sequentially.

[0615] The present application also provides the following specific embodiments.

[0616] Embodiment 1. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of:

[0617] (a) a compound of Formula I:

[0618]

[0619] wherein:

[0620] R 1a is selected from halogen, alkyl, alkoxy, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0621] Q 1 is selected from -C(R 1b )= and -N=;

[0622] Q 2 is selected from -C(R 1c )= and -N=;

[0623] Q3 selected from -C(R 1d )= and -N=;

[0624] provided that at least one of Q 1 , Q 2 or Q 3 is -C(R 1b )=, -C(R 1c )= or -C(R 1d )=, respectively;

[0625] R 1b , R 1c and R 1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl and alkoxy;

[0626] R 1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl and (cycloalkyl)alkyl;

[0627] is a single or double bond;

[0628] G 1 is selected from the group consisting of: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclyl; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclyl)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclyl)alkyl; (heteroaryl)(carboxamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclyl)(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

[0629] G 2 is selected from hydrogen and alkyl; or

[0630] G 1 and G 2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl,

[0631] The condition is that the compound of formula I is not N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-7-methyl-1H-indole-2-carboxamide; N-((1r,4r)-4-(3-aminopropionamido)cyclohexyl)-7-methyl-1H-indole-2-carboxamide; or N-((1r,4r)-4-aminocyclohexyl)-7-methyl-1H-indole-2-carboxamide,

[0632] Or its pharmaceutically acceptable salts or solvates; and

[0633] (b) Second therapeutic agent,

[0634] in:

[0635] The second therapeutic agent includes one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPO1 inhibitors, one or more histone deacetylases, or one or more EZH2 inhibitors, or combinations thereof.

[0636] Implementation Scheme 2. The method of Implementation Scheme 1, wherein the compound is a compound of Formula II:

[0637]

[0638] Or its pharmaceutically acceptable salts or solvates.

[0639] Implementation Scheme 3. The method of Implementation Scheme 1 or 2, wherein G 1 Selected from: Optionally substituted C6-C 10 aryl; optionally substituted 5- to 9-membered heteroaryl; optionally substituted 3- to 10-membered heterocyclic; 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,

[0640] Or its pharmaceutically acceptable salts or solvates.

[0641] Implementation Scheme 4. The method of Implementation Scheme 3, wherein the compound is a compound of Formula IV:

[0642]

[0643] in:

[0644] Z 4 Selected from -O-, -C(R) 28a)(R 28b )- and -N(R 23 )-; or Z 4 is absent;

[0645] Z 5 is selected from -CH2- and -CH2CH2-;

[0646] R 11a is selected from optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and -N(R 12b )C(=O)R 13c ;

[0647] R 12b is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl; and

[0648] R 13c is selected from alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl, amino, (amino)alkyl, (C3-C6 cycloalkyl)oxy, and (4- to 8-membered heterocyclyl)oxy;

[0649] R 23 is selected from hydrogen and C1-C4 alkyl; and

[0650] R 28a and R 28b are independently selected from hydrogen, alkyl, and halo;

[0651] or a pharmaceutically acceptable salt or solvate thereof.

[0652] Embodiment 5. The method of embodiment 4, wherein the compound is a compound of Formula IV-A:

[0653]

[0654] or a pharmaceutically acceptable salt or solvate thereof.

[0655] Embodiment 6. The method of embodiment 4, wherein the compound is a compound of Formula IV-B:

[0656]

[0657] or a pharmaceutically acceptable salt or solvate thereof.

[0658] Embodiment 7. The method of embodiment 4, wherein the compound is a compound of Formula IV-C:

[0659]

[0660] or a pharmaceutically acceptable salt or solvate thereof.

[0661] Embodiment 8. The method of embodiment 4, wherein the compound is a compound of Formula IV-D:

[0662]

[0663] or a pharmaceutically acceptable salt or solvate thereof.

[0664] Embodiment 9. The method of any one of embodiments 4-8, wherein:

[0665] R 11a is selected from:

[0666] (A) unsubstituted 4- to 14-membered heterocyclyl;

[0667] (B) substituted 4- to 14-membered heterocycle having 1, 2, or 3 substituents independently selected from:

[0668] (i) -N(R 12a )C(=O)R 13a ; (ii) -C(=O)R 13b ; (iii) C1-C4alkyl; (iv) (C1-C4alkoxy)C1-C4alkyl; (v) (hydroxy)C1-C4alkyl; (vi) C1-C4haloalkyl; (vii) amino; (vii) hydroxy; (viii) -N(R 12a )S(=O)2R 24 ; (ix) -S(=O)2R 24 ; (x) unsubstituted C3-C6cycloalkyl; (xi) substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from halogen, hydroxy, C1-C4alkyl, amino, and (amino)C1-C4alkyl; (xii) unsubstituted 4- to 14-membered heterocyclyl; and 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from amino, hydroxy, and C1-C4alkyl; (xiii) -C(=N-R 60 )R 61 ; and (xiv) -C(=C-NO2)R 64 ;

[0669] (C) unsubstituted 5- to 10-membered heteroaryl;

[0670] (D) substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from halogen and C1-C4alkyl;

[0671] (E) C1-C6alkyl; and

[0672] (F)-N(R 12b )C(=O)R 13c ;

[0673] R 12a R12b is independently selected from hydrogen, C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl;

[0674] R 13a R 13b and R 13c Each is independently selected from (A) C1-C6 alkyl; (B) C1-C6 haloalkyl; (C) unsubstituted C3-C6 cycloalkyl; (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)-substituted C6-C 10 An aryl group having 1, 2, 3, or 4 independently selected substituents from the group consisting of halogen, amino, hydroxyl, and C1-C4 alkyl; (J) an unsubstituted 5- or 6-membered heteroaryl; (K) a substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 independently selected substituents from the group consisting of halogen, amino, hydroxyl, and C1-C4 alkyl; (L) an unsubstituted 4- to 14-membered heterocyclic group; (M) a substituted 4- to 14-membered heterocyclic group having 1 or 2 independently selected substituents from the group consisting of amino, hydroxyl, and C1-C4 alkyl; (N) amino; (O) (amino)alkyl; (P) (C3-C6 cycloalkyl)oxy; and (Q) (4- to 8-membered heterocyclic)oxy; and

[0675] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[0676] R 60 Selected from cyano, nitro, hydroxy, C1-C6 alkoxy, -C(=O)R 62 and -S(=O)2R 62 ;

[0677] R 61 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[0678] R 62 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[0679] R 63aselected from hydrogen, C1-C6alkyl, and C3-C6cycloalkyl;

[0680] R 63b selected from hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0681] R 63a and R 63b together with the nitrogen atom to which they are attached form a 4- to 6- membered optionally substituted heterocyclyl;

[0682] R 64 selected from C1-C6alkyl, C3-C6cycloalkyl, and -NR 63c R 63d ;

[0683] R 63c selected from hydrogen, C1-C6alkyl, and C3-C6cycloalkyl;

[0684] R 63d selected from hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0685] R 63c and R 63d together with the nitrogen atom to which they are attached form a 4- to 6- membered optionally substituted heterocyclyl,

[0686] or a pharmaceutically acceptable salt or solvate thereof.

[0687] Embodiment 10. The method of embodiment 9, wherein R 11a is substituted 4- to 14-membered heterocyclyl selected from:

[0688]

[0689] R 12a selected from hydrogen, C1-C3alkyl, (C1-C4alkoxy)C1-C4alkyl; and (hydroxy)C1-C4alkyl;

[0690] R 13a selected from C1-C4alkyl; amino; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4alkyl, amino, and (amino)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (hydroxy)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxyl, and C1-C4alkyl;

[0691] R 13bselected from the group consisting of C1-C4alkyl; amino; C1-C4haloalkyl; C1-C4alkoxy; (hydroxy)C1-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (amino)alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; (C3-C6cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy;

[0692] R 21 is selected from the group consisting of hydrogen, -C(=O)R 13b , C1-C4alkyl, C1-C4haloalkyl, unsubstituted 4- to 14-membered heterocycle, and -S(=O)2R 24 ;

[0693] R 22 is C1-C4alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4alkyl, amino, and (amino)C1-C4alkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl;

[0694] R 24 is selected from the group consisting of C1-C4alkyl and (hydroxy)C1-C4alkyl;

[0695] R 25 is selected from the group consisting of hydrogen, C1-C4alkyl, and C1-C4haloalkyl;

[0696] R 25b and R 25c are independently selected from the group consisting of C1-C4alkyl and C1-C4haloalkyl;

[0697] R 26 is selected from the group consisting of unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; and

[0698] R 21a and R 25a together with the atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclyl,

[0699] or a pharmaceutically acceptable salt or solvate thereof.

[0700] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 11a R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl;

[0701]

[0702]

[0703] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 27a R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 27b each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, (C1-C4alkoxy)C1-C4alkyl; and (hydroxy)C1-C4alkyl;

[0704] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 27c R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 13b ; C1-C4alkyl; C1-C4haloalkyl; unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having one or two substituents independently selected from the group consisting of amino, hydroxy, and C1-C4alkyl; and -S(=O)2R 24 ;

[0705] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 27d R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl;

[0706] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 13b R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl;

[0707] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 24 R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0708] R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl; 11a R is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl;

[0709]

[0710]

[0711] or a pharmaceutically acceptable salt or solvate thereof.

[0712] Embodiment 13. The method of embodiment 9, wherein R 11a is a substituted 4- to 14-membered heterocyclyl selected from the group consisting of:

[0713]

[0714] or a pharmaceutically acceptable salt or solvate thereof.

[0715] Embodiment 14. The method of any one of embodiments 4-13, wherein Z 4 is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[0716] Embodiment 15. The method of any one of embodiments 1-14, wherein R 1d is fluoro, or a pharmaceutically acceptable salt or solvate thereof.

[0717] Embodiment 16. The method of embodiment 1, wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0718] Embodiment 17. The method of embodiment 1, wherein the compound is a compound of Table IB, or a pharmaceutically acceptable salt or solvate thereof.

[0719] Embodiment 18. The method of any one of embodiments 1-17, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist.

[0720] Embodiment 19. The method of embodiment 18, wherein the glucocorticoid receptor agonist is dexamethasone.

[0721] Embodiment 20. The method of any one of embodiments 1-19, wherein the second therapeutic agent comprises an immunomodulatory drug.

[0722] Embodiment 21. The method of embodiment 20, wherein the immunomodulatory drug is pomalidomide or lenalidomide.

[0723] Embodiment 22. The method of any one of embodiments 1-21, wherein the second therapeutic agent comprises a proteasome inhibitor.

[0724] Embodiment 23. The method of embodiment 22, wherein the proteasome inhibitor is bortezomib.

[0725] Embodiment 24. The method of any one of embodiments 1-23, wherein second therapeutic agent comprises a Bcl-2 inhibitor.

[0726] Embodiment 25. The method of embodiment 24, wherein the Bcl-2 inhibitor is venetoclax.

[0727] Embodiment 26. The method of any one of embodiments 1-25, wherein the second therapeutic agent comprises a pleiotropic pathway modulator.

[0728] Embodiment 27. The method of embodiment 26, wherein the pleiotropic pathway modulator is CC-122.

[0729] Embodiment 28. The method of any one of embodiments 1-27, wherein the second therapeutic agent comprises an XPOl inhibitor.

[0730] Embodiment 29. The method of embodiment 28, wherein the XPOl inhibitor is selinexor.

[0731] Embodiment 30. The method of any one of embodiments 1-29, wherein the second therapeutic agent comprises a histone deacetylase inhibitor.

[0732] Embodiment 31. The method of embodiment 30, wherein the histone deacetylase inhibitor is panobinostat.

[0733] Embodiment 32. The method of any one of embodiments 1-31, wherein the second therapeutic agent is an EZH2 inhibitor.

[0734] Embodiment 33. The method of embodiment 32, wherein the EZH2 inhibitor is tazemetostat.

[0735] Embodiment 34. The method of any one of embodiments 1-33, wherein the compound of Formula I and the second therapeutic agent are administered separately to the subject.

[0736] Embodiment 35. The method of any one of embodiments 1-34, wherein the subject in need thereof has a cancer.

[0737] Embodiment 36. The method of embodiment 35, wherein the cancer is any one or more of the cancers of Table 2.

[0738] Embodiment 37. The method of embodiment 38, wherein the cancer is a hematological cancer.

[0739] Embodiment 38. The method of embodiment 37, wherein the hematological cancer is any one or more of the cancers of Table 3.

[0740] Embodiment 39. A kit comprising:

[0741] (a) a compound of Formula I:

[0742]

[0743] wherein:

[0744] R 1a is selected from halogen, alkyl, alkoxy, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0745] Q1is selected from -C(R 1b )= and -N=;

[0746] Q2is selected from -C(R 1c )= and -N=;

[0747] Q3is selected from -C(R 1d )= and -N=;

[0748] provided at least one of Q 1 , Q 2 , or Q 3 is -C(R 1b )=, -C(R 1c )=, or -C(R 1d )=, respectively;

[0749] R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy;

[0750] R 1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0751] is a single or double bond;

[0752] G1is selected from: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclyl; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclyl)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclyl)alkyl; (heteroaryl)(carboxamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclyl)(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

[0753] G 2 is selected from hydrogen and alkyl; or

[0754] G 1 and G 2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl,

[0755] with the proviso that the compound of Formula I is not N-(1-(1-(L-alanyl)piperidin-4-yl)ethyl)-7-methyl-1H-indole-2-carboxamide; N-((1r,4r)-4-(3-aminopropanamido)cyclohexyl)-7-methyl-1H-indole-2-carboxamide; or N-((1r,4r)-4-aminocyclohexyl)-7-methyl-1H-indole-2-carboxamide,

[0756] or a pharmaceutically acceptable salt or solvate thereof; and

[0757] (b) a second therapeutic agent,

[0758] wherein:

[0759] the second therapeutic agent comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more multi- effector pathway modulators, one or more XPO1 inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or a combination thereof.

[0760] Embodiment 40. The kit of embodiment 39, further comprising instructions for administering the compound of Formula I and the second therapeutic agent to a subject having a cancer.

[0761] Embodiment 41. A compound selected from:

[0762] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0763] 4-fluoro-7-methyl-N-((1R,3R)-3-((3aS,6aS)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0764] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aR,6aR)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0765] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5- oxohexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide;

[0766] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5- oxohexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide;

[0767] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5- oxohexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide;

[0768] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5- oxohexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide; and

[0769] 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5- oxohexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide,

[0770] or a pharmaceutically acceptable salt or solvate thereof.

[0771] Embodiment 42. A pharmaceutical composition comprising a compound of Embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0772] Embodiment 43. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Embodiment 41, or a pharmaceutically acceptable salt or solvate thereof.

[0773] Embodiment 44. The method of Embodiment 43, wherein the subject in need has a cancer.

[0774] Embodiment 45. The method of Embodiment 44, wherein the cancer is any one or more of the cancers of Table 2.

[0775] Embodiment 46. The method of Embodiment 44, wherein the cancer is a hematological cancer.

[0776] Embodiment 47. The method of Embodiment 46, wherein the hematological cancer is any one or more of the cancers of Table 3.

[0777] Embodiment 48. The pharmaceutical composition of Embodiment 43, for use in treating a subject.

[0778] Embodiment 49. The pharmaceutical composition of Embodiment 48, wherein the subject has a cancer.

[0779] Embodiment 50. The pharmaceutical composition of Embodiment 49, wherein the cancer is any one or more of the cancers of Table 2.

[0780] Embodiment 51. The pharmaceutical composition of Embodiment 49, wherein the cancer is a hematological cancer.

[0781] Embodiment 52. The method of Embodiment 51, wherein the hematological cancer is any one or more of the cancers of Table 3.

[0782] Embodiment 53. The compound of Embodiment 41, for use in treating a subject.

[0783] Embodiment 54. The compound for use of Embodiment 53, wherein the subject has a cancer.

[0784] Embodiment 55. The compound for use of Embodiment 54, wherein the cancer is any one or more of the cancers of Table 2.

[0785] Embodiment 56. The compound for use of Embodiment 54, wherein the cancer is a hematological cancer.

[0786] Embodiment 57. The method of Embodiment 56, wherein the hematological cancer is any one or more of the cancers of Table 3.

[0787] Embodiment 58. Use of a compound of Embodiment 21 in the manufacture of a medicament for treating a subject.

[0788] Embodiment 59. The use of Embodiment 58, wherein the subject has a cancer.

[0789] Embodiment 60. The use of Embodiment 59, wherein the cancer is any one or more of the cancers of Table 2.

[0790] Embodiment 61. The use of Embodiment 59, wherein the cancer is a hematological cancer.

[0791] Embodiment 62. The use of Embodiment 61, wherein the hematological cancer is any one or more of the cancers of Table 3.

[0792] Embodiment 63. A kit comprising a compound of Embodiment 41 and instructions for administering the compound to a subject.

[0793] Embodiment 64. The kit of embodiment 63, wherein the subject has cancer.

[0794] The compounds of the present disclosure can be administered to a subject in the form of a raw chemical (in the absence of any excipients). The compounds of the present disclosure can also be administered to a subject as part of a pharmaceutical composition comprising the compound in combination with a suitable pharmaceutically acceptable carrier. Such carriers can be chosen from pharmaceutically acceptable excipients and auxiliaries. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" includes any standard pharmaceutical carrier, solvent, surfactant, or vehicle. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and non-aqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th Ed. 1995.

[0795] Pharmaceutical compositions within the scope of the present disclosure include all compositions wherein 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 which is effective for achieving its intended therapeutic purpose. The effective amount of each compound can vary according to, among other factors, the therapeutic index of the compound and the purpose of the treatment. Determining an optimal range of effective amounts is within the skill in the art. Typically, the compounds of the present disclosure can be orally administered to a mammal, for example, a human, in a dose range from about 0.0025 to about 1500 mg / kg of mammal body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day for the treatment of a particular disease. A useful oral dose of a compound of the present disclosure administered to a mammal is from about 0.0025 to about 50 mg / kg of mammal body weight, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about half of the oral dose.

[0796] A unit oral dose can contain from about 0.01 mg to about 1 g of a compound of the present disclosure, for example, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, for example, from about 0.1 mg to about 10 mg of the compound. The unit dose can be administered one or more times per day, for example, as one or more tablets or capsules each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0797] The compounds of the disclosure or pharmaceutical compositions comprising the compounds of the disclosure and optional second therapeutic agents can be administered to any subject who can experience the beneficial effects of the compounds of the disclosure, such as a cancer patient in need thereof. Of greatest importance are mammalian subjects, such as humans and companion animals, although the disclosure is not so limited. In one embodiment, the subject is a human.

[0798] The pharmaceutical compositions of the disclosure can be administered by any means that achieve their intended purpose. For example, they can be administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, intranasally, transmucosally, rectally, intravaginally, or buccally, or by inhalation. The dosage administered and the route and frequency of administration will vary depending upon the particular condition being treated, the severity of the condition being treated, the age, sex, weight, and health of the subject being treated, the kind of concurrent treatment being administered, the frequency and nature of the concurrent treatment being administered, and the nature of the effect desired.

[0799] In one embodiment, the pharmaceutical compositions of the disclosure can be administered orally. In another embodiment, the pharmaceutical compositions of the disclosure can be administered orally and formulated as tablets, dragees, capsules, or oral liquid preparations. In one embodiment, the oral formulation comprises an extruded multiparticulate containing a compound of the disclosure.

[0800] Alternatively, the pharmaceutical compositions of the disclosure can be administered rectally and formulated as suppositories.

[0801] Alternatively, the pharmaceutical compositions of the disclosure can be administered by injection.

[0802] Alternatively, the pharmaceutical compositions of the disclosure can be administered transdermally.

[0803] Alternatively, the pharmaceutical compositions of the disclosure can be administered by inhalation or by intranasal or transmucosal administration.

[0804] Alternatively, the pharmaceutical compositions of the disclosure can be administered by intravaginal routes.

[0805] The pharmaceutical compositions of the disclosure can contain from about 0.01 to 99% by weight, for example, from about 0.25 to 75% by weight, of a compound of the disclosure, for example, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a compound of the disclosure.

[0806] In view of the present disclosure, the pharmaceutical compositions of the present disclosure are manufactured in a manner that is itself known, e.g., by means of conventional mixing, granulating, sugar coating, dissolving, or lyophilizing processes. Thus, pharmaceutical compositions of the present disclosure suitable for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or sugar-coated tablets.

[0807] Suitable excipients include fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose derivatives, calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, gelatine, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches, and also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0808] Auxiliary agents are generally flow conditioners and lubricants, for example silicon dioxide, talc, stearic acid or its salts, for example magnesium or calcium stearate, and polyethylene glycol. The tablet cores are provided with a suitable enteric coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions, and various organic solvents or solvent mixtures. In order to produce enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, can be used. Dyes or colorings can be added to the tablet or dragee coatings, for example, for identification or to characterize the combination of active compound doses.

[0809] Examples of other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatine, as well as soft, sealed capsules made of gelatine and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules, which can be mixed with fillers (such as lactose, binders (such as starches), and / or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added.

[0810] Pharmaceutical formulations that can be used for rectal administration include, for example, suppositories, which are formed from one or more active compounds in combination with a suppository base. Suitable suppository bases include natural and synthetic triglycerides, as well as paraffin. Gelatin rectal capsules, consisting of an outer gelatin shell and an inner fluid formulation, can also be used.

[0811] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Alternatively, suspensions of the active compounds can be prepared as oil suspensions. Suitable lipophilic solvents or vehicles such as suspensions include fatty oils (such as sesame oil), synthetic fatty acid esters (such as ethyl oleate), triglycerides, or

[0812] In some embodiments, the compounds of the present application and the second therapeutic agent are administered to the subject as part of a single pharmaceutical composition.

[0813] In some embodiments, the compounds of the present application and the second therapeutic agent are administered to the subject separately in combination, e.g., as two or more separate pharmaceutical compositions. For example, the second therapeutic agent can include one of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. In this case, two separate pharmaceutical compositions are administered to the subject— one comprising the compound of the present application, and one comprising the second therapeutic agent. The second therapeutic agent can include a combination of two of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. In this case, three separate pharmaceutical compositions are administered to the subject— one comprising the compound of the present application, one comprising a first second therapeutic agent, and one comprising a second second therapeutic agent. Likewise, if the second therapeutic agent includes a combination of three or more of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a multi- effector pathway modulator, an XPOl inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. The separate pharmaceutical compositions can be administered at the same time, at different times during the course of treatment regimen, and / or at different durations, or by different routes of administration.

[0814] In some embodiments, the compound of the present application is administered to the patient prior to the administration of the second therapeutic agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the second therapeutic agent.

[0815] In some embodiments, the compound of the present application is administered after the second therapeutic agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the second therapeutic agent.

[0816] In some embodiments, the compound of the present disclosure and the second therapeutic agent are administered simultaneously.

[0817] In some embodiments, the compound of the present application and the second therapeutic agent are administered simultaneously, but on different schedules, e.g., the compound of the present application is administered daily, while the second therapeutic agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0818] In practice, a physician will determine the dosage regimen that is most appropriate for an individual patient, which can vary with the age, weight, and response of the particular patient.

[0819] 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 its use to practice the methods of the present disclosure. In one embodiment, a kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container such as a hermetically sealed bottle or a hermetically sealed tube, the kit having a label attached to the container or included in the kit that describes use of the compound or composition to practice the methods of the present disclosure. In one embodiment, the compound or composition is packaged in unit dosage form. The kit can also include a device suitable for administering the composition according to the intended route of administration. The kit can also include a second therapeutic agent. In some embodiments, the kit comprises a compound of the present disclosure and a second therapeutic agent as separate pharmaceutical compositions.

[0820] IV. Biomarkers

[0821] In another embodiment, the disclosure provides methods of treating a subject having a cancer, such as multiple myeloma, comprising (a) determining the presence or absence of a biomarker in a biological sample taken from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the disclosure and optionally a second therapeutic agent 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).

[0822] Biomarkers include, but are not limited to, cancer (e.g., multiple myeloma), chromosomal translocations in cells, and WHSC1 / NSD2 / MMSET expression. In one embodiment, the measurable aspect of a biomarker is its expression status. In one embodiment, the measurable aspect of a biomarker is its mutation status.

[0823] In one embodiment, the biomarker is WHSC1 / NSD2 / MMSET expression, which is differentially present in a subject of one phenotypic state (e.g., a normal, non-diseased subject or a cancer patient without overexpression of WHSC1 / NSD2 / MMSET) compared to a subject of another phenotypic state (e.g., a subject with a hematological cancer). In one embodiment, the biomarker is overexpression of WHSC1 / NSD2 / MMSET.

[0824] Biomarker criteria can be predetermined, determined contemporaneously, or determined after a biological sample is obtained from a subject. Biomarker criteria used with the methods described herein can, for example, include data from samples of subjects without cancer; data from samples of subjects with non-metastatic cancer (breast cancer); and data from samples of subjects with metastatic cancer (e.g., breast cancer). Comparisons can be made to establish predetermined threshold biomarker criteria for different classes of subjects (e.g., diseased versus non-diseased subjects). The criteria can be run in the same assay, or can be known criteria from a previous assay.

[0825] A biomarker is differentially present between different phenotypic state groups if the average or median expression or mutation level of the biomarker is calculated to be different, i.e., higher or lower, between the groups. Thus, the biomarker provides an indication that a subject (e.g., a cancer patient) belongs to one phenotypic state or another.

[0826] Any of a number of methods known in the art can be used to determine the expression level or mutation status of a biomarker in a patient. Any method known in the art for quantifying a particular protein and / or detecting WHSC1 / NSD2 / MMSET expression and / or chromosomal translocation, or any other biomarker expression or mutation level in a patient or biological sample can be used in the methods of the 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 disclosure include methods in which biomarker RNA expression (transcription) is determined. Other embodiments of the disclosure include methods in which protein expression in a biological sample is determined. See, e.g., Harlow 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 ed., (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 well known in the art.

[0827] In one embodiment of the disclosure, a biological sample is obtained from a patient and the biological sample is assayed to determine biomarker expression or mutation status.

[0828] In one embodiment, the disclosure provides a method of treating a subject having cancer, e.g., multiple myeloma, comprising: (a) determining whether a chromosomal translocation is present in a biological sample taken from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the disclosure and optionally a second therapeutic agent if a chromosomal translocation is present in the biological sample.

[0829] In another embodiment, the present disclosure provides a method of treating a subject having cancer, e.g., multiple myeloma, comprising administering to a subject having a chromosomal translocation a therapeutically effective amount of a compound of the present disclosure and an optional second therapeutic agent.

[0830] In another embodiment, the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure and an optional second therapeutic agent, wherein: (a) the subject has multiple myeloma; and (b) the multiple myeloma is characterized as having a chromosomal translocation.

[0831] In any of the above embodiments, the chromosomal translocation is a t(4; 14) translocation.

[0832] In one embodiment, the present disclosure provides a method of treating a subject having multiple myeloma, comprising: (a) determining whether overexpression of WHSC1 / NSD2 / MMSET is present in a biological sample taken from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure and an optional second therapeutic agent if overexpression of WHSC1 / NSD2 / MMSET is present in the biological sample.

[0833] In one embodiment, the present disclosure provides a method of treating a subject having multiple myeloma, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure and an optional second therapeutic agent if overexpression of WHSC1 / NSD2 / MMSET is present in the subject.

[0834] In another embodiment, the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure and an optional second therapeutic agent, wherein: (a) the subject has multiple myeloma; and (b) the multiple myeloma is characterized as having overexpression of WHSC1 / NSD2 / MMSET.

[0835] V. DEFINITIONS

[0836] The term "halogen," by itself or as part of another group, as used herein, refers to -Cl, -F, -Br, or -I.

[0837] The term "nitro," by itself or as part of another group, as used herein, refers to -NO2.

[0838] The term "cyano," by itself or as part of another group, as used herein, refers to -CN.

[0839] The term "hydroxyl," by itself or as part of another group, as used herein, refers to -OH.

[0840] The term "alkyl," by itself or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., C1-C12alkyl. 12 alkyl, or the specified number of carbon atoms, e.g., C1alkyl such as methyl, C2alkyl such as ethyl, and the like. In one embodiment, the alkyl is C1-C6alkyl. In another embodiment, the alkyl is C1-C4alkyl. In another embodiment, the alkyl is C1-C3alkyl, i.e., methyl, ethyl, propyl, or isopropyl. In another embodiment, the alkyl is C1-C2alkyl, i.e., methyl or ethyl. In another embodiment, the alkyl is C1alkyl, i.e., methyl. 10 alkyl. In another embodiment, the alkyl is C1-C6alkyl. In another embodiment, the alkyl is C1-C4alkyl. In another embodiment, the alkyl is C1-C3alkyl, i.e., methyl, ethyl, propyl, or isopropyl. In another embodiment, the alkyl is C1-C2alkyl, i.e., methyl or ethyl. In another embodiment, the alkyl is C1alkyl, i.e., methyl. 12 Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0841] The term "optionally substituted alkyl," by itself or as part of another group, refers to an alkyl group that is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamato, 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(=N-R 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=N-R 60 )R 61 , or -C(=C-NO2)R 64 ;

[0842] wherein:

[0843] R 56a is hydrogen or alkyl;

[0844] 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 heterocyclyl, optionally substituted C6-C10 aryl, or optionally substituted heteroaryl;

[0845] R 56c is hydrogen or alkyl;

[0846] R 56d is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl;

[0847] 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 heterocyclyl, optionally substituted C6-C 10 aryl, or optionally substituted heteroaryl;

[0848] 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 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, (C3-C6cycloalkyl)oxy, or (4- to 8-membered heterocyclyl)oxy;

[0849] R 58 is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

[0850] R 60 is selected from the group consisting of cyano, nitro, hydroxy, C1-C6alkoxy, -C(=O)R 62 , and -S(=O)2R 62 ;

[0851] R 61 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, and -NR 63a R 63b ;

[0852] R 62 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, and -NR63a R 63b ;

[0853] R 63a is selected from hydrogen, Ci-C6alkyl, and C3-C6cycloalkyl;

[0854] R 63b is selected from hydrogen, Ci-C6alkyl, and C3-C6cycloalkyl; or

[0855] R 63a and R 63b together with the nitrogen atom to which they are attached form a 4- to 6- membered optionally substituted heterocyclyl;

[0856] R 64 is selected from Ci-C6alkyl, C3-C6cycloalkyl, and -NR 63c R 63d ; and

[0857] R 63c is selected from hydrogen, Ci-C6alkyl, and C3-C6cycloalkyl;

[0858] R 63d is selected from hydrogen, Ci-C6alkyl, and C3-C6cycloalkyl; or

[0859] R 63c and R 63d together with the nitrogen atom to which they are attached form a 4- to 6- membered optionally substituted heterocyclyl.

[0860] In one embodiment, the optionally substituted alkyl is unsubstituted or substituted with 1, 2, or 3 substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl, carboxyalkyl, -N(R 56a )C(=0)R 56b , -N(R 56c )S(=0)2R 56d , -C(=0)R 57 , -S(=0)R 56e , or -S(=0)2R 58 .

[0861] 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-C6alkyl. In another embodiment, the optionally substituted alkyl is an optionally substituted C1-C4alkyl. In one embodiment, the optionally substituted alkyl is an optionally substituted C1or C2alkyl. Non-limiting exemplary optionally substituted alkyl groups include -CH(CO2Me)CH2CO2Me and -CH(CH3)CH2N(H)C(=O)O(CH3)3.

[0862] The term "alkenyl," by itself or as part of another substituent, as used herein, refers to an alkyl radical containing 1, 2, or 3 carbon-carbon double bonds. In one embodiment, the alkenyl radical is a C2-C6alkenyl radical. In another embodiment, the alkenyl radical is a C2-C4alkenyl radical. In another embodiment, the alkenyl radical has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0863] The term "optionally substituted alkenyl," by itself or as part of another substituent, as used herein, refers to an alkenyl that is unsubstituted or substituted with 1, 2, or 3 substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxyl, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, formamidyl, sulfonamidyl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. Non-limiting exemplary optionally substituted alkenyl groups include -CH=CHPh.

[0864] The term "alkynyl," by itself or as part of another substituent, as used herein, refers to an alkyl radical containing 1, 2, or 3 carbon-carbon triple bonds. In one embodiment, the alkynyl radical has one carbon-carbon triple bond. In another embodiment, the alkynyl radical is a C1-C6alkynyl. In another embodiment, the alkynyl radical is a C2-C4alkynyl. In another embodiment, the alkynyl radical has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl radicals.

[0865] The term "optionally substituted alkynyl," by itself or as part of another group, as used herein refers to an alkynyl group that is unsubstituted or substituted with 1, 2, or 3 substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxyl, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidine, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. Non-limiting exemplary optionally substituted alkynyl groups include -CH=CH-Ph.

[0866] The term "haloalkyl," by itself or as part of another group, as used herein refers to an alkyl group that is substituted with 1 or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl is substituted with 1, 2, or 3 fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted with 1, 2, or 3 fluorine atoms. In another embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4alkyl. In another embodiment, the alkyl group is a C1or C2alkyl. 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.

[0867] The term "hydroxyalkyl" or "(hydroxy)alkyl," by itself or as part of another group, as used herein refers to an alkyl group that is substituted with 1, 2, or 3 hydroxyl groups. In one embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4alkyl. In another embodiment, the alkyl is a C1or C2alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxyl group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxyl groups. Non-limiting exemplary (hydroxy)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-dihydroxypropan-2-yl.

[0868] The term "alkoxy," by itself or as part of another group, as used herein, refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a C1-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0869] The term "haloalkoxy," by itself or as part of another group, as used herein, refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6alkyl group. In another embodiment, the haloalkyl group is a C1-C4haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0870] The term "alkylthio," by itself or as part of another group, as used herein, refers to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is a C1-C4alkyl group. Non-limiting exemplary alkylthio groups include -SCH3and -SCH2CH3.

[0871] The term "alkoxyalkyl" or "(alkoxy)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one alkoxy group. In one embodiment, the alkoxy group is a C1-C6alkoxy group. In another embodiment, the alkoxy group is a C1-C4alkoxy group. In another embodiment, the alkyl group is a C1-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. 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 pentoxy-methyl.

[0872] The term "heteroalkyl," by itself or as part of another group, as used herein, refers to a stable straight or branched chain hydrocarbon group comprising 1 to 10 carbon atoms and at least two heteroatoms selected from O, N, or S, wherein the sulfur atom is optionally oxidized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at the position where the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, the heteroalkyl comprises two oxygen atoms. In another embodiment, the heteroalkyl comprises one oxygen atom and one nitrogen atom. In another embodiment, the heteroalkyl comprises two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -OCH2CH2NH2, -NHCH2CH2OCH3, and -OCH2CH2OCH3.

[0873] As used herein, the term "cycloalkyl" either on its own or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing 3 to 12 carbon atoms, i.e., C64-C ... 3-12 Cycloalkyl, or a specified number of carbon atoms, such as C3 cycloalkyl like cyclopropyl, C4 cycloalkyl like cyclobutyl, etc. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In yet another embodiment, the cycloalkyl is C3 cycloalkyl. 3-8 Cycloalkyl. In another embodiment, the cycloalkyl group is C10. 3-6 The cycloalkyl group is, in other words, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl group is a C5 cycloalkyl group, i.e., cyclopentyl. In another embodiment, the cycloalkyl group is a C6 cycloalkyl group, i.e., cyclohexyl. Non-limiting exemplary C 3-12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclohexenyl and spiroheptane[3.3].

[0874] The term "optionally substituted cycloalkyl" as used herein, either on its own or as part of another group, refers to a cycloalkyl group that is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently a halogen, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclic)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, arylalkyloxy, alkylthio, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carboxyl, carboxylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, ynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (formamido)alkyl, mercaptoalkyl, (heterocyclic)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 ; wherein R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 60 , R 61 , and R 64 are as defined for 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-l-yl)cyclohexyl, 3-(3-(N- methylacetamido)pyrrolidin-l-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, wherein each substituent is independently halogen, nitro, cyano, hydroxyl, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclyl)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 heterocyclyl, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)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 .

[0875] The term "heterocyclyl," as used herein by itself or as part of another group, refers to a saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic ring group containing 3-14 ring members, i.e., a 3-14 membered heterocyclic ring containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to a sulfoxide, i.e., S(=O), or a sulfone, i.e., S(=O)2.

[0876] The term heterocyclo includes groups in which one or more -CH2- groups are replaced by one or more -C(=0)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amido groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamato groups such as oxazolidinyl-2-one.

[0877] The term heterocyclo also includes groups having a fused optionally substituted aryl or optionally substituted heteroaryl group, for example indolin, indolin-2-one, 2,3-dihydro-lH-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-lH-benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0878] In one embodiment, the heterocyclo group is a 4-8 membered cyclic group containing one ring and one or two oxygen atoms, for example tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, for example pyrrolidine, piperidine or piperazine, or one oxygen and one nitrogen atom, for example morpholine, and optionally one -CH2- group is replaced by one -C(=0)- group, for example pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally one -CH2- group is replaced by one -C(=0)- group. In another embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally one -CH2- group is replaced by one -C(=0)- group. In another embodiment, the heterocyclo group is an 8-12 membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be attached to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include:

[0879]

[0880]

[0881] The term "optionally substituted heterocycle" as used herein by itself or as part of another group means a heterocyclic group that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxyl, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclyl)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 heterocyclyl, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)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(=N-R 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=N-R 60 )R 61 , or -C(=C-NO2)R 64 ; wherein R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 59 , R 60 , R 61 , and R 64As defined by the term "optionally substituted cycloalkyl." Substitution can occur at any available carbon or nitrogen atom of the heterocyclic group. In one embodiment, the optionally substituted heterocycle is unsubstituted or substituted with one to four substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxyl, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclyl)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidine, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 .

[0882] Non-limiting exemplary optionally substituted heterocyclic groups include:

[0883]

[0884]

[0885] The term "aryl," used alone or as part of another group, refers to an aromatic ring system having 6 to 14 carbon atoms, i.e., C6-C 14 aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0886] The term "optionally substituted aryl" as used herein by itself or as part of another group means aryl that is unsubstituted or substituted with one to five substituents, wherein each of said substituents is independently halogen, nitro, cyano, hydroxyl, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclyl)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 heterocyclyl, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)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(=N-R 60 )R 61 , -N(R 56a )C(=C-NO2)R 64 , -C(=N-R 60 )R 61 , or -C(=C-NO2)R 64 ; wherein R 56a , R 56b , R 56c , R 56d , R 56e , R 57 , R 58 , R 59 , R 60 , R 61 , and R 64as defined by the term "optionally substituted cycloalkyl." In one embodiment, the optionally substituted aryl is unsubstituted or substituted with one to five substituents, wherein each substituent is independently halogen, nitro, cyano, hydroxyl, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclyl)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 heterocyclyl, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 .

[0887] In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl group. In another embodiment, the optionally substituted phenyl group has four substituents. In another embodiment, the optionally substituted phenyl group has three substituents. In another embodiment, the optionally substituted phenyl group has two substituents. In another embodiment, the optionally substituted phenyl group 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-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl, 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylprop-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclic groups. Non-limiting examples include: 2,3-dihydro-lH-inden-l-yl, 1,2,3,4-tetrahydronaphthalen-l-yl, 1,3,4,5-tetrahydro-2H- benzo[c]azepin-2-yl, 1,2,3,4-tetrahydroisoquinolin-l-yl, and 2-oxo-2,3,4,5-tetrahydro-lH- benzo[d]azepin-l-yl.

[0888] The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members, i.e., 5- to 14-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, the heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. In another embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group has 5 ring atoms, for example, thienyl, a 5-membered heteroaryl group having 4 carbon atoms and 1 sulfur atom. In another embodiment, the heteroaryl group has 6 ring atoms, for example, pyridyl, a 6-membered heteroaryl group having 5 carbon atoms and 1 nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazinonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, beta-carbolinyl, phenanthrollinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl group is selected from thienyl (e.g., thien-2-yl and thien-3-yl), furanyl (e.g., 2-furanyl and 3-furanyl), 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., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidinyl (e.g., 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.

[0889] The term "optionally substituted heteroaryl" as used herein, either on its own or as part of another group, refers to a heteroaryl group that is unsubstituted or substituted with one to four substituents, wherein the substituents are independently halogen, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclic)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, arylalkyloxy, alkylthio, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carboxyl, carboxylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, ynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (formamido)alkyl, mercaptoalkyl, (heterocyclic)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 64As defined by the term "optionally substituted cycloalkyl." In one embodiment, the optionally substituted heteroaryl group is unsubstituted or substituted with one to four substituents, wherein the substituents are independently halogen, nitro, cyano, hydroxyl, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclyl)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 heterocyclyl, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, thioalkyl, (heterocyclyl)alkyl, (heteroaryl)alkyl, -N(R 56a )C(=O)R 56b , -N(R 56c )S(=O)2R 56d , -C(=O)R 57 , -S(=O)R 56e , -S(=O)2R 58 , or -OR 59 .

[0890] In one embodiment, the optionally substituted heteroaryl group has two substituents. In another embodiment, the optionally substituted heteroaryl group has one substituent. Any available carbon or nitrogen atom can be substituted.

[0891] The term "aryloxy," by itself or as part of another group, as used herein, refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0892] The term "heteroaryloxy," by itself or as part of another group, as used herein, refers to an optionally substituted heteroaryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is pyridyl-O-.

[0893] The term "aralkyloxy," by itself or as part of another group, as used herein, refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.

[0894] The term "(cycloalkyl)oxy," by itself or as part of another group, as used herein, refers to a cycloalkyl group attached to a terminal oxygen atom. A non-limiting exemplary cycloalkyloxy group is:

[0895]

[0896] The term "(heterocyclyl)oxy" used herein by itself or as part of another group refers to a heterocyclyl group attached to an terminal oxygen atom. Non-limiting exemplary (heterocyclyl)oxy groups are:

[0897]

[0898] The term "(cyano)alkyl" used herein by itself or as part of another group refers to an alkyl group substituted with one, two, or three cyano groups. In one embodiment, the alkyl group is substituted with one cyano group. In another embodiment, the alkyl group is a C1-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0899] The term "(cycloalkyl)alkyl" used herein by itself or as part of another group refers to an alkyl group substituted with one optionally substituted cycloalkyl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6cycloalkyl group. In another embodiment, the alkyl group is a C1-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (cycloalkyl)alkyl groups include:

[0900]

[0901] The term "sulfonamido" used herein by itself or as part of another group refers to a group of the formula -SO2NR50aR50b, where R50aand R50bare each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R50aand R50btogether with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclic ring. 50a R 50b 50a and R 50b are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R50aand R50btogether with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclic ring. Non-limiting exemplary sulfonamido groups include -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.

[0902] The term "alkylcarbonyl" used herein by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, which is substituted with an alkyl group. In one embodiment, the alkyl group is a C1-C4alkyl group. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0903] The term "arylcarbonyl" used herein by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, which is substituted with an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is -COPh. ​

[0904] The term "alkylsulfonyl," by itself or as part of another group, as used herein, refers to a sulfonyl group, i.e., -SO2-, which is substituted with an alkyl group. A non-limiting exemplary alkylsulfonyl is -SO2CH3.

[0905] The term "arylsulfonyl," by itself or as part of another group, as used herein, refers to a sulfonyl group, i.e., -SO2-, which is substituted with an optionally substituted aryl group. A non-limiting exemplary arylsulfonyl is -SO2Ph.

[0906] The term "mercaptoalkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with -SH.

[0907] The term "carboxyl," by itself or as part of another group, as used herein, refers to a group of formula -C(=O)OH.

[0908] The term "ureido," by itself or as part of another group, as used herein, refers to a group of formula -NR 51a -C(=O)-NR 51b R 51c , wherein R 51a is hydrogen or alkyl; and R 51b and R 51c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R 51b and R 51c , together with the nitrogen to which they are attached, form a 4- to 8- membered optionally substituted heterocyclic ring. Non-limiting exemplary ureido groups include -NH-C(=O)-NH2and -NH-C(=O)-NHCH3.

[0909] The term "guanidino," by itself or as part of another group, as used herein, refers to a group of formula -NR 52a -C(=NR 53 )-NR 52b R 52c , wherein R 52a is hydrogen or alkyl; R 52b and R 53c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 52b and R 52c , together with the nitrogen to which they are attached, form a 4- to 8- membered optionally substituted heterocyclic ring; and R 53hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include -NH-C(C=NH)-NH2, -NH-C(C=NCN)-NH2, and -NH-C(C=NH)-NHCH3.

[0910] The term "(heteroaryl)alkyl," by itself or as part of another substituent, as used herein, refers to an alkyl group substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 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-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0911]

[0912] The term "carbamate," by itself or as part of another substituent, as used herein, 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 heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting exemplary carbamate group is -NH-(C=O)-OtBu.

[0913] The term "(heteroaryl)alkyl," by itself or as part of another substituent, as used herein, refers to an alkyl group substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 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-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0914]

[0915] The term "(heteroaryl)(aryl)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one optionally substituted heteroaryl 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-C6alkyl group. In another embodiment, the alkyl is a C1-C4alkyl group. In another embodiment, the alkyl is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)(aryl)alkyl groups include:

[0916]

[0917] The term "(heteroaryl)(heterocyclyl)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one optionally substituted heteroaryl and one optionally substituted heterocyclyl 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 heterocyclyl is an optionally substituted 5- to 8-membered heterocyclyl. In another embodiment, the heterocyclyl is an optionally substituted 5- or 6-membered heterocyclyl. In one embodiment, the alkyl is a C1-C6alkyl group. In another embodiment, the alkyl is a C1-C4alkyl group. In another embodiment, the alkyl is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)(heterocyclyl)alkyl groups are:

[0918]

[0919] The term "(heteroaryl)(formylamido)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one optionally substituted heteroaryl group and one formylamido 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-C6alkyl group. In another embodiment, the alkyl is a C1-C4alkyl group. In another embodiment, the alkyl is a C1-C3alkyl group. Non-limiting exemplary (heteroaryl)(formylamido)alkyl groups include:

[0920]

[0921] The term "formylamido," by itself or as part of another group, as used herein, refers to a group of formula -C(=O)NR 55a R55b -NR 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 heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, or (heteroaryl)alkyl; or R 55a and R 55b together with the nitrogen to which they are attached form a 4- to 8- membered optionally substituted heterocyclyl group. Non-limiting exemplary carboxamide groups include: morpholin-4-ylcarbonyl, N,N-dimethylaminocarbonyl, N-(l-methylpiperidin-4-yl)aminocarbonyl, 4-methylpiperazin-l-ylcarbonyl, N-(3-aminocyclopentyl)aminocarbonyl, N-(pyridin-3-yl)aminocarbonyl, and N-(tetrahydrofuran-3-yl)aminocarbonyl.

[0922] The term "(heteroaryl)(cycloalkyl)alkyl," by itself or as part of another group, as used herein 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 group. In one embodiment, the alkyl is a C1-C6 alkyl group. In another embodiment, the alkyl is a C1-C4 alkyl group. In another embodiment, the alkyl is a C1-C3 alkyl group. Non-limiting exemplary (heteroaryl)(C3-C6 cycloalkyl)alkyl groups are:

[0923]

[0924] The term "(heteroaryl)(cycloalkyl)alkyl," by itself or as part of another group, as used herein 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 group. In one embodiment, the alkyl is a C1-C6 alkyl group. In another embodiment, the alkyl is a C1-C4 alkyl group. In another embodiment, the alkyl is a C1-C3 alkyl group. Non-limiting exemplary (heteroaryl)(C3-C6 cycloalkyl)alkyl groups are:

[0925]

[0926] ​The term "alkoxycarbonyl," by itself or as part of another group, as used herein, refers to a carbonyl group, i.e., -C(=O)-, which is substituted with a C1-C6alkoxy group. In one embodiment, the alkoxy group is a C1-C4alkoxy group. In another embodiment, the alkoxy group is a C1-C3alkoxy group. Non-limiting exemplary alkoxycarbonyl groups include -CO2-Me and -CO2Et.

[0927] The term "(heteroaryl)(amino)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group that is 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-C6alkyl group. In another embodiment, the alkyl is a C1-C4alkyl group. In another embodiment, the alkyl is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)(amino)alkyl groups are:

[0928]

[0929] The term "(heteroaryl)(amino)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group that is 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-C6alkyl group. In another embodiment, the alkyl is a C1-C4alkyl group. In another embodiment, the alkyl is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)(amino)alkyl groups are:

[0930]

[0931] The term "(heteroaryl)(amino)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group that is 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-C6alkyl group. In another embodiment, the alkyl is a C1-C4alkyl group. In another embodiment, the alkyl is a C1or C2alkyl group. Non-limiting exemplary (heteroaryl)(amino)alkyl groups are:

[0932]

[0933] The term "(heterocyclyl)(cycloalkyl)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one optionally substituted heterocyclic group and one optionally substituted cycloalkyl group. In one embodiment, the heterocycle is an optionally substituted 5- to 8-membered heterocycle. In another embodiment, the heterocycle is an optionally substituted 5- or 6-membered heterocycle. 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 (heterocyclyl)(cycloalkyl)alkyl groups are:

[0934]

[0935] The term "(heterocyclyl)(cycloalkyl)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one optionally substituted heterocyclic group and one optionally substituted cycloalkyl group. In one embodiment, the heterocycle is an optionally substituted 5- to 8-membered heterocycle. In another embodiment, the heterocycle is an optionally substituted 5- or 6-membered heterocycle. 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 (heterocyclyl)(cycloalkyl)alkyl groups are:

[0936]

[0937] The term "arylalkyl," or "(aryl)alkyl," by itself or as part of another group, as used herein, refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or an optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0938] The term "(aryl)(hydroxy)alkyl," by itself or in combination with another term, as used herein, means an alkyl group substituted with one aryl group and one hydroxy group. In one embodiment, the aryl group is an optionally substituted phenyl group or an optionally substituted naphthyl group. In another embodiment, the aryl group is an optionally substituted phenyl group. In one embodiment, the alkyl group is a C1-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (aryl)(hydroxy)alkyl groups include:

[0939]

[0940] The term "(cycloalkyl)(hydroxy)alkyl," by itself or in combination with another term, as used herein, means an alkyl group substituted with one cycloalkyl group and one hydroxy group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6cycloalkyl group. In one embodiment, the alkyl group is a C1-C6alkyl group. In another embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (cycloalkyl)(hydroxy)alkyl groups are:

[0941]

[0942] The term "(alkoxycarbonyl)alkyl," by itself or in combination with another term, as used herein, means an alkyl group substituted with one or two alkoxycarbonyl groups. In one embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (alkoxycarbonyl)alkyl groups are:

[0943]

[0944] The term "(aryl)(haloalkyl)alkyl," by itself or in combination with another term, as used herein, means an alkyl group substituted with one aryl group and one haloalkyl group. In one embodiment, the aryl group is an optionally substituted phenyl group or an optionally substituted naphthyl group. In another embodiment, the aryl group is an optionally substituted phenyl group. In one embodiment, the haloalkyl group is a C1-C4haloalkyl group. In one embodiment, the alkyl group is a C1-C4alkyl group. In another embodiment, the alkyl group is a C1or C2alkyl group. Non-limiting exemplary (aryl)(haloalkyl)alkyl groups are:

[0945]

[0946] The term "(cycloalkyl)(haloalkyl)alkyl," by itself or as part of another group, as used herein refers to an alkyl group substituted with one optionally substituted cycloalkyl group and one haloalkyl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In one embodiment, the haloalkyl group is a C1-C4 haloalkyl group. In one embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (cycloalkyl)(haloalkyl)alkyl groups are:

[0947]

[0948] The term "(hydroxy)(haloalkyl)alkyl," by itself or as part of another group, as used herein refers to an alkyl group substituted with one hydroxy group and one haloalkyl group. In one embodiment, the haloalkyl group is a C1-C4 haloalkyl group. In one embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (hydroxy)(haloalkyl)alkyl groups are:

[0949]

[0950] The term "(alkoxycarbonyl)(haloalkyl)alkyl," by itself or as part of another group, as used herein refers to an alkyl group substituted with one alkoxycarbonyl group and one haloalkyl group. In one embodiment, the haloalkyl group is a C1-C4 haloalkyl group. In one embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (alkoxycarbonyl)(haloalkyl)alkyl groups are:

[0951]

[0952] The term "(carboxamide)alkyl," by itself or as part of another group, as used herein refers to an alkyl group substituted with a carboxamide group. In one embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (carboxamide)alkyl groups include -CH2C(=O)NH2, -C(H)(CH3)C(=O)NH2, -CH2C(=O)N(H)CH3, and -CH2C(=O)N(CH3)2.

[0953] As used herein, the term "(carboxy)alkyl," by itself or as part of another group, refers to an alkyl group substituted with -C(=O)OH. In one embodiment, the alkyl group is C1-C4 alkyl. In another embodiment, the alkyl group is C1or C2alkyl. A non-limiting exemplary (carboxy)alkyl group is -CH2CO2H.

[0954] As used herein, the term "(amino)(hydroxy)alkyl," by itself or as part of another group, refers to an alkyl group substituted with one hydroxyl group and one amino group. In one embodiment, the alkyl group is C1-C4 alkyl. A non-limiting exemplary "(amino)(hydroxy)alkyl" group is:

[0955]

[0956] As used herein, the term "(amino)(aryl)alkyl," by itself or as part of another group, refers to an alkyl group substituted with one amino 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 group is C1-C6 alkyl. In another embodiment, the alkyl group is C1-C4 alkyl. Non-limiting exemplary (amino)(aryl)alkyl groups include:

[0957]

[0958] As used herein, the term "amino," by itself or as part of another group, refers to a group of the formula: 55a R 55b wherein R 55a and R 55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, or (heteroaryl)alkyl.

[0959] In one embodiment, the amino group is -NH2.

[0960] In another embodiment, the amino group is "alkylamino," i.e., an amino group in which R 55a is C 1-6 alkyl and R 55b is hydrogen. In one embodiment, R 55a is C1-C4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3and -N(H)CH2CH3.

[0961] In another embodiment, the amino group is a "dialkylamino" group, i.e., an amino group wherein R 55a and R 55b are each independently C 1-6 alkyl. In one embodiment, R 55a and R 55b are each independently C1-C4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2and -N(CH3)CH2CH(CH3)2.

[0962] In another embodiment, the amino group is a "hydroxyalkylamino" group, i.e., an amino group wherein R 55a is a (hydroxy)alkyl group and R 55b is hydrogen or C1-C4 alkyl.

[0963] In another embodiment, the amino group is a "cycloalkylamino" group, i.e., an amino group wherein R 55a is an optionally substituted cycloalkyl group and R 55b is hydrogen or C1-C4 alkyl.

[0964] In another embodiment, the amino group is an "aralkylamino" group, i.e., an amino group wherein R 55a is an aralkyl group and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0965] In another embodiment, the amino group is a "(cycloalkyl)alkylamino" group, i.e., an amino group wherein R 55a is a (cycloalkyl)alkyl group and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary (cycloalkyl)alkylamino groups include:

[0966]

[0967] In another embodiment, the amino group is a "(heterocyclyl)alkylamino" group, i.e., an amino group wherein R 55a is a (heterocyclyl)alkyl group and R 55b is hydrogen or C1-C4 alkyl. Non-limiting exemplary (heterocyclyl)alkylamino groups include:

[0968]

[0969] The term "(amino)alkyl" as used herein by itself or as part of another group, refers to an alkyl group substituted with one amino group. In one embodiment, the amino group is -NH2. In one embodiment, the amino group is alkylamino. In another embodiment, the amino group is dialkylamino. In another embodiment, the alkyl group is C1-C6alkyl. In another embodiment, the alkyl group is C1-C4alkyl. Non-limiting exemplary (amino)alkyl groups include -CH2NH2, CH2CH2N(H)CH3, -CH2CH2N(CH3)2, CH2N(H)cyclopropyl, -CH2N(H)cyclobutyl, and -CH2N(H)cyclohexyl, and -CH2CH2CH2N(H)CH2Ph and -CH2CH2CH2N(H)CH2(4-CF3-Ph).

[0970] The present disclosure includes any of the compounds of the present disclosure that are isotopically-labeled (i.e., radiolabeled) by having one or more atoms replaced by an atom having the same atomic number, but a different atomic mass. Examples of isotopes that can be present in the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H (or deuterium, D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, for example, 3 H, 11 C, and 14 C. In one embodiment, a composition is provided in which substantially all of the atoms within a compound of the present disclosure are replaced with atoms having different atomic masses or mass numbers. In another embodiment, a composition is provided in which a portion of the atoms within a compound of the present disclosure are replaced, i.e., the compound of the present disclosure is enriched at a position with atoms having different atomic masses or mass numbers. Isotopically-labeled compounds of the present disclosure can be prepared by methods known in the art.

[0971] The compounds of the present disclosure can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses all such possible forms, as well as the racemic and resolved forms and mixtures thereof. Individual enantiomers can be isolated in accordance with methods known to those skilled in the art. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless indicated otherwise, it is intended that the compounds include both E and Z geometric isomers. The present disclosure encompasses all tautomers.

[0972] The term "stereoisomers" as used herein is a general term for all isomers of a molecule that have the same number and kind of atoms, but differ in the spatial arrangement of the atoms. It includes enantiomeric and diastereomeric forms of compounds having more than one chiral center, where the chiral centers are not mirror images of one another (diastereomers).

[0973] The term "chiral center" or "asymmetric carbon atom" means a carbon atom to which four different groups are attached.

[0974] The terms "enantiomeric" and "enantiomeric" refer to molecules that are not superimposable on their mirror image, and thus are optically active, wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0975] The term "racemic" refers to an equimolar mixture of enantiomeric forms that is optically inactive. In one embodiment, the compounds of the present disclosure are racemic.

[0976] The term "absolute configuration" refers to the spatial arrangement of atoms and their stereochemistry description (e.g., R or S) of a chiral molecular entity (or group).

[0977] The stereochemical terminology and conventions used in the specification are intended to be consistent with those used in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0978] The term "enantiomeric excess" or "ee" refers to a measure of the amount of one enantiomer present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R-S|*100, where R and S are each the molar or weight fraction of the enantiomer in the mixture, such that R+S = 1. By knowing the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([a]obs / [a]max)*100, where [a]obs is the optical rotation of the enantiomeric mixture and [a]max is the optical rotation of the pure enantiomer. The enantiomeric excess can be determined using various analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry.

[0979] In one embodiment, a compound of the disclosure having one or more chiral centers is enantiomerically enriched, e.g., the ee is about 5% or more. 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 another embodiment, 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%.

[0980] The terms“a” and“an” refer to one or more.

[0981] The term“about” as used herein includes ±10% of the recited value. Thus,“about 10” means 9 to 11.

[0982] As used herein, the terms“treat,”“treating,” or“treatment,” and the like, refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. While it is not required, treatment of a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms“treat,”“treating,” or“treatment,” and the like, can include“prophylactic treatment,” which refers to a reduction in the likelihood of redeveloping a disease or condition or recurrence of a previously controlled disease or condition in a subject who does not have the disease or condition, but is at risk of redeveloping the disease or condition or recurrence of the disease or condition, or is predisposed to redeveloping the disease or condition or recurrence of the disease or condition. The term“treat” and synonyms contemplate administration of a therapeutically effective amount of a compound of the disclosure to an individual in need of such treatment.

[0983] Within the meaning of the present disclosure, "treatment" also includes relapse prevention or stage prevention, as well as the treatment of acute or chronic signs, symptoms, and / or malfunctions. For example, treatment can be symptom-directed, such that symptoms are inhibited. It can be effected over a short period, be directed at an intermediate term, or be long-term treatment, for example in the context of maintenance therapy.

[0984] The term "therapeutically effective amount" or "effective dose" as used herein refers to the amount of one or more active ingredients that is sufficient to effectively deliver one or more active ingredients useful for the treatment of a disorder or disease of interest to an individual in need thereof 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 can reduce (i.e., slow to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in target cells; and / or relieve to some extent one or more of the symptoms associated with the cancer. The compounds or compositions administered result in inhibition of growth and / or killing of existing cancer cells to some extent, which can be cytostatic and / or cytotoxic.

[0985] The term "container" refers to any container and closure suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0986] The term "insert" means the information that accompanies a pharmaceutical product, which provides instructions on how to administer the product along with the safety and efficacy data needed to allow physicians, pharmacists, and patients to make informed decisions regarding the use of the product. The package insert is generally considered the "label" for a pharmaceutical product.

[0987] The term "disease" or "disorder" or "disorder" means a disturbance and / or abnormality that is generally considered to be in a pathological state or function, and can manifest itself in the form of specific signs, symptoms, and / or malfunctions. The compounds of the present disclosure inhibit SETD2 protein, and can be used to treat diseases and disorders, such as proliferative diseases, in which inhibition of SETD2 protein provides a benefit. See, e.g., U.S. Patent Publication No. 62 / 545,353.

[0988] In some embodiments, the compounds of the present disclosure can be used to treat a "SETD2 protein-mediated disorder." A SETD2 protein-mediated disorder is any pathological disorder in which SETD2 protein is known to play a role. In some embodiments, the SETD2-mediated disorder is a proliferative disorder.

[0989] In some embodiments, inhibiting a SETD2 protein is an inhibition of one or more activities of a SETD2 protein. In some embodiments, the activity of a SETD2 protein is the ability of the SETD2 protein to transfer a methyl group to a target protein (e.g., a histone). It will 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.

[0990] As used herein, the term "biological sample" refers to any tissue or fluid from a subject that is suitable for detecting chromosomal translocations. Examples of useful biological samples include, but are not limited to, biopsy tissue and / or cells (e.g., solid tumors, lymph nodes, inflamed tissue, tissue and / or cells associated with a condition or disease), blood, plasma, serum, cerebrospinal fluid, saliva, urine, lymphatic fluid, cerebral spinal fluid, and the like. Those of ordinary skill in the relevant art will be familiar with other suitable biological samples. The biological sample 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) methods, reverse transcription-polymerase chain reaction (RT-PCR) methods, or cell- centric light chain immunofluorescence combined with fluorescence in situ hybridization (cIg-FISH). The biological sample can be obtained using techniques well within the range of ordinary skill of a clinician. In one embodiment of the disclosure, the biological sample comprises blood cells.

[0991] The phrase "in combination with" in connection with the administration of a compound of the application and a second therapeutic agent to a subject means that the compound of the application and the second therapeutic agent can be administered to the subject together, e.g., as part of a single pharmaceutical composition or formulation, or separately, e.g., as part of two or more separate pharmaceutical compositions or formulations. Thus, the phrase "in combination with" in connection with the administration of a compound of the application and a second therapeutic agent to a subject is intended to encompass administration of the compound of the application and the second therapeutic agent in a sequential manner, wherein the compound of the application and the second therapeutic agent are administered to the subject at different times, as well as simultaneously or substantially simultaneously. Simultaneous administration can be achieved, for example, by administration of a single capsule having a fixed ratio of each of the compounds of the application and the second therapeutic agent to the subject, or multiple single capsules for each of the compounds of the application and the second therapeutic agent. Sequential or substantially simultaneous administration of the compound of the application and the second therapeutic agent can be achieved by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The compound of the application and the second therapeutic agent can be administered by the same route or by different routes. For example, the second therapeutic agent of the combination can be administered by intravenous injection, while the compound of the disclosure of the combination can be administered orally. Alternatively, for example, both the compound of the application and the second therapeutic agent can be administered orally, or both the compound of the application and the second therapeutic agent can be administered by intravenous injection. The compound of the application and the second therapeutic agent can also be administered alternately. In one embodiment, the compound of the application and the second therapeutic agent are administered separately to the subject, e.g., as part of two or more separate pharmaceutical compositions or formulations.

[0992] General synthesis of compounds

[0993] The compounds of the disclosure are prepared using the methods disclosed in PCT / US2019 / 046569 or by the illustrative methods shown in the general schemes below. In the general schemes, R 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 connection with Formula II, III, IV, V, or VI, unless otherwise indicated. In any of the general schemes, appropriate protecting groups can be used in the synthesis, e.g., when Z is (amino)alkyl or any other group that can require protection, or when R 8is amino, (amino)alkyl or any other group that can require protection. (See, Wuts P.G.M. and T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4thedition, J. Wiley & Sons, NY, 2007), unless otherwise indicated.

[0994] In General Scheme 1, an aryl hydrazine having formula (1) is reacted with ethyl 2- oxopropanoate to give a compound having formula (2). In step 2, the compound having formula (2) is converted to an indole having formula (3) under acidic conditions. In step 3, the compound having formula (3) is hydrolyzed to give an indole-2-carboxylic acid having formula (4). In step 4, the compound having formula (4) is reacted with G 1 NH2under standard coupling conditions to give a compound having formula II.

[0995] General Scheme 1

[0996]

[0997] In General Scheme 2, a compound of formula (5) is reacted with R 2b -H, wherein R 2b is a heterocyclyl group, for example, R 2b -H is piperidine or an amine, for example, R 2b -H is dimethylamine to give a compound of formula (6). The nitro group of the compound of formula (6) is reduced to give a compound of formula (7). In step 3, the compound of formula (7) is reacted with a compound of formula (4) under standard coupling conditions, see General Scheme 1, to give a compound of formula III, wherein A 1 and A 2 is CH, R 2b is an optionally substituted heterocyclyl group or an amino group.

[0998] General Scheme 2

[0999]

[1000] (wherein A 1 and A 2 is CH; and R 2b is an optionally substituted heterocyclyl group or an amino group)

[1001] In General Scheme 3, a compound of formula (8) is reacted with R 2b -H, wherein R 2b is a heterocyclyl group, for example, R 2b -H is piperidine or an amine, for example, R 2b- H is dimethylamine to give a compound of formula (9). 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, R 2b is optionally substituted heterocyclyl or amino.

[1002] General Scheme 3

[1003]

[1004] (wherein A 1 and / or A 2 is N; and R 2b is optionally substituted heterocyclyl or amino)

[1005] In General Scheme 4, a compound of formula (11) is reacted with R 11a - H, wherein R 11a is heterocyclyl, for example R 11a - H is piperidine to give a compound of formula (12). In 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 optionally substituted heterocyclyl, Z 5 is -CH2-.

[1006] General Scheme 4

[1007]

[1008] (wherein R 11a is optionally substituted heterocyclyl; and Z 5 is CH2)

[1009] 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.

[1010] General Scheme 5

[1011]

[1012] (wherein p is 0)

[1013] 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, wherein p is 1.

[1014] General Scheme 6

[1015]

[1016] (wherein p is 1)

[1017] In General Scheme 7, a nitrile of formula (24) is reduced to give an amine of formula (25). Coupling of the compound of formula (25) with a compound of formula (4) gives a compound of formula VI.

[1018] General Scheme 7

[1019] Example

[1020] Example 1

[1021] Synthesis of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H- indole-2-carboxamide (Compound No. 15)

[1022] Step 1. Synthesis of (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazine-1-ylidene]propionic acid ethyl ester

[1023]

[1024] A 1000-mL round bottom flask was charged with (5-fluoro-2-methylphenyl)hydrazine hydrochloride (100 g, 572.73 mmol, 1.00 eq) in ethanol (400 mL), 2-oxoethyl propionate (66 g, 1.20 eq), sulfuric acid (10 mL). The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solid was collected by filtration. This gave 120 g (yield = 88%) of (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazine-1-ylidene]propionic acid ethyl ester as a yellow solid. LCMS (Method A: ESI): RT = 1.399 min, m / z = 239.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.96 (d, J = 2.0 Hz, 1H), 7.15 (m, 2H), 6.62 (m, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.12 (d, J = 9.3 Hz, 6H), 1.29 (t, J = 7.1 Hz, 3H) ppm.

[1025] Step 2. Synthesis of 4-fluoro-7-methyl-lH-indole-2-carboxylic acid ethyl ester

[1026]

[1027] A 1000-mL round bottom flask was charged with (2E)-2-[2-(5-fluoro-2- methylphenyl)hydrazine-l-ylidene]propionic acid ethyl ester (40 g, 167.89 mmol, 1.00 equiv) in toluene (400 mL), 4-methylbenzene-l-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 ethyl acetate. The resulting mixture was washed with 3 x 200 mL saturated aqueous NaHC03solution. The residue was applied to 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 9.1 g (yield = 24%) of 4-fluoro-7-methyl-lH-indole-2-carboxylic acid ethyl ester as a yellow solid. LCMS (Method A, ESI): RT = 1.354 min, m / z = 222.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.00 (m, 1H), 6.77 (m, 7.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.49 (d, J = 1.0 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm.

[1028] Step 3. Synthesis of 4-fluoro-7-methyl-lH-indole-2-carboxylic acid

[1029]

[1030] A 500-mL round-bottom flask was charged with 4-fluoro-7-methyl-lH-indole-2-carboxylic acid ethyl ester (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), methanol (2 mL). The resulting solution was stirred at 25 °C for 6 h. The resulting mixture was concentrated in vacuo. The residue was diluted with water 50 ml, then adjusted to pH 5 with hydrogen chloride (3.0 mol / L). The resulting solution was extracted with 3 x 50 mL ethyl acetate. The solids were collected by filtration. This resulted in 8.0 (yield = 81%) g of 4-fluoro-7-methyl-lH-indole-2-carboxylic acid as a brown solid. LCMS (Method C, ESI): RT = 0.989 min, m / z = 192.0 [M-H] + . 1 H NMR (300 MHz, DMSO-d6) δ 13.10 (s, 1H), 11.94 (s, 1H), 7.09 (d, J = 2.1 Hz, 1H), 6.96 (m, 1H), 6.73 (m, 1H), 2.46 (d, J = 1.1 Hz, 3H) ppm.

[1031] Step 4. Synthesis of tert-butyl N-[3-(4-acetylpiperazin-l-yl)cyclohexyl]carbamate

[1032]

[1033] A 100-mL round-bottom flask was charged with tert-butyl N-(3-oxocyclohexyl)carbamate (800 mg, 3.75 mmol, 1.00 equiv), l-(piperazin-l-yl)ethan-l-one (800 mg, 6.24 mmol, 1.66 equiv), methanol (10 mL), Pd / C (0.2 g), and the above mixture was introduced with hydrogen gas. The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated in vacuo. The crude product (900 mg) was purified by Flash-Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase; detector, UV 254 / 220 nm. This resulted in 700 mg (yield = 57%) of tert-butyl N-[3-(4-acetylpiperazin-l-yl)cyclohexyl]carbamate as a colorless oil. LCMS (Method A, ESI): RT = 1.361 min, m / z = 325.9 [M+H] + .

[1034] Step 5. Synthesis of l-[4-(3-aminocyclohexyl)piperazin-l-yl]ethan-l-one

[1035]

[1036] A 100-mL round-bottom flask was charged with N-[3-(4-acetylpiperazin-1-yl)cyclohexyl] tert-butylcarbamate (700 mg, 2.15 mmol, 1.00 equiv), dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added dropwise. The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. This gave 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] + .

[1037] Step 6. Synthesis of N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7- methyl-1H-indole-2-carboxamide (as TFA salt)

[1038]

[1039] Compound No. 15

[1040] To a 100-mL round-bottom flask was added 4-fluoro-7-methyl-lH-indole-2-carboxylic acid (100 mg, 0.52 mmol, 1.00 equiv), l-[4-(3-aminocyclohexyl)piperazin-l- yl]ethan-l-one (110 mg, 0.49 mmol, 0.94 equiv), N,N-dimethylformamide (4 mL), DIEA (200 mg, 1.55 mmol, 2.99 equiv), HATU (260 mg, 0.68 mmol, 1.32 equiv) portionwise. The resulting solution was stirred at 25 °C for 2 h. 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 x 15 mL of ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 : 1). The crude product was purified by Chiral-Prep-HPLC with the following conditions: Column, (R, R)-WHELK-01 4.6*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 Prep Phenyl OBD Column, 5 μm, 19 x 150 mm; Mobile phase, water containing 10 mmol TFA and MeCN (20.0% MeCN up to 30.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 20.0% in 2 min); Detector, UV 254 / 220 nm. This gave 30.5 mg (yield = 11%) of N-[(lR,3S)-3-(4-acetylpiperazin-l-yl)cyclohexyl]-4-fluoro-7-methyl-lH-indole-2- carboxamide trifluoroacetic acid salt as a white solid. LCMS (Method B, ES): RT = 1.138 min, m / z = 401.0 [M-TFA] + . 1 H NMR (300 MHz, 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 = 16.4 Hz, 5H), 2.48 (t, J = 1.0 Hz, 3H), 2.23 (d, J = 12.0 Hz, 1H), 2.09 (s, 3H), 1.93 (d, J = 12.2 Hz, 3H), 1.53 - 1.18 (m, 4H) ppm.

[1041] Example 2

[1042] Combination study

[1043] Multiple myeloma (MM) and mantle cell lymphoma (MCL) cell line cultures were treated with combinations of Compound No. 15 and combination partners according to a co-treatment model. Assay-ready plates were prepared by dispensing compounds onto 384-well white opaque plates (CulturPlate-384, white opaque 384-well microplates, sterile and tissue culture treated) with an HP-D300 nanoliter dispenser (Tecan, Mannedorf, Switzerland) to achieve 2-fold or 3-fold serial dilutions in a concentration range around the IC50of Compound No. 15 and combination partners. Concentrations were matrixed in an 8 x 9 array (8 concentrations of Compound No. 15 and 9 concentrations of its combination partner). Each combination was tested in quadruplicate. The final concentration of DMSO (vehicle) in the assay was 0.1% v / v. Fifty microliters of cell line suspension were dispensed directly onto the assay-ready plates with an automated multichannel dispenser on a 384-well assay-ready plate. The assay plates were incubated at 37°C in a humidified atmosphere of 5% CO2for 7 days. CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) was used to measure the number of viable cells in each well. The assay was performed according to the manufacturer's instructions. Briefly, CellTiter-Glo® reagent was added to each well and the plates were mixed on an orbital shaker for 15 minutes at room temperature. The plates were then incubated at room temperature for 30 minutes to allow cellular components to completely solubilize. The plates were mixed again on an orbital shaker for 15 minutes at room temperature. Luminescence was measured on a Tecan UltraVioletOr Microplate Reader (Tecan, Mannedorf, Switzerland). The data were analyzed using XLfit® software (Millennium House, Widbrook, UK). The IC50values were calculated by non-linear regression analysis using the XLfit® software. The results are shown in Table 1. CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) by measuring cellular adenosine triphosphate (ATP) to quantify the effect of single agents or combinations on cell viability. Luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). Concentration response graphs were generated in GraphPad Prism version 7.0 for Windows, GraphPad Software, (La Jolla, California) and curves were fit to a four-parameter logistic model with variable slope. Percent inhibition was calculated for each treatment concentration. Quantification of synergy used the Loewe additivity model and VLoewe was calculated by using CHALICE software (Horizon Discovery, Cambridge, UK) (Lehar 2007). (VLoewe > 1: synergy, between 1 and -1: additivity, and <-1: antagonism; “ineffective” if neither of the two drugs or the combination reached 50% inhibition of proliferation. See Loewe, Arzneimittelforschung 3(6):285-290 (1953) and Lehar et al., Mol Syst Biol 3:80 (2007). Cell lines used in these studies were purchased from commercial suppliers. For example, NCI-H929, MM1.S, MINO, REC1, MAVER1, Z138, JEKO1, JVM2, and RPMI-8226 cell lines were purchased from American Type Culture Collection (ATCC, Manassas VA); KMS-11, KMS34, and KMS-28-BM were purchased from Japanese Collection of Research Bioresources (JCRB, Osaka, Japan); and L-363 and GRANTA519 were purchased from Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures.

[1044] Results for these combinations are summarized in Tables A and B (multiple myeloma cell lines) and Tables C and D (mantle cell lymphoma cell lines).

[1045] For example, Figure 3 It was shown that the combination of Compound No. 15 and pomalidomide has synergistic anti-proliferative activity in KMS-11 cells in a 7-day co-treatment study. Figure 4A Loewe model analysis of the compound no. 15 / pomalidomide combination study in KMS-11 cells is shown.

[1046] Diffuse large B-cell lymphoma cells were seeded into flasks and pre-treated with several concentrations of compound no. 15 or DMSO. Cells were then split to initial density, replated and co-treated with compound no. 15 and a second agent of interest for an additional 3 days in tissue culture treated solid white 384-well plates using the HP D300 Digital dispenser (Tecan Group, Mannedorf, Switzerland). Both agents were serially diluted and combined in a matrix format with constant ratios diagonally across the plate with a final DMSO content of 0.11% (v / v). After 3 days of co-treatment, cell viability was measured by ATP content using CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) and luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). (Promega, Madison, WI) by ATP content using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA).

[1047] Example 3

[1048] Combination studies

[1049] Diffuse large B-cell lymphoma (DLBCL) cell line cultures in log-linear growth rate were treated with combinations of compound no. 15 and combination partners according to a pre-treatment model. Cells were first seeded into 8 flasks and pre-treated with 7 different concentrations of compound no. 15 (concentrations around the IC50 of compound no. 15 with a 3-fold dilution range) and DMSO for 4 days. On day 4, assay ready plates were prepared by dispensing the compounds onto 384-well white opaque plates (CulturPlate-384, white opaque 384-well microplates, sterile and tissue culture treated) with a HP-D300 nanoliter dispenser (Tecan, Mannedorf, Switzerland) to achieve a 3-fold serial dilution in a concentration range around the IC50 of the combination partner. Cells were harvested from each flask and re-seeded into the corresponding 384-well plates in triplicate wells with the same concentration of compound no. 15 and 9 concentrations of its combination partner. The final concentration of DMSO (vehicle) in the assay was 0.1% v / v. Fifty microliters of cell line suspension were dispensed directly onto the assay ready plates with an automated multichannel dispenser. The assay plates were incubated at 37°C in a humidified atmosphere of 5% CO2for three days. CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) was used to measure cell viability by ATP content using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) was used to quantify the effect of single agents or combinations on cell viability by measuring cellular adenosine triphosphate (ATP). Luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). Concentration response graphs were generated in GraphPad Prism version 8.0 for Windows, GraphPad Software, (La Jolla, California) and curves were fit to a four-parameter logistic model with variable slope. Percent inhibition was calculated for each treatment concentration. Quantification of synergy was performed using the Loewe additivity model and by calculating the Loewe volume (VLoewe) using CHALICE software (Horizon Discovery, Cambridge, UK) (Lehar 2007). (VLoewe > 1: synergy, between 1 and -1: additivity, and <-1: antagonism; no effect was considered if neither of the two drugs or the combination reached 50% inhibition. See Loewe, Arzneimittelforschung 3(6):285-290 (1953) and Lehar et al., Mol Syst Biol 3:80 (2007). SUDHL6 and SUDHL2 cell lines were purchased from American Type Culture Collection (ATCC, Manassas VA). WSUDLCL2 was purchased from Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures and KARPAS422 was purchased from Sigma Aldrich (St. Louis, MO). Results for these combinations are summarized in Table E (Diffuse Large B Cell Lymphoma Cell Lines).

[1050] Table A

[1051]

[1052] Table B

[1053]

[1054]

[1055] Table C

[1056]

[1057] Table D

[1058]

[1059]

[1060] Table E

[1061]

[1062] Example 4

[1063] Combination studies

[1064] Long-term KMS-11 proliferation assay: Log-linear growth rate cells were treated with Compound No. 15 (500 nM) and combination partners thalidomide (100 nM) and / or lenalidomide (1000 nM) for a total of 14 days. For each of these agents, the concentration used at day 14 was near the IC50value. On day 0, exponentially growing cells were dispensed into three 96-well plates in six replicates. Cell cultures were incubated in the presence of DMSO, single agents, and double or triple combinations of the above agents for 4 and 7 days at 37°C in a humidified atmosphere containing 5% CO2. These plates were developed on days 0, 4, 7, and the effect of single agents and combinations on cell viability was quantified by measuring cellular adenosine triphosphate (ATP) using CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI). Luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). In addition, on day 0, log-linear growth rate cells were also seeded into three 6-well plates and treated with DMSO, single agents, and double or triple combinations with the respective agents. These 6-well plates were incubated at 37°C in a humidified atmosphere containing 5% CO2for 7 days. On day 7, cells from each treatment were trypsinized, counted, and split back to the original plating density into 3 96-well plates in six replicate wells for analysis on days 7, 11, and 14. These replated cells were treated identically to day 0. CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI) was then used on days 7, 11, and 14 to measure cellular ATP. The plates were developed with CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI). Luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). Cell viability versus time plots (corrected for cell number division) were generated in GraphPad Prism version 8.0 for Windows, GraphPad Software (La Jolla, California). Statistical analysis was performed on the triple combination versus each double combination using one-way ANOVA and Tukey’s multiple comparisons (****p < 0.0001). Figure 1 and Figure 2 Results of long-term KMS-11 proliferation assay are shown.

[1065] Having now fully described the application, it will be apparent to one of ordinary skill in the art that many modifications, alterations, additions, and permutations of the embodiments of the application can be made without departing from the scope of the application or the spirit thereof.

[1066] Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the application being indicated by the following claims.

[1067] All patents, patent applications (e.g., PCT / US2019 / 046569), and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. Use of a compound, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for treating cancer, wherein the compound is: wherein the second therapeutic agent is dexamethasone, pomalidomide, lenalidomide, bortezomib, venetoclax, CC-122, selinexor, pracinostat, or tasidotin, or a combination thereof.

2. The use of claim 1, wherein the second therapeutic agent is dexamethasone.

3. The use of claim 1, wherein the second therapeutic agent is pomalidomide or lenalidomide.

4. The use of claim 1, wherein the second therapeutic agent is bortezomib.

5. The use of claim 1, wherein the second therapeutic agent is venetoclax.

6. The use of claim 1, wherein the second therapeutic agent is CC-122.

7. The use of claim 1, wherein the second therapeutic agent is selinexor.

8. The use of claim 1, wherein the second therapeutic agent is pracinostat.

9. The use of claim 1, wherein the second therapeutic agent is tasidotin.

10. The use of claim 1, wherein the compound and the second therapeutic agent are administered separately to a subject.

11. The use of any one of claims 1-10, wherein the cancer is lung cancer, squamous carcinoma, lymphoma, leukemia, thyroid cancer, breast cancer, melanoma, glioma, germ cell tumor, or sarcoma.

12. The use of any one of claims 1-10, wherein the cancer is:

13. The use of any one of claims 1-10, wherein the cancer is a hematological cancer.

14. The use of claim 13, wherein the hematological cancer is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma.

15. The use of claim 13, wherein the hematological cancer is a B-cell lymphoma or a T-cell lymphoma.

16. The use of claim 13, wherein the hematological cancer is:

17. A kit comprising: (a) a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof; and (b) a second therapeutic agent, wherein: the second therapeutic agent is dexamethasone, pomalidomide, lenalidomide, bortezomib, venetoclax, CC-122, selinexor, pracinostat, or tasidotin, or a combination thereof.

18. The kit of claim 17, further comprising instructions for administering the compound and the second therapeutic agent to a subject having cancer.

19. A compound selected from the group consisting of: 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-1-methyl-2-oxohexahydro pyrrolo[3,4-b]pyrrol-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide; 4-fluoro-7-methyl-N-((1R,3R)-3-((3aS,6aS)-1-methyl-2-oxohexahydro pyrrolo[3,4-b]pyrrol-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide; 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2- b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide; 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2- b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide; 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2- b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide; 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2- b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide; 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2- b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide; and 4-fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2- b]pyrrol-l(2H)-yl)cyclohexyl)-lH-indole-2-carboxamide, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. Use of a compound of claim 19, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

22. The use of claim 21, wherein the cancer is lung cancer, squamous carcinoma, lymphoma, leukemia, thyroid cancer, breast cancer, melanoma, glioma, germ cell tumor, or sarcoma.

23. The use of claim 21, wherein the cancer is 24. The use of claim 21, wherein the cancer is a hematological cancer.

25. The use of claim 24, wherein the hematological cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

26. The use of claim 24, wherein the hematological cancer is B-cell lymphoma or T-cell lymphoma.

27. The use of claim 24, wherein the hematological cancer is:

28. A kit comprising a compound of claim 19 and instructions for administering the compound to a subject.

29. The kit of claim 28, wherein the subject has cancer.

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