SETD2 inhibitors and related methods and uses, including combination therapies

Abstract

The present invention provides SETD2 protein inhibitors, as well as methods, compositions and kits for treating a disease, disorder or condition in a subject using a SETD2 protein inhibitor and optionally a second therapeutic agent, wherein the second therapeutic agent comprises one or more glycocortin receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more multi-effect pathway modulators, one or more XPO1 inhibitors, and one or more pharmaceutically acceptable salts thereof, one or more histone deacetylase inhibitors or one or more EZH2 inhibitors, or a combination thereof.

Description

[0001] This application is a divisional application of a Chinese patent application (Filing date: February 19, 2021; Application No. 202180028429X). 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 using the SETD2 protein inhibitors for treating a disease, disorder, or condition 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

[0003] 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 affected by the presence or absence of one or more methyl groups at relevant histone sites. The specific effects of methyl groups at particular histone sites persist until the methyl groups are removed by histone demethylases, or until the modified histone is replaced by nucleosome turnover. In a similar manner, other enzyme classes can modify DNA and histones with other chemical species, while still other enzymes can remove these species to provide control over gene expression.

[0004] SETD2 is a human histone methyltransferase located at cytogenetic band p21.31 of chromosome 3 (3p21.31). 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).

[0005] 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 have been 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

[0006] 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.

[0007] 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:

[0008] (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 a compound of Table IB, and pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "a compound of the present disclosure"; and

[0009] (2) a therapeutically effective amount of a second therapeutic agent,

[0010] 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 a combination thereof.

[0011] In another aspect, the present invention 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.

[0012] In another aspect, the present invention provides a compound of the present disclosure for use in the preparation of a medicament for treating cancer in a mammal, 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 invention provides a kit comprising a compound of the present disclosure and a second therapeutic agent.

[0014] 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.

[0015] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] Additional embodiments and advantages of the disclosure will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following and / 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.

[0020] 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

[0021] 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.

[0022] 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.

[0023] Figure 3is a line plot showing synergistic anti-proliferative activity of the combination of Compound No. 15 and pomalidomide in KMS-11 cells in a 7-day co-treatment study.

[0024] Figure 4 is a table showing 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

[0025] I. Compounds of the Disclosure

[0026] 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.

[0027] In one embodiment, a compound of the disclosure is a compound of Formula I:

[0028]

[0029] wherein:

[0030] R1ais selected from halogen, alkyl, alkoxy, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0031] Q1is selected from -C(R 1b )= and -N=;

[0032] Q2is selected from -C(R 1c )= and -N=;

[0033] Q3is selected from -C(R 1d )= and -N=;

[0034] with the proviso that at least one of Q1, Q2, or Q3 is -C(R1b)=, -C(R1c)=, or -C(R1d)=, respectively;

[0035] R1b, R1c, and R1dare each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy;

[0036] R 1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0037] is a single or double bond;

[0038] G1is 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

[0039] G 2 is selected from the group consisting of hydrogen and alkyl; or

[0040] G 1 and G 2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl,

[0041] or a pharmaceutically acceptable salt or solvate thereof.

[0042] 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.

[0043] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein:

[0044] R 1a is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, (hydroxy)C1-6alkyl, and (C3-C6cycloalkyl)C 1-6 alkyl;

[0045] R1b, R1c, and R1dare each independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, (hydroxy)C1-C6alkyl, and C1-C6alkoxy;

[0046] R 1e is selected from the group consisting of hydrogen and C1-C6alkyl;

[0047] G 1Selected 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-C6 alkyl, (5- to 10-membered heteroaryl)C1-C6 alkyl, (3- to 10-membered heterocyclic)C1-C6 alkyl, (amino)(C6-C 10 (aryl)C1-C6 alkyl, (5- to 14-membered heteroaryl)(C6-C 10 (aryl)C1-C6 alkyl, (5- to 10-membered heteroaryl) (3- to 10-membered heterocyclic)C1-C6 alkyl, (5- to 10-membered heteroaryl) (formamido)C1-C6 alkyl, (5- to 10-membered heteroaryl) (C3-C6 cycloalkyl)C1-C6 alkyl, (C6-C 10 aryl)(alkoxycarbonyl)C1-C6 alkyl, (C3-C6 cycloalkyl)C1-C6 alkyl, (5- to 10-membered heteroaryl)(amino)C1-C6 alkyl, (C3-C6 cycloalkyl)(alkoxycarbonyl)C1-C6 alkyl, (5- to 14-membered heteroaryl)(alkoxycarbonyl)C1-C6 alkyl, (3- to 14-membered heterocyclic)(C3-C8 cycloalkyl)C1-C6 alkyl, (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

[0048] G 2 Selected from hydrogen and C1-C6 alkyl; or

[0049] G1 and G2, together with the nitrogen atoms they are attached to, form 5- to 10-membered, optionally substituted heterocycles.

[0050] Or its pharmaceutically acceptable salts or solvates.

[0051] In another embodiment, the compound disclosed herein is a compound having formula I, wherein:

[0052] R 1a Selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkyl groups, and (hydroxy)C 1-4alkyl and (C3-C6cycloalkyl)C 1-4 alkyl;

[0053] R1b, R1c, and R1dare each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, C2-C4alkenyl, (hydroxy)C1-C4alkyl, and C1-C3alkoxy;

[0054] R 1e selected from the group consisting of hydrogen and C1-C3alkyl;

[0055] G 1 selected from the group consisting of 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-C4alkyl, (5- to 10-membered heteroaryl)C1-C6alkyl, (3- to 10-membered heterocyclo)C1-C4alkyl, (amino)(C6-C 10 aryl)C1-C6alkyl, (5- to 14-membered heteroaryl)(C6-C 10 aryl)C1-C4alkyl, (5- to 10-membered heteroaryl)(3- to 10-membered heterocyclo)C1-C4alkyl, (5- to 10-membered heteroaryl)(carboxamido)C1-C4alkyl, (5- to 10-membered heteroaryl)(C3-C6cycloalkyl)C1-C4alkyl, (C6-C 10 aryl)(alkoxycarbonyl)C1-C4alkyl, (C3-C6cycloalkyl)C1-C4alkyl, (5- to 10-membered heteroaryl)(amino)C1-C4alkyl, (C3-C6cycloalkyl)(alkoxycarbonyl)C1-C4alkyl, (5- to 14-membered heteroaryl)(alkoxycarbonyl)C1-C4alkyl, (3- to 14-membered heterocyclo)(C3-C6cycloalkyl)C1-C4alkyl, (C6- 10 aryl)(C3-C6cycloalkyl)C1-C4alkyl, (C6-C 10 aryl)(hydroxy)C1-C4alkyl, (C3-C6cycloalkyl)(hydroxy)C1-C4alkyl, (hydroxy)C1-C4alkyl, optionally substituted C1-C4alkyl, (C6-C 10 aryl)(C1-C4haloalkyl)C1-C4alkyl, (C3-C6cycloalkyl)(C1-C4haloalkyl)C1-C4alkyl, (hydroxy)(C1-C4haloalkyl)C1-C4alkyl, and (alkoxycarbonyl)(C1-C4haloalkyl)C1-C4alkyl; and

[0056] G 2 selected from the group consisting of hydrogen and C1-C4alkyl; or

[0057] G1and G2, together with the nitrogen atom to which they are attached, form a 5- to 10- membered optionally substituted heterocycle, or a pharmaceutically acceptable salt or solvate thereof.

[0058] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein is a double bond, or a pharmaceutically acceptable salt or solvate thereof.

[0059] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein Q1and Q2are -C(H)=, or a pharmaceutically acceptable salt or solvate thereof.

[0060] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein Q3is -C(R1d)=; and R1dis selected from hydrogen and halogen, or a pharmaceutically acceptable salt or solvate thereof.

[0061] 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.

[0062] In another embodiment, the compound of the present disclosure is a compound of Formula I, wherein R 1a is C1-C3alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0063] 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.

[0064] In another embodiment, the compound of the present disclosure is a compound of Formula II:

[0065]

[0066] or a pharmaceutically acceptable salt or solvate thereof, wherein R1dand G1are defined as in Formula I.

[0067] In another embodiment, the compound of the present disclosure is a compound of Formula I or II, wherein R1dis selected from hydrogen and fluorine, or a pharmaceutically acceptable salt or solvate thereof.

[0068] In another embodiment, the compound of the present disclosure is a compound of Formula II-A:

[0069]

[0070] or a pharmaceutically acceptable salt or solvate thereof, wherein G1is defined as in Formula II.

[0071] In another embodiment, the compound of the disclosure is a compound of Formula I, II, or III-A, wherein G1is selected from optionally substituted C6-C10aryl, optionally substituted 5- to 9-membered heteroaryl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C6-C8cycloalkyl, (5- to 9-membered heteroaryl)C1-C6alkyl, (5- to 9-membered heteroaryl)(C6- 10 C4alkyl, (5- to 9-membered heteroaryl)(C3-C6cycloalkyl)C1-C4alkyl, and (C3-C6cycloalkyl)C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof. 10 C4alkyl, (5- to 9-membered heteroaryl)(C3-C6cycloalkyl)C1-C4alkyl, and (C3-C6cycloalkyl)C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0072] In another embodiment, the compound of the disclosure is a compound of Formula III:

[0073]

[0074] wherein:

[0075] A1is selected from -N= and -C(R2a)=;

[0076] R2a is selected from hydrogen, alkyl, halo, and haloalkyl;

[0077] R2b is selected from optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, (formamidyl)alkyl, -OR10c, amino, (heterocycloalkyl)alkyl, (amino)alkyl, (hydroxyl)alkyl, formamidyl, (heteroaryl)alkyl, -S(=O)R 9b , -S(=O)2R 9b , and -C(=O)R 9c ;

[0078] A2is selected from -N= and -C(R2c)=;

[0079] R2c is selected from hydrogen, alkyl, halo, and haloalkyl;

[0080] R2d is selected from hydrogen, alkyl, halo, cyano, and haloalkyl;

[0081] R2e is selected from hydrogen, alkyl, halo, and haloalkyl;

[0082] R9b is selected from amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;

[0083] R9c is selected from amino, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl; and

[0084] R10cis selected from alkyl, (hydroxy)alkyl, and (amino)alkyl; and

[0085] R1dis defined as described in Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0086] In another embodiment, the compound of the present disclosure is a compound of Formula III-A:

[0087]

[0088] wherein R1d, R2a, R2b, R2c, R2d, and R2e are defined as described in Formula III, or a pharmaceutically acceptable salt or solvate thereof.

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

[0090] R 2a is selected from hydrogen, C1-C4alkyl, halogen, and C1-C4haloalkyl;

[0091] R2bis selected from:

[0092] (A) an unsubstituted 4- to 10-membered heterocycle;

[0093] (B) a substituted 4- to 10-membered heterocycle having 1, 2, 3, or 4 substituents independently selected from (i) -N(R3a)C(=O)R4a; (ii) -NR5aR5b; (iii) an unsubstituted 4- to 10-membered heterocycle; (iv) a substituted 4- to 10-membered heterocycle having 1, 2, or 3 substituents independently selected from 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; (v) unsubstituted C3-C6cycloalkyl; (vi) (hydroxy)C1-C4alkyl; (vii) C1-C6alkyl; (viii) -C(=O)NR 5g R 5h ; (ix) halogen; (x) -C(=O)R 4c ; (xi) C1-C6haloalkyl; (xii) hydroxy; (xiii) (amino)C1-C4alkyl; (xiv) (C1-C4alkoxy)C1-C4alkyl; (xv) -S(=O)2R 9a(xvi) (3- to 8-membered heterocyclo)Ci-C4alkyl; (xvii) Ci-C6alkoxy; (xviii) (C3-C6cycloalkyl)Ci-C4alkyl; (xix) (C6- 1-4 aryl)Ci-C4alkyl; and (xx) -OR10b; 10 (xxi) -NR10bR10c;

[0094] (C) unsubstituted C3-C8cycloalkyl;

[0095] (D) substituted C3-C8cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of: (i) unsubstituted 4- to 10-membered heterocyclo; (ii) substituted 4- to 10-membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of: amino and Ci-C4alkyl; (iii) unsubstituted 5- or 6-membered heteroaryl; (iv) substituted 5- or 6-membered heteroaryl having 1, 2, or 3 substituents independently selected from the group consisting of: halo, Ci-C4alkyl, (3- to 8-membered heterocyclo)alkyl, hydroxy, and amino; (v) -NR 5i R 5j ; (vi) cyano; (vii) -N(R 3d )C(=0)R 4f ; (viii) hydroxy; and (ix) Ci-C4alkyl;

[0096] (E) unsubstituted 5- to 10-membered heteroaryl;

[0097] (F) substituted 5- to 10-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of: (i) halo; (ii) Ci-C4alkyl; (C1-C4alkoxy)Ci-C4alkyl; (hydroxy)Ci-C4alkyl; C3-C6cycloalkyl; (amino)Ci-C4alkyl; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1, 2, 3, or 4 substituents independently selected from the group consisting of: -NR5gR5h; unsubstituted 4- to 14-membered heterocyclo; substituted 4- to 14-membered heterocyclo having 1 or 2 substituents independently selected from the group consisting of: hydroxy, amino, and Ci-C4alkyl; -NR 5q R 5r ; and (ix) (3- to 8-membered heterocyclo)Ci-C4alkyl;

[0098] (G) unsubstituted C6-C 10 aryl;

[0099] (H) substituted C6-C 10aryl having 1, 2, 3, or 4 substituents independently selected from (i) halogen; (ii) C1-C4alkyl; (iii) -CH2N(H)S(=O)2R 8 ; (iv) (5- to 9-membered heteroaryl)C1-C4alkyl; (v) -OR 10a ; (vi) -N(R 3b )C(=O)R 4b ; (vii) (amino)C1-C4alkyl; and (viii) (hydroxy)C1-C4alkyl;

[0100] (I) (formamidyl)C1-C4alkyl;

[0101] (J) -OR 10c ;

[0102] (K) -NR 5o R 5p ;

[0103] (L) (3- to 8-membered heterocyclo)C1-C4alkyl;

[0104] (M) (amino)C1-C4alkyl;

[0105] (N) (hydroxy)C1-C4alkyl;

[0106] (O) -C(=O)NR 5s R 5t ;

[0107] (P) (5- to 9-membered heteroaryl)C1-C4alkyl; and

[0108] (Q) -S(=O)2R 9b ;

[0109] R2c is selected from hydrogen, C1-C4alkyl, halogen, and C1-C4haloalkyl;

[0110] R 2d is selected from hydrogen, C1-C4alkyl, halogen, cyano, and C1-C4haloalkyl;

[0111] R 2e is selected from hydrogen, C1-C4alkyl, halogen, and C1-C4haloalkyl;

[0112] R3a, R3b, R3c, and R3d are each independently selected from hydrogen, C1-C4alkyl, optionally substituted C3-C6cycloalkyl, and optionally substituted 4- to 14-membered heterocyclyl;

[0113] R4a, R4b, R4c, R4d, R4e, and R4fare each independently selected from the group consisting of C1-C6alkyl; C1-C6haloalkyl; C3-C6cycloalkyl; C1-C6alkoxy; (C1-C4alkoxy)C1-C4alkyl; (C6- 10 aryl)C1-C4alkyl; (5- to 9-membered heteroaryl)C1-C4alkyl; (amino)C1-C4alkyl; (hydroxy)C1-C4alkyl; (cyano)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 halogen and C1-C4alkyl; unsubstituted C6-C 10 aryl; substituted C6-C 10 aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen and C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; and substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen and C1-C4alkyl;

[0114] R5aand R5bare 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;

[0115] R5cand R5dare 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

[0116] R5cand R5d, together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 14-membered heterocyclyl;

[0117] R5eand R5fare independently selected from 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

[0118] R5eand R5fare taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 14-membered heterocyclyl;

[0119] R5gand R5hare independently selected from 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

[0120] R5gand R5hare taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 14-membered heterocyclyl;

[0121] R5iand R5jare independently selected from 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

[0122] R5iand R5jare taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 14-membered heterocyclyl;

[0123] R5kand R5lare 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

[0124] R5kand R5l, together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 14-membered heterocyclyl;

[0125] R5m and R5n 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

[0126] R5m and R5n, together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 14-membered heterocyclyl;

[0127] R5o and R5p 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

[0128] R5o and R5p, together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 14-membered heterocyclyl;

[0129] R5qand R5rare independently selected from 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;

[0130] R5qand R5rare independently selected from 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;

[0131] R6a, R6b, R6c, and R6dare each independently selected from hydrogen and Ci-C4alkyl;

[0132] R 8 is Ci-C6alkyl;

[0133] R 9a is selected from the group consisting of Ci-C6alkyl; unsubstituted C3-C8cycloalkyl; and substituted C3-C8cycloalkyl having 1 or 2 substituents independently selected from the group consisting of halogen, Ci-C4alkyl, amino and (amino)Ci-C4alkyl;

[0134] R 9b is selected from the group consisting of Ci-C6alkyl and amino;

[0135] R 10a is selected from the group consisting of alkyl, (hydroxy)Ci-C4alkyl and (amino)Ci-C4alkyl;

[0136] R 10b is (amino)Ci-C4alkyl; and

[0137] R 10c is (amino)Ci-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0138] In another embodiment, the compound of the present disclosure is a compound of Formula III or Formula III-A, wherein R2b is an optionally substituted 3- to 10-membered heterocycle attached to the rest of the molecule through a nitrogen atom, e.g., R2b is:

[0139] etc.

[0140] In another embodiment, the compound of the present disclosure is a compound of Formula III or Formula III-A, wherein:

[0141] R2b is selected from:

[0142]

[0143]

[0144]

[0145] Ra1is selected from -N(R3a)C(=0)R4a; -NR5aR5b; 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(=0)NR 5e R 5f , -C(=0)R 4b , (hydroxy)C1-C4alkyl, and halogen;

[0146] Ra2and Ra3are each hydrogen; or

[0147] Ra2and Ra3, together with the carbon atom to which they are attached, form a C(=0) group;

[0148] Ra4is selected from hydrogen, halogen, and hydroxy;

[0149] R a5 is selected from hydrogen, C1-C4alkyl, and C3-C6cycloalkyl;

[0150] R b1 is selected from hydrogen, C1-C4alkyl, and C3-C6cycloalkyl;

[0151] R c1 is selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl, and -C(=0)R 4c ;

[0152] Rc2and Rc3are each independently selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl; or

[0153] Rc2and Rc3together with the carbon atom to which they are attached form a C(=0) group;

[0154] R c4 is selected from hydrogen and C1-C4alkyl;

[0155] m is 1 or 2;

[0156] R d1 is selected from hydrogen, C1-C4alkyl and -C(=0)R4c,

[0157] Rd2and Rd3are each independently selected from hydrogen and fluoro;

[0158] R e1 is selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=0)R 4c ;

[0159] R f1 is selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=0)R 4c ,

[0160] R g1 is selected from hydrogen, C1-C4alkyl, -C(=0)R 4c , C1-C4haloalkyl, (C1-C4alkoxy)C1-C4alkyl,

[0161] R h1 is selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=0)R 4c ;

[0162] R h2 is selected from hydrogen and C1-C4alkyl;

[0163] Rh3and Rh4are each independently selected from hydrogen and C1-C4alkyl; or

[0164] Rh3and Rh4together with the carbon atom to which they are attached form a C(=0) group;

[0165] R i1 is selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl, (hydroxy)C1-C4alkyl, -N(R 3a )C(=0)R 4a and (amino)C1-C4alkyl;

[0166] Z 1 is selected from -CH2- and -0-;

[0167] R j1 is selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl and -C(=0)R 4c;

[0168] R k1 is selected from the group consisting of C1-C4alkyl, unsubstituted 4- to 14- membered heterocyclyl, and -NR5aR5b;

[0169] R k2 is selected from the group consisting of hydrogen, hydroxy, and C1-C4alkyl;

[0170] r is 0, 1, or 2;

[0171] Z 2 is selected from the group consisting of -O- and -N(R m3 )-;

[0172] R m3 is selected from the group consisting of hydrogen, C1-C4alkyl, and C1-C4haloalkyl;

[0173] R n3 is selected from the group consisting of hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0174] 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;

[0175] R o2 is selected from the group consisting of hydrogen, C1-C4alkyl, and (C1-C4alkoxy)C1-C4alkyl,

[0176] R o3 is selected from the group consisting of hydrogen, fluorine, and C1-C4alkyl;

[0177] R p1 is selected from the group consisting of hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0178] Z3is selected from the group consisting of -O- and -N(Rq1)-;

[0179] R q1 is selected from the group consisting of hydrogen and C1-C4alkyl;

[0180] R r1 is selected from the group consisting of hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0181] R s1 is selected from the group consisting of hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0182] R t1selected from hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0183] R u1 selected from hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0184] R v1 selected from hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0185] R w1 selected from hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0186] R x1 selected from hydrogen, C1-C4alkyl, and -C(=O)R4c;

[0187] R y1 selected from hydrogen and C1-C4alkyl; and

[0188] R z1 selected from hydrogen and C1-C4alkyl,

[0189] or a pharmaceutically acceptable salt or solvate thereof.

[0190] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein:

[0191] R2bis selected from:

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] or a pharmaceutically acceptable salt or solvate thereof.

[0198] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2bis R2b-1, R2b-1A, R2b-1B, R2b-1C, or R2b-1D, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rais -N(R3a)C(=O)R4a. In another embodiment, Rais -NR5aR5b. In another embodiment, Rais -NR5aR5b and R5aand R5bare independently selected from hydrogen and C1-C4alkyl. In another embodiment, R a1 is an optionally substituted 4- to 10-membered heterocycle.

[0199] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-2, R2b-2A, or R2b-2b, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R b1 is C1-C4 alkyl.

[0200] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-3, R2b-3A, or R2b-3B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R 4c In another embodiment, Rc2 and Rc3 are each hydrogen. In another embodiment, Rc2 and Rc3, together with the carbon atom to which they are attached, form a C(=O) group. In another embodiment, Rc4 is hydrogen. In another embodiment, m is 1.

[0201] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rd1 is C(=O)R4c. In another embodiment, Rd2 and Rd3 are each hydrogen or fluoro.

[0202] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-5, R2b-5A, or R2b-5B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Re1 is -C(=O)R4c.

[0203] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-6, R2b-6A, or R2b-6B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rf1 is C(=O)R4c.

[0204] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-7, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rg1 is C(=O)R4c.

[0205] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-8, R2b-8A, R2b-8B, R2b-8C, or R2b-8D, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rhi is -C(=0)R4c. In another embodiment, Rh2is selected from hydrogen and C1-C3 alkyl. In another embodiment, R h3 is hydrogen.

[0206] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-9, or a pharmaceutically acceptable salt or solvate thereof.

[0207] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is selected from R2b-10, R2b-10A, R2b-10B, R2b-10C, and R2b-10d, or a pharmaceutically acceptable salt or solvate thereof.

[0208] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is selected from R2b-11, R2b-11A, and R2b-11B, or a pharmaceutically acceptable salt or solvate thereof.

[0209] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-12, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rj1is -C(=0)R4c.

[0210] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is selected from R2b-13, R2b-13A, R2b-13B, R2b-13C, R2b-13D, R2b-13E, and R2b-13F, or a pharmaceutically acceptable salt or solvate thereof.

[0211] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-14, or a pharmaceutically acceptable salt or solvate thereof.

[0212] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-15, or a pharmaceutically acceptable salt or solvate thereof.

[0213] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is selected from R2b-16, R2b-16A, and R2b-16B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rn3 is -C(=0)R4c.

[0214] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-17, or a pharmaceutically acceptable salt or solvate thereof.

[0215] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-18, or a pharmaceutically acceptable salt or solvate thereof.

[0216] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-19, or a pharmaceutically acceptable salt or solvate thereof.

[0217] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-20, or a pharmaceutically acceptable salt or solvate thereof.

[0218] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is selected from R2b-21, R2b-21A, and R2b-21B, or a pharmaceutically acceptable salt or solvate thereof.

[0219] In another embodiment, a compound of the disclosure is a compound of Formula III, wherein R2b is selected from R2b-22, R2b-22A, and R2b-22B, or a pharmaceutically acceptable salt or solvate thereof.

[0220] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-23, or a pharmaceutically acceptable salt or solvate thereof.

[0221] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-24, or a pharmaceutically acceptable salt or solvate thereof.

[0222] In another embodiment, a compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2b is R2b-25, 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 R2b is selected from R2b-26, R2b-26A, and R2b-26B, 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 R2b is selected from R2b-27, R2b-27A, and R2b-27B, 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 R2b is selected from R2b-28, R2b-28A, and R2b-28B, 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 R2b is R2b-29, 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 R2b is R2b-30, R2b-30A, or R2b-30B, 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 R2b is any one or more of the R11a groups provided with respect to Formula IV, see below, 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 4c is C1-C4 alkyl, 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 R2d is selected from hydrogen, fluoro, and chloro, or a pharmaceutically acceptable salt or solvate thereof.

[0231] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2d is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0232] In another embodiment, the compound of the disclosure is a compound of Formula III in any of the above embodiments, wherein A1 and A2 are -C(H)=; R2e is hydrogen; and R2d is selected from hydrogen and halo, or a pharmaceutically acceptable salt or solvate thereof.

[0233] In another embodiment, the compound of the disclosure is a compound of Formula III or Formula III-A, wherein R2d is fluoro, or a pharmaceutically acceptable salt or solvate thereof.

[0234] In another embodiment, the compound of the disclosure is a compound of Formula IV:

[0235]

[0236] wherein:

[0237] Z4is selected from -O-, -C(R28a)(R28b)-, and -N(R23)-; or Z4is absent;

[0238] Z 5 is selected from -CH2- and -CH2CH2-;

[0239] R11ais selected from optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and -N(R12b)C(=0)R13c;

[0240] R12bis selected from hydrogen, alkyl, cycloalkyl, and heterocycle;

[0241] R13cis 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;

[0242] R 23 is selected from hydrogen and C1-C4alkyl;

[0243] R28aand R28bare independently selected from hydrogen, alkyl, and halo; and

[0244] R1dis defined as described for Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0245] In another embodiment, the compound of the disclosure is a compound of Formula IV, wherein Z 4 is selected from -O- and -CH2-; or Z 4 is absent, or a pharmaceutically acceptable salt or solvate thereof.

[0246] In another embodiment, the compound of the disclosure is a compound of Formula IV, wherein:

[0247] Z 4 is selected from -O- and -CH2-; or Z 4 is absent;

[0248] Z 5 is selected from -CH2- and -CH2CH2-;

[0249] R13cis 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

[0250] R1dis defined as described in formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0251] In another embodiment, the compound of the disclosure is a compound of Formula IV-A:

[0252]

[0253] or a pharmaceutically acceptable salt or solvate thereof, wherein R1d, R11a, and Z4are defined as in Formula IV.

[0254] In another embodiment, the compound of the disclosure is a compound of Formula IV-B:

[0255]

[0256] or a pharmaceutically acceptable salt or solvate thereof, wherein R1d, R11a, and Z4are defined as in Formula IV.

[0257] In another embodiment, the compound of the disclosure is a compound of Formula IV-C:

[0258]

[0259] or a pharmaceutically acceptable salt or solvate thereof, wherein R1d, R11a, and Z4are defined as in Formula IV.

[0260] In another embodiment, the compound of the disclosure is a compound of Formula IV-D:

[0261]

[0262] or a pharmaceutically acceptable salt or solvate thereof, wherein R1d, R11a, and Z4are defined as in Formula IV.

[0263] 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:

[0264] R11ais 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-C4alkyl; (C1-C4alkoxy)C1-C4alkyl; (hydroxy)C1-C4alkyl; C1-C4haloalkyl; amino; hydroxy; -N(R 12a )S(=O)2R 24 ; -S(=O)2R 24 ; unsubstituted C3-C6cycloalkyl; substituted C3-C6cycloalkyl having 1 or 2 substituents independently selected from the group consisting of: halo, 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; (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: halo, C1-C4alkyl, and (amino)alkyl; (E) C1-C6alkyl; and (F) -N(R 12b )C(=O)R 13c ;

[0265] R12aand R12bare each independently selected from the group consisting of: hydrogen, C1-C4alkyl, (C1-C4alkoxy)C1-C4alkyl, and (hydroxy)C1-C4alkyl;

[0266] R13a, R13b, and R13care each independently selected from the group consisting of: C1-C6alkyl; C1-C6haloalkyl; unsubstituted C3-C6cycloalkyl; C1-C6alkoxy; (C1-C4alkoxy)C1-C4alkyl; (hydroxy)C1-C4alkyl; (cyano)alkyl; unsubstituted C6-C 10 aryl; substituted C6-C 10 aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of: halo, amino, hydroxy, and C1-C4alkyl; unsubstituted 5- or 6-membered heteroaryl; substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of: halo, amino, hydroxy, and C1-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; amino; (amino)alkyl; (C3-C6cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy; and

[0267] R 24C1-C4alkyl and (hydroxy)C1-C4alkyl.

[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 Z4is -C(R28a)(R28b)-; and R28aand R28bare independently selected from hydrogen, 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 Z4is -C(R28a)(R28b)-; R28ais hydrogen; and R 28b C1-C4alkyl and fluoro, 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 Z4is -C(R28a)(R28b)-; and R28aand R28bare independently C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0271] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein Z4is selected from -O-, -CH2-, and -N(R 23 ), or Z 4 is absent, or a pharmaceutically acceptable salt or solvate thereof.

[0272] 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 -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[0273] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais an optionally substituted 3- to 10-membered heterocycle attached to the rest of the molecule through a nitrogen atom, e.g., R11ais

[0274] and the like.

[0275] In another embodiment, the compound of the disclosure is a compound of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais a substituted 4- to 14-membered heterocyclyl selected from:

[0276]

[0277]

[0278] R 12a is selected from hydrogen, C1-C3 alkyl, (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl;

[0279] R 13a is selected from C1-C4 alkyl; amino; 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; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)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;

[0280] R 13b is selected from C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having 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; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclyl)oxy;

[0281] R 21 is selected from hydrogen, -C(=O)R 13b , C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted 4- to 14-membered heterocycle and -S(=O)2R 24 ;

[0282] R 22 is C1-C4 alkyl; 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;

[0283] R 24 is selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[0284] R25 selected from hydrogen, C1-C4alkyl, and C1-C4haloalkyl;

[0285] R 25b and R 25c are independently selected from C1-C4alkyl and C1-C4haloalkyl;

[0286] R26is selected from unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from amino, hydroxy, and C1-C4alkyl; and

[0287] R21aand R25a, together with the atoms to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl, or a pharmaceutically acceptable salt or solvate thereof.

[0288] 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 selected from:

[0289]

[0290]

[0291]

[0292]

[0293] wherein:

[0294] R27aand R27bare each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, (C1-C4alkoxy)C1-C4alkyl; and (hydroxy)C1-C4alkyl;

[0295] 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 1 or 2 substituents independently selected from amino, hydroxy, and C1-C4alkyl; and -S(=O)2R 24 ;

[0296] R 27d is selected from hydrogen; C1-C4alkyl; and C1-C4haloalkyl;

[0297] 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; 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; and

[0298] R 24 selected from the group consisting of C1-C4alkyl and (hydroxy)C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0299] 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 selected from the group consisting of:

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] or a pharmaceutically acceptable salt or solvate thereof

[0306] 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 selected from the group consisting of unsubstituted 4- to 14-membered heterocyclyl; substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from the group consisting of -N(R 12a )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.

[0307] 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 substituted 4- to 14-membered heterocyclyl selected from the group consisting of:

[0308]

[0309] or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R12ais selected from hydrogen and C1-C3alkyl; R13ais methyl; and R13bis methyl, or a pharmaceutically acceptable salt or solvate thereof. 13a is C1-C4alkyl; and R 13b is C1-C4alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R12ais selected from hydrogen and methyl; R13ais methyl; and R13bis methyl, or a pharmaceutically acceptable salt or solvate thereof.

[0310] 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 any one or more of the R2bgroups provided with respect to Formula III, supra, or a pharmaceutically acceptable salt or solvate thereof.

[0311] 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:

[0312] R11ais selected from:

[0313]

[0314] and R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R c1 , R c2 , R c3 , R c4 , m, R d1 , R d2 , R d3 , R e1 , R f1 , R g1 , R h1 , Rh2, Rh3, Rh4, Ri1, Z1, Rj1, Rk1, Rk2, r, Z2, Rn3, Ro1, Ro2, Ro3, Rp1, Z3, Rr1, Rs1, Rt1, Ru1, Rv1, Rw1, Rx1, Ry1, and Rz1are defined as described for Formula III; or a pharmaceutically acceptable salt or solvate thereof.

[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:

[0316] R11a is selected from:

[0317]

[0318]

[0319] and Ra1, Ra5, Rb1, Re1, Rf1, Rh1, Rh2, Rh3, Rk1, Rn3, Rs1, Rt1, Rw1, Rx1, and Ry1 are defined as described for Formula III; or a pharmaceutically acceptable salt or solvate thereof.

[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 R11a is R11a-1, R11a-1A, R11a-1B, R11a-1C, or R11a-1D, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Ra1 is -N(R3a)C(=0)R4a. In another embodiment, Ra1 is -NR5aR5b. In another embodiment, Ra1 is -NR5aR5b and R5a and R5b are independently selected from hydrogen and C1-C4 alkyl. In another embodiment, R a1 is an optionally substituted 4- to 10-membered heterocycle.

[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 R11a is R11a-2, R11a-2A, or R11a-2b, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R b1 is C1-C4 alkyl.

[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 R11a is R11a-3, R11a-3A, or R11a-3B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R c1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, and -C(=0)R4c. In another embodiment, Rc2 and Rc3 are each hydrogen. In another embodiment, Rc2 and Rc3, together with the carbon atom to which they are attached, form a C(=0) group. In another embodiment, Rc4 is hydrogen. In another embodiment, m is 1.

[0323] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rd1is C(=0)R4c. In another embodiment, Rd2and Rd3are each hydrogen or fluoro.

[0324] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-5, R11a-5A, or R11a-5B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Re1is -C(=0)R4c.

[0325] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-6, R11a-6A, or R11a-6B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rf1is C(=0)R4c.

[0326] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-7, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rg1is C(=0)R4c.

[0327] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-8, R11a-8A, R11a-8B, R11a-8C, or R11a-8D, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rh1is -C(=0)R4c. In another embodiment, Rh2is selected from hydrogen and C1-C3alkyl. In another embodiment, R h3 is hydrogen.

[0328] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-9, or a pharmaceutically acceptable salt or solvate thereof.

[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 R11ais selected from R11a-10, R11a-10A, R11a-10B, R11a-10C, and R11a-10d, 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 R11ais selected from R11a-11, R11a-11A, and R11a-11B, 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 R11ais R11a-12, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rj1is -C(=O)R4c.

[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 R11ais selected from R11a-13, R11a-13A, R11a-13B, R11a-13C, R11a-13D, R11a-13E, and R11a-13F, 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 R11ais R11a-14, 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 R11ais R11a-15, 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 R11ais selected from R11a-16, R11a-16A, and R11a-16B, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, Rn3is -C(=O)R4c.

[0336] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-17, or a pharmaceutically acceptable salt or solvate thereof.

[0337] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-18, or a pharmaceutically acceptable salt or solvate thereof.

[0338] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-19, or a pharmaceutically acceptable salt or solvate thereof.

[0339] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-20, or a pharmaceutically acceptable salt or solvate thereof.

[0340] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais selected from R11a-21, R11a-21A, and R11a-21B, or a pharmaceutically acceptable salt or solvate thereof.

[0341] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais selected from R11a-22, R11a-22A, and R11a-22B, or a pharmaceutically acceptable salt or solvate thereof.

[0342] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-23, or a pharmaceutically acceptable salt or solvate thereof.

[0343] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-24, or a pharmaceutically acceptable salt or solvate thereof.

[0344] In another embodiment, a compound of the disclosure is a compound of any one of Formula IV, IV-A, IV-B, IV-C, or IV-D, wherein R11ais R11a-25, or a pharmaceutically acceptable salt or solvate thereof.

[0345] In another embodiment, the compound disclosed herein is a compound having any one of formula IV, IV-A, IV-B, IV-C or IV-D, wherein R11a is selected from R11a-26, R11a-26A and R11a-26B, or a pharmaceutically acceptable salt or solvate thereof.

[0346] In another embodiment, the compound disclosed herein is a compound having any one of formula IV, IV-A, IV-B, IV-C or IV-D, wherein R11a is selected from R11a-27, R11a-27A and R11a-27B, or a pharmaceutically acceptable salt or solvate thereof.

[0347] In another embodiment, the compound disclosed herein is a compound having any one of formula IV, IV-A, IV-B, IV-C or IV-D, wherein R11a is selected from R11a-28, R11a-28A and R11a-28B, or a pharmaceutically acceptable salt or solvate thereof.

[0348] In another embodiment, the compound disclosed herein is a compound having any one of formula IV, IV-A, IV-B, IV-C or IV-D, wherein R11a is R11a-29, or a pharmaceutically acceptable salt or solvate thereof.

[0349] In another embodiment, the compound disclosed herein is a compound having any one of formula IV, IV-A, IV-B, IV-C or IV-D, wherein R11a is R11a-30, R11a-30A or R11a-30B, or a pharmaceutically acceptable salt or solvate thereof.

[0350] In another embodiment, the compound disclosed herein is a compound having any one of formula IV-A, IV-B, IV-C, or IV-D, wherein:

[0351] Z 4 It is -CH2-;

[0352] R11a is selected from:

[0353]

[0354] R 12a Selected from hydrogen and C1-C3 alkyl groups;

[0355] R 21 -C(=O)R 13b ;

[0356] R 27c -C(=O)R 13b ;

[0357] R 13bC1-C4alkyl and (hydroxy)C1-C4alkyl;

[0358] R 24 is C1-C4alkyl;

[0359] R 25 is selected from hydrogen, C1-C4alkyl and C1-C4haloalkyl; and

[0360] R 25b and R 25c are independently selected from C1-C4alkyl and C1-C4haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

[0361] 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:

[0362] Z 4 is -CH2-; and

[0363] R11ais selected from:

[0364]

[0365] or a pharmaceutically acceptable salt or solvate thereof.

[0366] 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:

[0367] Z 4 is -CH2-; and

[0368] R11ais selected from:

[0369]

[0370] or a pharmaceutically acceptable salt or solvate thereof.

[0371] 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:

[0372] Z 4 is -CH2-;

[0373] R11ais:

[0374] and

[0375] R 27aR27a 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, R27a is methyl.

[0376] In another embodiment, the compound of the disclosure is a compound of Formula V:

[0377]

[0378] wherein: R1d, R14a, R14d, and p are as defined for Formula V, or a pharmaceutically acceptable salt or solvate thereof.

[0379] R14a is selected from optionally substituted alkyl and optionally substituted heteroaryl;

[0380] R14b is selected from optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and carboxamido; and

[0381] p is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

[0382] In another embodiment, the compound of the disclosure is a compound of Formula V-A:

[0383]

[0384] wherein R1d, R14a, R14d, and p are as defined for Formula V, or a pharmaceutically acceptable salt or solvate thereof.

[0385] In another embodiment, the compound of the disclosure is a compound of Formula V-B:

[0386]

[0387] wherein R1d, R14a, R14d, and p are as defined for Formula V, or a pharmaceutically acceptable salt or solvate thereof.

[0388] In another embodiment, the compound of the disclosure is a compound of any of Formulae V, V-A, or V-B, wherein:

[0389] R14a is selected from (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 (i) halogen; (ii) C1-C4alkyl; (iii) C1-C4alkoxy; (iv) (3- to 8-membered heterocyclo)C1-C4alkyl; (v) (5- to 9-membered heteroaryl)C1-C4alkyl; (vi) -C(=O)NR 15a R 15b(vii) Unsubstituted 5- to 10-membered heteroaryl; (viii) Substituted 5- or 10-membered heteroaryl having one, two, or three independent substituents selected from: halogen, C1-C4 alkyl, (3- to 8-membered heterocyclic) C1-C4 alkyl, 5- to 9-membered heteroaryl, and -NR. 15e R 15f ;(ix) -OR 16 (x) Unsubstituted C3-C6 cycloalkyl; (xi) Substituted C3-C6 cycloalkyl having 1, 2, 3 or 4 substituents independently selected from: C1-C4 alkyl and -N(R) 17a )C(=O)R 18a (xii) Cyano; (xiii) Unsubstituted 4- to 14-membered heterocyclic group; (xiv) Substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from: C1-C4 alkyl, (5- to 9-membered heteroaryl) C1-C4 alkyl; (xv) (carboxyl) C1-C4 alkyl; (xvi) (formamido) C1-C4 alkyl; and (xvii) carboxyl; and (C) C1-C6 alkyl;

[0390] R14b is selected from: (A) unsubstituted 5- to 10-membered heteroaryl groups; (B) substituted 5- or 10-membered heteroaryl groups having 1, 2, 3, or 4 independently selected substituents from: halogen, C1-C4 alkyl, and (C3-C6 cycloalkyl)C1-C4 alkyl groups; (C) unsubstituted C6-C4 alkyl groups. 10 Aryl; (D)-substituted C6-C 10 Aryl group, substituted with 1, 2, 3 or 4 independently selected from the following substituents: halogen, C1-C4 alkyl and (3- to 8-membered heterocyclic) C1-C4 alkyl; (E) unsubstituted 4- to 14-membered heterocyclic group; (F) substituted 4- to 14-membered heterocyclic group having 1, 2, 3 or 4 independently selected from the following substituents: hydroxyl, amino and C1-C4 alkyl; (G)-C(=O)NR 15c R 15d (H) Unsubstituted C3-C6 cycloalkyl; and (I) C1-C6 alkyl;

[0391] p is 0, 1, 2 or 3;

[0392] R15a and R15b are independently 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 10substituted C6-C10aryl; (H) C3-C8cycloalkyl; (I) -NR15aR15b; (J) -OR15c; (K) -S(O)mR15d; (L) -NR15eCOR15f; (M) -NR15gR15h; or (N) -CN; or

[0393] R15aand R15bare taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 14-membered heterocyclyl;

[0394] R15cand R15dare independently selected from: (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; (I) C3-C8cycloalkyl; (J) -NR15eCOR15f; (K) -NR15gR15h; or (L) -CN; 10 substituted C6-C10aryl; (H) C3-C8cycloalkyl; (I) -NR15aR15b; (J) -OR15c; (K) -S(O)mR15d; (L) -NR15eCOR15f; (M) -NR15gR15h; or (N) -CN; or 10 substituted C6-C10aryl; (H) C3-C8cycloalkyl; (I) -NR15aR15b; (J) -OR15c; (K) -S(O)mR15d; (L) -NR15eCOR15f; (M) -NR15gR15h; or (N) -CN; or

[0395] R15cand R15dare taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 14-membered heterocyclyl;

[0396] R15eand R15fare independently selected from: (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; (I) C3-C8cycloalkyl; (J) -NR15gR15h; or (K) -CN; 10 substituted C6-C10aryl; (H) C3-C8cycloalkyl; (I) -NR15aR15b; (J) -OR15c; (K) -S(O)mR15d; (L) -NR15eCOR15f; (M) -NR15gR15h; or (N) -CN; or 10aryl 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 having 1, 2, 3, or 4 independent substituents selected from: C1-C6 alkyl and -NR15gR15h; or

[0397] R15e and R15f, together with the nitrogen atom to which they are attached, form optionally substituted 4- to 14-membered heterocyclic groups;

[0398] R15g and R15h are 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 groups having 1, 2, 3, or 4 independently selected substituents 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 independently selected substituents from: halogen, amino, hydroxyl, and C1-C4 alkyl; (L) unsubstituted 4- to 14-membered heterocyclic groups; (M) substituted 4- to 14-membered heterocyclic groups having 1 or 2 independently selected substituents from: amino, hydroxyl, and C1-C4 alkyl; (N) unsubstituted C3- to C8 cycloalkyl; and (O) substituted C3- to C8 cycloalkyl groups having 1, 2, 3, or 4 independently selected substituents from: C1-C6 alkyl and -NR. 15g R 15h ;or

[0399] R15g and R15g together with the nitrogen atom to which they are attached form optionally substituted 4- to 14-membered heterocyclic groups;

[0400] R 16 It is (amino) (hydroxy) C1-C4 alkyl;

[0401] R 17a Selected from hydrogen and C1-C4 alkyl groups;

[0402] R 18aselected 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, hydroxyl, 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, hydroxyl, 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, hydroxyl, 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, hydroxyl, and C1-C4alkyl, 10 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-C 10 10aryl; (H) substituted C6-C10aryl having 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, amino, hydroxyl, 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, hydroxyl, 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, hydroxyl, 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, hydroxyl, and C1-C4alkyl,

[0403] or a pharmaceutically acceptable salt or solvate thereof.

[0404] In another embodiment, the compound of the present disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R14a 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 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 halogen, C1-C4alkyl, (3- to 8-membered heterocyclyl)C1-C4alkyl, 5- to 9-membered heteroaryl, and -NR 15e R 15f ; unsubstituted C3-C6cycloalkyl; and substituted C3-C6cycloalkyl having 1, 2, or 3 substituents independently selected from C1-C4alkyl and -N(R17a)C(=O)R18a, or a pharmaceutically acceptable salt or solvate thereof.

[0405] In another embodiment, the compound of the disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R14a is substituted pyridyl having 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(=0)NR 15a R 15b ; unsubstituted 5- to 10-membered heteroaryl; substituted 5- to 10-membered heteroaryl having 1, 2, or 3 substituents independently selected from the group consisting of 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 having 1, 2, or 3 substituents independently selected from the group consisting of C1-C4alkyl and -N(R 17a )C(=0)R 18a , or a pharmaceutically acceptable salt or solvate thereof.

[0406] In another embodiment, the compound of the disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R14b is selected from the group consisting of unsubstituted 5- to 10-membered heteroaryl; substituted 5- to 10-membered heteroaryl having 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 having 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 heterocyclo; substituted 4- to 14-membered heterocyclo having 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.

[0407] In another embodiment, the compound of the disclosure is a compound of any one of Formulae V, V-A, or V-B, wherein R14b is selected from the group consisting of unsubstituted 5- or 6-membered heteroaryl; substituted 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.

[0408] 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.

[0409] 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.

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

[0411]

[0412] wherein:

[0413] R19is selected from unsubstituted 4- to 14-membered heterocyclyl; and substituted 4- to 14-membered heterocyclyl having 1 or 2 substituents independently selected from amino, hydroxy, and C1-C4alkyl;

[0414] R 20 selected from hydrogen, halogen, and C1-C4alkyl; and

[0415] q is 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

[0416] In another embodiment, the compound of the disclosure is a compound of Formula VI, wherein q is 1.

[0417] In another embodiment, the compound of the disclosure is a compound of Formula VII:

[0418]

[0419] wherein:

[0420] R 11b selected from C1-C4alkyl, halogen, and C1-C4haloalkyl; and

[0421] R1dand R11aare defined as in Formula IV, or a pharmaceutically acceptable salt or solvate thereof.

[0422] In another embodiment, the compound of the disclosure is a compound of Formula VII-A:

[0423]

[0424] wherein R1d, R11a, and R11bare defined as in Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0425] In another embodiment, the compound of the disclosure is a compound of Formula VII-B:

[0426]

[0427] wherein R1d, R11a, and R11bare as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0428] In another embodiment, the compound of the disclosure is a compound of Formula VII-C:

[0429]

[0430] wherein R1d, R11a, and R11bare as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0431] In another embodiment, the compound of the disclosure is a compound of Formula VII-D:

[0432]

[0433] wherein R1d, R11a, and R11bare as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0434] In another embodiment, the compound of the disclosure is a compound of Formula VII-E:

[0435]

[0436] wherein R1d, R11a, and R11bare as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0437] In another embodiment, the compound of the disclosure is a compound of Formula VII-F:

[0438]

[0439] wherein R1d, R11a, and R11bare as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0440] In another embodiment, the compound of the disclosure is a compound of Formula VII-G:

[0441]

[0442] wherein R1d, R11a, and R11bare as defined for Formula VII, or a pharmaceutically acceptable salt or solvate thereof.

[0443] In another embodiment, the compound of the disclosure is a compound of Formula VII-H:

[0444]

[0445] R1d, R11a, and R11b are as defined in Formula VII, or pharmaceutically acceptable salts or solvates thereof.

[0446] In another embodiment, the compound disclosed herein is a compound having formula VIII:

[0447]

[0448] in:

[0449] R 30 Selected from hydrogen; C1-C6 alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl and C1-C4 alkyl; -C(=O)R 13b and -S(=O)2R 24 ;

[0450] R 13b Selected from C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic group; substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from: amino, hydroxyl and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclic)oxy;

[0451] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[0452] u is 0, 1, 2, or 3; and

[0453] R1d is as defined in Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0454] In another embodiment, the compounds disclosed herein are compounds having formula VIII-A:

[0455]

[0456] R1d, R30, and u are as defined in Formula VII I, or their pharmaceutically acceptable salts or solvates.

[0457] In another embodiment, the compound disclosed herein is a compound having formula VIII-B:

[0458]

[0459] R1d, R30, and u are as defined in Formula VII I, or their pharmaceutically acceptable salts or solvates.

[0460] In another embodiment, the compounds of this disclosure are the compounds in Table 1, and their pharmaceutically acceptable salts or solvates. The chemical names of the compounds in Table 1 were generated using Chemdraw® Professional version 17.0.0.206. Mass spectrometric and biological data for representative compounds of this disclosure are provided in Table 1B and / or PCT / US2019 / 046569. In another embodiment, the compounds of this disclosure are the compounds in Table 1B, and their pharmaceutically acceptable salts or solvates. The biological data in Table 1B were generated according to the protocols described in Examples 11 and 12 of PCT / US2019 / 046569.

[0461] In another embodiment, the compounds disclosed herein are selected from compounds numbered 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 their pharmaceutically acceptable salts or solvates. In another embodiment, the compounds disclosed herein are selected from compound numbers 15, 922, 930, 942, 1055, 1070, 1117, 1180, 1184, and 1192, and their pharmaceutically acceptable salts or solvates. In another embodiment, the compounds disclosed herein are selected from compound numbers 1228, 1229, 1230, 1231, 1232, 1233, 1234, and 1235, and their pharmaceutically acceptable salts or solvates.

[0462] In another embodiment, the compounds disclosed herein are selected from compound numbers 15, 942, 1184 and 1232, and their pharmaceutically acceptable salts or solvates.

[0463] In a non-limiting embodiment, the compound disclosed herein is compound number 15. In a non-limiting embodiment, the compound disclosed herein is compound number 1228. In a non-limiting embodiment, the compound disclosed herein is compound number 1229. In a non-limiting embodiment, the compound disclosed herein is compound number 1230. In a non-limiting embodiment, the compound disclosed herein is compound number 1231. In a non-limiting embodiment, the compound disclosed herein is compound number 1232. In a non-limiting embodiment, the compound disclosed herein is compound number 1233. In a non-limiting embodiment, the compound disclosed herein is compound number 1234. In a non-limiting embodiment, the compound disclosed herein is compound number 1235. In a non-limiting embodiment, the compound disclosed herein is a pharmaceutically acceptable salt or solvate of compound number 15. In a non-limiting embodiment, the compound disclosed herein is a pharmaceutically acceptable salt or solvate of compound number 1228. In a non-limiting embodiment, the compound disclosed herein is a pharmaceutically acceptable salt or solvate of compound number 1229. In a non-limiting embodiment, the compound of this disclosure is a pharmaceutically acceptable salt or solvate of compound number 1230. In a non-limiting embodiment, the compound of this disclosure is a pharmaceutically acceptable salt or solvate of compound number 1231. In a non-limiting embodiment, the compound of this disclosure is a pharmaceutically acceptable salt or solvate of compound number 1232. In a non-limiting embodiment, the compound of this disclosure is a pharmaceutically acceptable salt or solvate of compound number 1233. In a non-limiting embodiment, the compound of this disclosure is a pharmaceutically acceptable salt or solvate of compound number 1234. In a non-limiting embodiment, the compound of this disclosure is a pharmaceutically acceptable salt or solvate of compound number 1235.

[0464] Table 1

[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]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523] Table 1B

[0524]

[0525]

[0526] This disclosure includes the preparation and use of salts of the compounds disclosed herein, including pharmaceutically acceptable salts that are non-toxic. 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 salts, potassium salts, cesium salts, etc.; alkaline earth metals such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salts, pyridinium salts, methylpyridinium salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.; inorganic acid salts such as hydrochloride salts, hydrobromide salts, phosphates, sulfates, etc.; organic acid salts such as citrate salts, lactate salts, tartrate salts, maleate salts, fumarate salts, mandelate salts, acetate salts, dichloroacetic acid salts, trifluoroacetic acid salts, oxalate salts, formate salts, etc.; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, etc.; and amino acid salts such as arginine salts, aspartate salts, glutamate salts, etc. As used herein, the term "pharmaceutically acceptable salt" refers to a compound disclosed herein that is physiologically tolerated in the target subject (e.g., a mammal, such as a human).

[0527] Acid addition salts can be formed by mixing a solution of the specific compound disclosed herein with a pharmaceutically acceptable, non-toxic acid (such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, etc.). Basic salts can be formed by mixing a solution of the compound disclosed herein with a pharmaceutically acceptable, non-toxic alkali (such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.).

[0528] This disclosure includes the preparation and use of solvates of the compounds disclosed herein. Solvates generally do not significantly alter the physiological activity or toxicity of the compounds and are therefore used as pharmacological equivalents. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of the disclosed compounds with solvent molecules, such as disolvates, monosolvates, or hemisolvates, wherein the ratio of solvent molecules to the disclosed compounds is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Therefore, "solvate" encompasses both the solution phase and the separable solvate. The disclosed compounds can exist as solvated forms with pharmaceutically acceptable solvents such as water, methanol, ethanol, etc., and this disclosure is intended to include both solvated and unsolvated forms of the disclosed compounds. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecules are water. Solvates are commonly used as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci. 93(3): 601-611 (2004), which describes the preparation of a solvate of fluconazole using ethyl acetate and water. Similar preparations of solvates, hemisols, hydrates, etc., are described by EC. van Tonder et al., AAPS Pharm. Sci. Tech. 5(1): 12 (2004) and A. Bingham et al., Chem. Commun 603-604 (2001). Typical non-limiting methods for preparing solvates would involve dissolving the compound disclosed herein 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 separating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvents in crystalline solvate form.

[0529] II. Second therapeutic agent

[0530] In some embodiments, the treatment method of the present invention includes administering a combination of a therapeutically effective amount of the disclosed compound and a therapeutically effective amount of a second therapeutic agent.

[0531] As used herein, the term "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 deacetylase inhibitors, or one or more EZH2 inhibitors, or combinations thereof. In one embodiment, the second therapeutic agent comprises a compound from one pharmaceutical class, namely, a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a pleiotropic pathway modulator, an XPO1 inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. In another embodiment, the second therapeutic agent comprises two different compounds from one pharmaceutical class, for example, two different glucocorticoid receptor agonists, such as dexamethasone and prednisone, two different immunomodulatory drugs, two different proteasome inhibitors, two different Bcl-2 inhibitors, two different pleiotropic pathway modulators, two different XPO1 inhibitors, two different histone deacetylase inhibitors, or two different EZH2 inhibitors. In another embodiment, the second therapeutic agent comprises three different compounds from one pharmaceutical class, for example, three different glucocorticoid receptor agonists, such as dexamethasone, prednisone, and methylprednisolone; three different immunomodulatory drugs; three different proteasome inhibitors; three different Bcl-2 inhibitors; three different pleiotropic pathway modulators; three different XPO1 inhibitors; three different histone deacetylase inhibitors; or three different EZH2 inhibitors. In another embodiment, the second therapeutic agent comprises three different compounds from two pharmaceutical classes, for example, two different glucocorticoid receptor agonists, such as dexamethasone and prednisone; and one immunomodulatory drug; two different glucocorticoid receptor agonists and one proteasome inhibitor; and so on.

[0532] In another embodiment, the second therapeutic agent comprises compounds from different drug classes, such as a first compound from a first drug class and a second compound from a second drug class, wherein the first and second drug classes are different. As a specific, non-limiting example, the second therapeutic agent comprises an EZH2 inhibitor, such as tazestat, and an immunomodulatory drug, such as lenoliminide. The table below provides non-limiting examples of drug class combinations:

[0533]

[0534] 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, second, and third drug classes are different. The following table provides non-limiting examples of drug class combinations:

[0535]

[0536]

[0537] As used herein, the term "glucocorticoid receptor agonist" or "GR agonist" refers to a compound that activates a glucocorticoid receptor. Glucocorticoid receptor agonists and methods of administering glucocorticoid receptor agonists to subjects are known in the art. See, for example, Pufall, MA, Adv Exp Med Biol. 872:315–333 (2015). Exemplary glucocorticoid receptor agonists include, but are not limited to, dexamethasone, hydrocortisone, corticosteroids, prednisolone, methylprednisolone, prednisone, triamcinolone, mapracorat, cyclosonepine, and (20S)-protopanaxadione. In one embodiment, the glucocorticoid receptor agonist is prednisone. In another embodiment, the glucocorticoid receptor agonist is dexamethasone.

[0538] As used herein, the term "immunomodulatory drug" or "IMiD" refers to a compound that inhibits the production of tumor necrosis factor, interleukin-6, immunoglobulin G, and / or VEGF, and / or co-stimulates T cells and NK cells, and / or increases the production of interferon-γ and interleukin-2. Immunomodulatory drugs and methods of administering immunomodulatory drugs to subjects 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.

[0539] As used herein, the term "proteasome inhibitor" refers to a compound that blocks the action of the proteasome, thereby preventing the degradation of pro-apoptotic factors such as p53 protein. Proteasome inhibitors and methods of administering proteasome inhibitors to subjects are known in the art. Exemplary proteasome inhibitors include, but are not limited to, bortezomib, carfilzomib, and esazomib. In one embodiment, the proteasome inhibitor is bortezomib.

[0540] As used herein, the term "Bcl-2 inhibitor" refers to a compound that inhibits the anti-apoptotic Bcl-2 protein. Bcl-2 inhibitors and methods of administering Bcl-2 inhibitors to subjects 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, venetumola (ABT-199), obatoclax, HA14-1, A-1155463, A-1331852, and WEHI-539. In one embodiment, the Bcl-2 inhibitor is venetumola.

[0541] As used herein, the term "pleiotropic pathway modulator" refers to a compound that binds to cereblon to promote protein degradation. Pleiotropic pathway modulators and methods of administering them to subjects are known in the art. See, for example, Hagner et al., Blood 126:779-789 (2017). A non-limiting exemplary pleiotropic pathway modulator is CC-122.

[0542] As used herein, the term "XPO1 inhibitor" refers to an inhibitor of export protein-1 (also known as a chromosomal region-stabilizing protein 1 homologue; CRM1). XPO1 inhibitors and methods of administering XPO1 inhibitors to subjects are known in the art. See, for example, Wang and Liu, Stem Cell Invest 6:6 (2019). A non-limiting exemplary XPO1 inhibitor is celiniso.

[0543] As used herein, the term "histone deacetylase inhibitor" or "HD inhibitor" refers to a compound that inhibits histone deacetylases. Histone deacetylase inhibitors and methods of administering them to a subject are known in the art. See, for example, Eckschlager et al., Int. J. Mol. Sci. 18:1414 (2017) doi:10.3390 / ijms18071414. Exemplary histone deacetylase inhibitors include, but are not limited to, romidesin, belipista, pabisostat, and vorinostat. In one embodiment, the histone deacetylase inhibitor is pabisostat.

[0544] As used herein, the term "EZH2 inhibitor" refers to a compound that inhibits the zeste gene enhancer homolog 2 enzyme. EZH2 inhibitors and methods of administering EZH2 inhibitors to subjects are known in the art. See, for example, Lue and Amengual, Curr Hematol Malig Rep 13:369–382 (2018). Exemplary EZH2 inhibitors include, but are not limited to, tazestat, EPZ011989, EPZ005687, GSK126, PF-06821497, and valemetostat. In one embodiment, the EZH2 inhibitor is tazestat.

[0545] This invention provides the following specific implementation schemes involving combination therapy (CT):

[0546] CT Implementation Scheme I. A method of treating a subject in need, the method comprising administering to the subject: (a) a therapeutically effective amount of the 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 pleiotropic pathway modulator, an XPO1 inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor, or a combination thereof; and the subject has cancer.

[0547] CT Implementation Scheme II. The method of CT Implementation Scheme I, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist.

[0548] CT Implementation Scheme III. The method of CT Implementation Scheme II, wherein the glucocorticoid receptor agonist is dexamethasone.

[0549] CT Implementation Scheme IV. The method of any one of CT Implementation Schemes I-III, wherein the second therapeutic agent comprises an immunomodulatory drug.

[0550] CT Implementation Scheme V. CT Implementation Scheme IV method, wherein the immunomodulatory drug is pomalidomide or lenalidomide.

[0551] CT Implementation Scheme VI. The method of any one of CT Implementation Scheme IV, wherein the second therapeutic agent comprises a proteasome inhibitor.

[0552] CT Implementation Scheme VII. The method of CT Implementation Scheme VI, wherein the proteasome inhibitor is bortezomib.

[0553] CT Implementation Scheme VIII. The method of any one of CT Implementation Schemes I-VII, wherein the second therapeutic agent comprises a Bcl-2 inhibitor.

[0554] CT Implementation Scheme IX. CT Implementation Scheme VIII method, wherein the Bcl-2 inhibitor is venetum.

[0555] CT implementation scheme X. The method of any one of CT implementation schemes I-IX, wherein the second therapeutic agent comprises a pleiotropic modulator.

[0556] CT Implementation Scheme XI. The method of CT Implementation Scheme X, wherein the pleiotropic modulator is CC-122.

[0557] CT Implementation Scheme XII. The method of any one of CT Implementation Schemes I-XI, wherein the second therapeutic agent comprises an XPO1 inhibitor.

[0558] CT Implementation Scheme XIII. The method of CT Implementation Scheme XII, wherein the XPO1 inhibitor is celiniso.

[0559] CT implementation scheme XIV. The method of any one of CT implementation schemes I-XIII, wherein the second therapeutic agent comprises a histone deacetylases inhibitor.

[0560] CT Implementation Scheme XV. CT Implementation Scheme XIV, wherein the histone deacetylase inhibitor is palbistat.

[0561] CT implementation scheme XVI. The method of any one of CT implementation schemes I-XV, wherein the second therapeutic agent is an EZH2 inhibitor.

[0562] CT Implementation Scheme XVII. CT Implementation Scheme XVI, wherein the EZH2 inhibitor is tazetine.

[0563] III. Treatment Methods

[0564] This disclosure generally relates to methods for treating a subject who has or may have a disease, condition, or disorder, the method comprising administering to the subject an effective amount of a compound of this disclosure and optionally a second therapeutic agent. In one embodiment, the disease, condition, or disorder is in response to or mediated by inhibition of the SETD2 protein by the compound of the invention.

[0565] In the treatment methods provided herein, the compounds of the present invention can be administered as a single agent to a subject suffering from cancer. The compounds of this disclosure can also be administered in combination with a second therapeutic agent to a subject suffering from cancer. The compounds of the present invention and the second therapeutic agent can be administered in combination under one or more of the following conditions: as separate pharmaceutical compositions, at different cycles, e.g., simultaneously or sequentially, at different durations, at different concentrations, via different routes of administration, etc. Additional optional therapeutic agents, such as anticancer agents, can also be administered to cancer patients.

[0566] This disclosure also relates to a method for inhibiting the SETD2 protein in a subject in need, the method comprising administering the subject a therapeutically effective amount of the compound of this disclosure.

[0567] On the one hand, this disclosure provides a method for treating a subject’s disease, disorder or ailment, including administering a therapeutically effective amount of the compound of this disclosure.

[0568] On the other hand, this disclosure provides methods for treating a subject’s disease, disorder or ailment, including administering a therapeutically effective amount of the compound of this disclosure in combination with a second therapeutic agent.

[0569] On the other hand, the present invention provides a method for treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of the present invention. In another aspect, the present invention provides a method for treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of the present invention in combination with a second therapeutic agent. Although not limited to a specific mechanism, in some embodiments, the compounds of the present disclosure treat cancer by inhibiting the SETD2 protein. Examples of treatable cancers include, but are not limited to, the cancers listed in Table 2.

[0570] Table 2

[0571]

[0572]

[0573]

[0574]

[0575] In another embodiment, the cancer is pancreatic cancer or esophageal cancer.

[0576] In another embodiment, the cancer is selected from esophageal cancer, kidney cancer, gastric cancer, hepatocellular carcinoma, glioblastoma, central nervous system (CNS) cancer, soft tissue cancer, lung cancer, breast cancer, bladder / urinary tract cancer, head and neck cancer, prostate cancer, blood cancer, pancreatic cancer, skin cancer, endometrial cancer, ovarian cancer, and colorectal cancer.

[0577] In another embodiment, the cancer or cancer cells are blood cancers. Exemplary blood cancers include, but are not limited to, the cancers listed in Table 3.

[0578] Table 3

[0579]

[0580] In another embodiment, the cancer is multiple myeloma.

[0581] In another embodiment, multiple myeloma is characterized by a chromosomal translocation at 14q32 involving an immunoglobulin heavy chain locus. In yet another embodiment, the chromosomal translocation is a t(4;14) translocation, i.e., the multiple myeloma is a t(4;14) multiple myeloma.

[0582] In another embodiment, the cancer is mantle cell lymphoma.

[0583] In another embodiment, the cancer is diffuse large B-cell lymphoma.

[0584] In another embodiment, the present invention provides a treatment method for regulating protein methylation, gene expression, cell proliferation, cell differentiation and / or apoptosis in vivo in the aforementioned cancers, which is achieved by administering a therapeutically effective amount of the disclosed compound to a subject requiring the treatment and optionally a second therapeutic agent.

[0585] The present invention provides the following specific embodiments, which relate to the compounds of the present invention, methods for treating cancer with the compounds of the present invention, and methods for treating cancer by combining the compounds of the present invention with a second therapeutic agent.

[0586] Implementation Scheme I. A method of treating a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound of the present disclosure and optionally, a second therapeutic agent, wherein the subject has cancer, and the second therapeutic agent is selected from glucocorticoid receptor agonists, immunomodulatory drugs, proteasome inhibitors, Bcl-2 inhibitors, pleiotropic modulators, XPO1 inhibitors, histone deacetylase inhibitors, and EZH2 inhibitors, or combinations thereof.

[0587] Implementation scheme II. The method of implementation scheme I, wherein the cancer is any one or more of the cancers in Table 2.

[0588] Implementation scheme III. The method of implementation scheme I, wherein the cancer is a blood cancer.

[0589] Implementation Scheme IV. The method of Implementation Scheme III, wherein the blood cancer is any one or more of the cancers in Table 3, for example, multiple myeloma.

[0590] Implementation scheme V. The method of implementation scheme IV, wherein the blood cancer is t(4;14) multiple myeloma.

[0591] Implementation Scheme VI. The method of any of Implementation Scheme IV further includes administering a therapeutically effective amount of a second therapeutic agent.

[0592] Implementation Scheme VII. A pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier for treating cancer, wherein the pharmaceutical composition comprising a compound of the present disclosure is optionally administered in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from glucocorticoid receptor agonists, immunomodulatory drugs, proteasome inhibitors, Bcl-2 inhibitors, pleiotropic modulators, XPO1 inhibitors, histone deacetylase inhibitors, and EZH2 inhibitors, or combinations thereof.

[0593] Implementation scheme VIII. The pharmaceutical composition of implementation scheme VII, wherein the cancer is any one or more of the cancers in Table 2.

[0594] Implementation scheme IX. Pharmaceutical composition of implementation scheme VII, wherein the cancer is a blood cancer.

[0595] Implementation Scheme X. The pharmaceutical composition of Implementation Scheme IX, wherein the blood cancer is any one or more of the cancers listed in Table 3, for example, multiple myeloma.

[0596] Implementation Scheme XI. The pharmaceutical composition of Implementation Scheme X, wherein the hematologic cancer is t(4;14) multiple myeloma.

[0597] Implementation Scheme XII. The compounds of this disclosure for the treatment of cancer, wherein the compounds of this disclosure are optionally administered in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from glucocorticoid receptor agonists, immunomodulatory drugs, proteasome inhibitors, Bcl-2 inhibitors, pleiotropic modulators, XPO1 inhibitors, histone deacetylase inhibitors and EZH2 inhibitors, or combinations thereof.

[0598] Implementation scheme XIII. The compound of implementation scheme XII for the stated use, wherein the cancer is any one or more of the cancers in Table 2.

[0599] Implementation scheme XIV. The compound of implementation scheme XII for the stated use, wherein the cancer is a blood cancer.

[0600] Implementation scheme XV. The compound of implementation scheme XIV for the said use, wherein the blood cancer is any one or more of the cancers in Table 3, for example, multiple myeloma.

[0601] Implementation scheme XVI. The compound of implementation scheme XV for the said use, wherein the blood cancer is t(4;14) multiple myeloma.

[0602] Implementation Scheme XVII. Use of the compounds of this disclosure in the preparation of a medicament for treating cancer, wherein the medicament is optionally administered in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from glucocorticoid receptor agonists, immunomodulatory drugs, proteasome inhibitors, Bcl-2 inhibitors, pleiotropic modulators, XPO1 inhibitors, histone deacetylase inhibitors, and EZH2 inhibitors, or combinations thereof.

[0603] Implementation scheme XVIII. Implementation scheme XVII, wherein the cancer is any one or more of the cancers listed in Table 2.

[0604] Implementation scheme XVIII. Use of implementation scheme XVII, wherein the cancer is a blood cancer.

[0605] Implementation scheme XIX. Use of implementation scheme XVII, wherein the blood cancer is any one or more of the cancers in Table 3, for example, multiple myeloma.

[0606] Implementation scheme XX. Use of implementation scheme XIX, wherein the blood cancer is t(4;14) multiple myeloma.

[0607] The use of any one of the following implementation schemes XXI, XVII-XX, which includes a second therapeutic agent.

[0608] Implementation scheme XXII. A kit comprising the compound of the present disclosure and an optional second therapeutic agent, and instructions for administering the compound of the present disclosure to a subject with cancer.

[0609] Implementation scheme XXIII. The kit of implementation scheme XXII, wherein the cancer is any one or more of the cancers in Table 2.

[0610] Implementation scheme XXIV. Implementation scheme XXII's kit, wherein the cancer is a blood cancer.

[0611] Implementation scheme XXV. Implementation scheme XXIV kit, wherein the blood cancer is any one or more of the cancers in Table 3, for example, multiple myeloma.

[0612] Implementation scheme XXVI. Implementation scheme XXV kit, wherein the hematologic malignancy is t(4;14) multiple myeloma.

[0613] Implementation scheme XXVII. The kit according to any one of implementation schemes XXII-XXVI, which further comprises a second therapeutic agent.

[0614] Implementation scheme XXVIII. Implementation scheme VI method, wherein the compound of this disclosure and the second therapeutic agent are administered simultaneously.

[0615] Implementation scheme XXIX. Implementation scheme VI method, wherein the compound of this disclosure and the second therapeutic agent are administered sequentially.

[0616] Implementation scheme XXX. A pharmaceutical composition according to any one of implementation schemes VII-XI, wherein the pharmaceutical composition is formulated for simultaneous administration of the compound of the present disclosure and the second therapeutic agent.

[0617] Implementation scheme XXXI. A pharmaceutical composition of any one of implementation schemes VII-XI, wherein the pharmaceutical composition is formulated for sequential administration of the compound of the present disclosure and the second therapeutic agent.

[0618] Implementation scheme XXXII. The compound of any one of implementation schemes XII-XVI, wherein the compound of this disclosure and the combination of the second therapeutic agent are administered simultaneously.

[0619] Implementation scheme XXXIII. The compound of any one of implementation schemes XII-XVI, wherein the compound of this disclosure and the combination of the second therapeutic agent are administered sequentially.

[0620] Implementation scheme XXXIV. Use of any one of implementation schemes XVII-XX, wherein the compound of this disclosure and the second therapeutic agent are administered simultaneously.

[0621] Implementation scheme XXXV. Use of any one of implementation schemes XVII-XX, wherein the combination of the compound of this disclosure and the second therapeutic agent is administered sequentially.

[0622] The present invention also provides the following specific embodiments.

[0623] Implementation Plan 1. A method for treating a subject in need, the method comprising administering to the subject a therapeutically effective dose of:

[0624] (a) Compounds of Formula I:

[0625]

[0626] in:

[0627] R1a is selected from halogens, alkyl groups, alkoxy groups, cycloalkyl groups, (hydroxy)alkyl groups, and (cycloalkyl)alkyl groups;

[0628] Q 1 Selected from -C(R) 1b = and –N=;

[0629] Q 2 Selected from -C(R) 1c = and –N=;

[0630] Q3 Selected from -C(R) 1d = and –N=;

[0631] The condition is that at least one of Q1, Q2, or Q3 is -C(R1b)=, -C(R1c)=, or -C(R1d)=;

[0632] R1b, R1c, and R1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy.

[0633] R1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0634] It can be a single bond or a double bond;

[0635] G 1 Selected from: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclic)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclic)alkyl; (heteroaryl)(formamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclic))(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

[0636] G2 is selected from hydrogen and alkyl groups; or

[0637] G1 and G2, together with the nitrogen atoms they are attached to, form optionally substituted heterocyclic groups.

[0638] 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,

[0639] Or its pharmaceutically acceptable salts or solvates; and

[0640] (b) Second therapeutic agent,

[0641] in:

[0642] 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.

[0643] Implementation Scheme 2. The method of Implementation Scheme 1, wherein the compound is a compound of Formula II:

[0644]

[0645] Or its pharmaceutically acceptable salts or solvates.

[0646] Implementation Scheme 3. The method of Implementation Scheme 1 or 2, wherein G1 is 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- to C8 cycloalkyl; (5- to 9-membered heteroaryl)C1- to C6 alkyl; (5- to 9-membered heteroaryl)(C6- 10 (aryl)C1-C4 alkyl; (5- to 9-membered heteroarylheteroaryl)(C3-C6 cycloalkyl)C1-C4 alkyl; and (C3-C6 cycloalkyl)C1-C4 alkyl,

[0647] Or its pharmaceutically acceptable salts or solvates.

[0648] Implementation Scheme 4. The method of Implementation Scheme 3, wherein the compound is a compound of Formula IV:

[0649]

[0650] in:

[0651] Z4 is selected from -O-, -C(R28a)(R28b)-, and -N(R23)-; or Z4 does not exist;

[0652] Z 5 Selected from -CH2- and -CH2CH2-;

[0653] R11a is selected from optionally substituted alkyl groups, optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, and -N(R12b)C(=O)R13c;

[0654] R12b is selected from hydrogen, alkyl, cycloalkyl and heterocyclic groups, (C1-C4 alkoxy)C1-C4 alkyl and (hydroxy)C1-C4 alkyl; and

[0655] R13c is selected from alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclic, amino, (amino)alkyl, (C3-C6 cycloalkyl)oxy and (4- to 8-membered heterocyclic)oxy.

[0656] R 23 Selected from hydrogen and C1-C4 alkyl; and

[0657] R 28a and R 28b Independently selected from hydrogen, alkyl, and halogen;

[0658] Or its pharmaceutically acceptable salts or solvates.

[0659] Implementation Scheme 5. The method of Implementation Scheme 4, wherein the compound is a compound of Formula IV-A:

[0660]

[0661] Or its pharmaceutically acceptable salts or solvates.

[0662] Implementation Scheme 6. The method of Implementation Scheme 4, wherein the compound is a compound of Formula IV-B:

[0663]

[0664] Or its pharmaceutically acceptable salts or solvates.

[0665] Implementation Scheme 7. The method of Implementation Scheme 4, wherein the compound is a compound of Formula IV-C:

[0666]

[0667] Or its pharmaceutically acceptable salts or solvates.

[0668] Implementation Scheme 8. The method of Implementation Scheme 4, wherein the compound is a compound of Formula IV-D:

[0669]

[0670] Or its pharmaceutically acceptable salts or solvates.

[0671] Implementation Plan 9. The method of any one of Implementation Plans 4-8, wherein:

[0672] R 11a Selected from:

[0673] (A) Unsubstituted 4- to 14-membered heterocyclic groups;

[0674] (B) Substituted 4- to 14-membered heterocycles having 1, 2, or 3 independent substituents selected from the following:

[0675] (i) -N(R 12a )C(=O)R 13a (ii) -C(=O)R 13b (iii) C1-C4 alkyl; (iv) (C1-C4 alkoxy)C1-C4 alkyl; (v) (hydroxy)C1-C4 alkyl; (vi) C1-C4 haloalkyl; (vii) amino; (vii) hydroxyl; (viii) -N(R 12a )S(=O)2R 24 ;(ix) -S(=O)2R 24 (x) Unsubstituted C3-C6 cycloalkyl; (xi) Substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; (xii) Unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; (xiii) -C(=NR) 60 )R 61 ; and (xiv) -C(=C-NO2)R 64 ;

[0676] (C) Unsubstituted 5- to 10-membered heteroaryl groups;

[0677] (D) Having 1, 2, 3 or 4 independently substituted 5- or 6-membered heteroaryl groups selected from the following: halogens and C1-C4 alkyl groups;

[0678] (E) C1-C6 alkyl; and

[0679] (F)-N(R 12b )C(=O)R 13c ;

[0680] R12a and R12b are each independently selected from hydrogen, C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl;

[0681] R13a, R13b, and R13c are each 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-C6 cycloalkyl. 10Aryl; (I) substituted C6-C 10 aryl group having 1, 2, 3, or 4 independently selected substituents 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 independently selected substituents 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 independently selected substituents from: 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

[0682] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[0683] R 60 Selected from cyano, nitro, hydroxy, C1-C6 alkoxy, -C(=O)R 62 and -S(=O)2R 62 ;

[0684] R 61 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[0685] R 62 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[0686] R 63a Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0687] R 63b Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or

[0688] R 63a and R 63b Together with the nitrogen atoms attached to them, they form 4- to 6-membered, optionally substituted heterocyclic groups;

[0689] R 64 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63c R 63d ;

[0690] R 63c Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0691] R63d Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or

[0692] R 63c and R 63d Together with the nitrogen atoms attached to them, they form 4- to 6-membered, optionally substituted heterocyclic groups.

[0693] Or its pharmaceutically acceptable salts or solvates.

[0694] Implementation Scheme 10. The method of Implementation Scheme 9, wherein R 11a The substituted 4- to 14-membered heterocyclic groups are selected from:

[0695]

[0696]

[0697]

[0698]

[0699] R 12a Selected from hydrogen, C1-C3 alkyl, (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl;

[0700] R 13a Selected from C1-C4 alkyl; amino; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from the following: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic group; and substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: amino, hydroxy and C1-C4 alkyl;

[0701] R 13b Selected from C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclic)oxy;

[0702] R 21Selected from hydrogen, -C(=O)R 13b C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted 4- to 14-membered heterocycles and -S(=O)2R 24 ;

[0703] R 22 It is a C1-C4 alkyl; an unsubstituted C3-C6 cycloalkyl; a substituted C3-C6 cycloalkyl having one or two independent substituents selected from the following: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; an unsubstituted 4- to 14-membered heterocyclic group; and a substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: amino, hydroxyl and C1-C4 alkyl;

[0704] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[0705] R 25 Selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;

[0706] R 25b and R 25c Independently selected from C1-C4 alkyl and C1-C4 haloalkyl;

[0707] R 26 Selected from unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; and

[0708] R 21a and R 25a Together with the atoms attached to them, they form optionally substituted 4- to 8-membered heterocyclic groups.

[0709] Or its pharmaceutically acceptable salts or solvates.

[0710] Implementation Scheme 11. The method of Implementation Scheme 9, wherein R 11a The substituted 4- to 14-membered heterocyclic groups are selected from:

[0711]

[0712]

[0713]

[0714]

[0715] R 27a and R 27bEach is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl;

[0716] R 27c Selected from hydrogen; -C(=O)R 13b C1-C4 alkyl; C1-C4 haloalkyl; unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; and -S(=O)2R 24 ;

[0717] R 27d Selected from hydrogen; C1-C4 alkyl; and C1-C4 haloalkyl;

[0718] R 13b Selected from C1-C4 alkyl; amino-C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxy, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic groups; substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxy and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclic)oxy; and

[0719] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl, or pharmaceutically acceptable salts or solvates thereof.

[0720] Implementation Scheme 12. The method of Implementation Scheme 11, wherein R 11a The substituted 4- to 14-membered heterocyclic groups are selected from:

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] Or its pharmaceutically acceptable salts or solvates.

[0727] Implementation Scheme 13. The method of Implementation Scheme 9, wherein R11a is a substituted 4- to 14-membered heterocyclic group selected from:

[0728]

[0729] Or its pharmaceutically acceptable salts or solvates.

[0730] Implementation Scheme 14. The method of any one of Implementation Schemes 4-13, wherein Z4 is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[0731] Implementation Scheme 15. The method of any one of Implementation Schemes 1-14, wherein R1d is fluorine, or a pharmaceutically acceptable salt or solvate thereof.

[0732] Implementation Scheme 16. The method of Implementation Scheme 1, wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0733] Implementation Scheme 17. The method of Implementation Scheme 1, wherein the compound is a compound of Table 1B, or a pharmaceutically acceptable salt or solvate thereof.

[0734] Implementation Scheme 18. The method of any one of Implementation Schemes 1-17, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist.

[0735] Implementation Scheme 19. The method of Implementation Scheme 18, wherein the glucocorticoid receptor agonist is dexamethasone.

[0736] Implementation Scheme 20. The method of any one of Implementation Schemes 1-19, wherein the second therapeutic agent comprises an immunomodulatory drug.

[0737] Implementation Scheme 21. The method of Implementation Scheme 20, wherein the immunomodulatory drug is pomalidomide or lenalidomide.

[0738] Implementation Scheme 22. The method of any one of Implementation Schemes 1-21, wherein the second therapeutic agent comprises a proteasome inhibitor.

[0739] Implementation Scheme 23. The method of Implementation Scheme 22, wherein the proteasome inhibitor is bortezomib.

[0740] Implementation Scheme 24. The method of any one of Implementation Schemes 1-23, wherein the second therapeutic agent includes a Bcl-2 inhibitor.

[0741] Implementation Scheme 25. The method of Implementation Scheme 24, wherein the Bcl-2 inhibitor is venetum.

[0742] Implementation Scheme 26. The method of any one of Implementation Schemes 1-25, wherein the second therapeutic agent comprises a pleiotropic modulator.

[0743] Implementation Scheme 27. The method of Implementation Scheme 26, wherein the pleiotropic pathway modulator is CC-122.

[0744] Implementation Scheme 28. The method of any one of Implementation Schemes 1-27, wherein the second therapeutic agent comprises an XPO1 inhibitor.

[0745] Implementation Scheme 29. The method of Implementation Scheme 28, wherein the XPO1 inhibitor is celiniso.

[0746] Implementation Scheme 30. The method of any one of Implementation Schemes 1-29, wherein the second therapeutic agent comprises a histone deacetylase inhibitor.

[0747] Implementation Scheme 31. The method of Implementation Scheme 30, wherein the histone deacetylase inhibitor is palbistat.

[0748] Implementation Scheme 32. The method of any one of Implementation Schemes 1-31, wherein the second therapeutic agent is an EZH2 inhibitor.

[0749] Implementation Scheme 33. The method of Implementation Scheme 32, wherein the EZH2 inhibitor is tazetan.

[0750] Implementation Scheme 34. The method of any one of Implementation Schemes 1-33, wherein the compound of Formula I and the second therapeutic agent are administered separately to the subject.

[0751] Implementation scheme 35. The method of any one of implementation schemes 1-34, wherein the subject is required to have cancer.

[0752] Implementation scheme 36. The method of implementation scheme 35, wherein the cancer is any one or more of the cancers in Table 2.

[0753] Implementation scheme 37. The method of implementation scheme 38, wherein the cancer is a blood cancer.

[0754] Implementation scheme 38. The method of implementation scheme 37, wherein the blood cancer is any one or more of the cancers in Table 3.

[0755] Implementation Scheme 39. A reagent kit comprising:

[0756] (a) Compounds of Formula I:

[0757]

[0758] in:

[0759] R1a is selected from halogens, alkyl groups, alkoxy groups, cycloalkyl groups, (hydroxy)alkyl groups, and (cycloalkyl)alkyl groups;

[0760] Q1 is selected from -C(R) 1b = and –N=;

[0761] Q2 is selected from -C(R) 1c = and –N=;

[0762] Q3 is selected from -C(R) 1d = and –N=;

[0763] The condition is that at least one of Q1, Q2, or Q3 is -C(R1b)=, -C(R1c)=, or -C(R1d)=;

[0764] R 1b R 1c and R 1d Each is independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy;

[0765] R 1e Selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[0766] It can be a single bond or a double bond;

[0767] G1 is selected from: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclic)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclic)alkyl; (heteroaryl)(formamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclic)alkyl (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

[0768] G2 is selected from hydrogen and alkyl groups; or

[0769] G1 and G2, together with the nitrogen atoms they are attached to, form optionally substituted heterocyclic groups.

[0770] 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,

[0771] Or its pharmaceutically acceptable salts or solvates; and

[0772] (b) Second therapeutic agent,

[0773] in:

[0774] 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 deacetylase inhibitors, or one or more EZH2 inhibitors, or combinations thereof.

[0775] Implementation Scheme 40. The kit of Implementation Scheme 39 further includes instructions for administering the compound of Formula I and the second therapeutic agent to a subject suffering from cancer.

[0776] Implementation Scheme 41. A compound selected from:

[0777] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0778] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aS,6aS)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0779] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aR,6aR)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0780] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aR,6aR)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0781] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0782] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aR,6aR)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[0783] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide; and

[0784] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aR,6aR)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide,

[0785] Or its pharmaceutically acceptable salts or solvates.

[0786] Implementation Scheme 42. A pharmaceutical composition comprising the compound of Implementation Scheme 41, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0787] Implementation Scheme 43. A method for treating a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound of Implementation Scheme 41, or a pharmaceutically acceptable salt or solvate thereof.

[0788] Implementation scheme 44. The method of implementation scheme 43, wherein the required subject has cancer.

[0789] Implementation Scheme 45. The method of Implementation Scheme 44, wherein the cancer is any one or more of the cancers listed in Table 2.

[0790] Implementation scheme 46. The method of implementation scheme 44, wherein the cancer is a blood cancer.

[0791] Implementation scheme 47. The method of implementation scheme 46, wherein the blood cancer is any one or more of the cancers in Table 3.

[0792] Implementation Scheme 48. The pharmaceutical composition of Implementation Scheme 43, which is used to treat a subject.

[0793] Implementation Scheme 49. The pharmaceutical composition of Implementation Scheme 48, wherein the subject has cancer.

[0794] Implementation Scheme 50. The pharmaceutical composition of Implementation Scheme 49, wherein the cancer is any one or more of the cancers listed in Table 2.

[0795] Implementation Scheme 51. The pharmaceutical composition of Implementation Scheme 49, wherein the cancer is a blood cancer.

[0796] Implementation Scheme 52. The method of Implementation Scheme 51, wherein the blood cancer is any one or more of the cancers in Table 3.

[0797] Implementation scheme 53. The compound of implementation scheme 41, which is used to treat a subject.

[0798] Implementation Scheme 54. The compound of Implementation Scheme 53 for the stated use, wherein the subject has cancer.

[0799] Implementation Scheme 55. The compound of Implementation Scheme 54 for the stated use, wherein the cancer is any one or more of the cancers listed in Table 2.

[0800] Implementation Scheme 56. The compound of Implementation Scheme 54 for the stated use, wherein the cancer is a blood cancer.

[0801] Implementation scheme 57. The method of implementation scheme 56, wherein the blood cancer is any one or more of the cancers in Table 3.

[0802] Implementation Scheme 58. Use of the compound of Implementation Scheme 21 in the preparation of a medicament for treating a subject.

[0803] Implementation scheme 59. Use of implementation scheme 58, wherein the subject has cancer.

[0804] Implementation scheme 60. Use of implementation scheme 59, wherein the cancer is any one or more of the cancers in Table 2.

[0805] Implementation Scheme 61. Use of Implementation Scheme 59, wherein the cancer is a blood cancer.

[0806] Implementation Scheme 62. Use of Implementation Scheme 61, wherein the blood cancer is any one or more of the cancers in Table 3.

[0807] Implementation Scheme 63. A kit comprising the compound of Implementation Scheme 41 and instructions for administering the compound to a subject.

[0808] Implementation scheme 64. The kit of implementation scheme 63, wherein the subject has cancer.

[0809] The compounds disclosed herein may be administered to a subject as a raw material chemical (without any other ingredients). The compounds disclosed herein may 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 may be selected from pharmaceutically acceptable excipients and adjuvants. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable delivery vehicle” includes any standard pharmaceutical carrier, solvent, surfactant, or delivery vehicle. Suitable pharmaceutically acceptable delivery vehicles include aqueous and non-aqueous delivery vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th edition, 1995.

[0810] Pharmaceutical compositions within the scope of this disclosure include all compositions in which the compounds of this disclosure are combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compounds of this disclosure are present in the composition in an amount that effectively achieves their intended therapeutic purpose. While individual needs may vary, the determination of the optimal range of effective amounts for each compound is within the scope of the art. Typically, the compounds of this disclosure can be orally administered daily to mammals, such as humans, at doses ranging from about 0.0025 to about 1500 mg / kg of mammalian body weight or equivalent pharmaceutically acceptable salts or solvates thereof to treat a specific disease. A useful oral dose of the compounds of this disclosure administered to mammals is from about 0.0025 to about 50 mg / kg of mammalian body weight or equivalent pharmaceutically acceptable salts or solvates thereof. For intramuscular injection, the dose is typically about half the oral dose.

[0811] A single oral dose may contain from about 0.01 mg to about 1 g of the compound disclosed herein, 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, from about 0.01 mg to about 50 mg, or, for example, from about 0.1 mg to about 10 mg of the compound. The unit dose may be administered once or more daily, 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.

[0812] The compounds disclosed herein, or pharmaceutical compositions comprising the compounds disclosed herein and optionally a second therapeutic agent, may be administered to any subject who may experience the beneficial effects of the compounds disclosed herein, such as cancer patients in need. Most importantly, these subjects are mammals, such as humans and companion animals, although this disclosure is not limited thereto. In one embodiment, the subject is a human.

[0813] The pharmaceutical compositions disclosed herein can be administered in any manner to achieve their intended purpose. For example, they can be administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, percutaneously, intranasally, transmucosally, rectally, vaginally, or orally, or by inhalation. The dosage and route of administration will vary depending on the specific subject and will take into account the subject's age, sex, health and weight, the condition or disorder to be treated, the type of concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect.

[0814] In one embodiment, the pharmaceutical composition disclosed herein can be administered orally. In another embodiment, the pharmaceutical composition disclosed herein can be administered orally and formulated as tablets, sugar-coated pills, capsules, or oral liquid preparations. In one embodiment, the oral formulation comprises extruded multigranules containing the compounds disclosed herein.

[0815] Alternatively, the pharmaceutical compositions disclosed herein may be administered rectally and formulated as suppositories.

[0816] Alternatively, the pharmaceutical compositions disclosed herein may be administered by injection.

[0817] Alternatively, the pharmaceutical compositions disclosed herein can be administered transdermally.

[0818] Alternatively, the pharmaceutical compositions disclosed herein may be administered by inhalation or by intranasal or transmucosal application.

[0819] Alternatively, the pharmaceutical compositions disclosed herein may be administered via the intravaginal route.

[0820] The pharmaceutical compositions disclosed herein may contain from about 0.01 to 99% by weight, for example from about 0.25 to 75% by weight, of the compounds disclosed herein, for example from 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.

[0821] In light of the present disclosure, the pharmaceutical compositions disclosed herein are manufactured in a manner known per se, such as by conventional methods of mixing, granulation, coating, dissolving, extrusion, or lyophilization. Therefore, oral pharmaceutical compositions can be obtained by combining these active compounds with solid excipients (optionally grinding the resulting mixture) and processing the granular mixture (after adding suitable adjuvants, if desired or necessary) to obtain tablets or sugar-coated cores.

[0822] Suitable excipients include sugars (e.g., lactose, sucrose, mannitol, or sorbitol), cellulose preparations, fillers such as calcium phosphates (e.g., tricalcium phosphate or dicalcium phosphate), and binders such as starch pastes (e.g., corn starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, one or more disintegrants may be added, such as the starches described above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts such as sodium alginate.

[0823] Excipients are typically flow conditioners and lubricants, such as silica, talc, stearic acid or its salts (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. The sugar-coated core provides a suitable coating resistant to gastric juices. For this purpose, concentrated sugar solutions can be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and a variety of suitable organic solvents or solvent mixtures. To produce a gastric juice-resistant coating, solutions of suitable cellulose formulations such as acetylcellulose phthalate or hydroxypropyl methylcellulose phthalate can be used. Dyes or colorants can be added to the tablet or sugar-coated core coating, for example, for identifying or characterizing combinations of active compound dosages.

[0824] Examples of other orally administered pharmaceutical formulations include push-fit capsules made of gelatin or sealed soft capsules made of gelatin and a plasticizer (such as glycerin or sorbitol). Push-fit capsules may contain compounds in granular form (which may be mixed with fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally with stabilizers), or in extruded multigranular form. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid, such as fatty oil or liquid paraffin. Stabilizers may also be added.

[0825] Pharmaceutical formulations suitable for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds and a suppository matrix. Suitable suppository matrices include natural and synthetic triglycerides, as well as alkanes. Gelatin rectal capsules, consisting of a combination of an active compound and a base material such as liquid triglycerides, polyethylene glycol, or alkanes, can also be used.

[0826] Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form (e.g., water-soluble salts, alkaline solutions, or acidic solutions). Alternatively, suspensions of the active compound can be prepared as oily suspensions. Suitable lipophilic solvents or carriers such as suspensions may include fatty oils (e.g., sesame oil), synthetic fatty acid esters (e.g., ethyl oleate), triglycerides, or polyethylene glycols such as polyethylene glycol 400 (PEG-400). Aqueous suspensions may contain one or more substances that increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. The suspension may also optionally contain stabilizers.

[0827] In some embodiments, the compounds of the present invention and the second therapeutic agent are administered to the subject as part of a single pharmaceutical composition.

[0828] In some embodiments, the compound of the present invention and the second therapeutic agent are administered to the subject in combination, for example, as two or more separate pharmaceutical compositions. For example, the second therapeutic agent may include one of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a pleiotropic pathway modulator, an XPO1 inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. In this case, the subject is given two separate pharmaceutical compositions—one containing the compound of the present invention and the other containing the second therapeutic agent. The second therapeutic agent may contain a combination of two of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a pleiotropic pathway modulator, an XPO1 inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. In this case, the subject is given three separate pharmaceutical compositions—one containing the compound of the present invention, one containing the first and second therapeutic agents, and one containing the second second therapeutic agent. Similarly, if the second therapeutic agent contains a combination of three or more of a glucocorticoid receptor agonist, an immunomodulatory drug, a proteasome inhibitor, a Bcl-2 inhibitor, a pleiotropic pathway modulator, an XPO1 inhibitor, a histone deacetylase inhibitor, or an EZH2 inhibitor. For example, individual drug compositions can be administered to subjects at different cycles, for different durations, or via different routes of administration.

[0829] In some embodiments, the compound of the present invention is administered to the patient before the administration of a second therapeutic agent, for example, 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.

[0830] In some embodiments, the compounds of the present invention are administered after a second therapeutic agent, for example, 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 administration of the second therapeutic agent.

[0831] In some embodiments, the disclosed compound and a second therapeutic agent are administered simultaneously.

[0832] In some embodiments, the compound of the present invention and the second therapeutic agent are administered simultaneously, but at different times. For example, the compound of the present invention 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.

[0833] In practice, doctors determine the most suitable dosing regimen for each individual patient, which can vary depending on the patient's age, weight, and response.

[0834] In another embodiment, this disclosure provides kits containing compounds of this disclosure (or compositions containing compounds of this disclosure), packaged in a manner that facilitates their use in carrying out the methods of this disclosure. In one embodiment, the kit comprises the compound of this disclosure (or a composition containing the compound of this disclosure) packaged in a container such as a sealed bottle or sealed tube, the kit having a label affixed to the container or included in the kit describing the use of the compound or composition for carrying out the methods of this disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may also include means suitable for administering the composition according to the intended route of administration. The kit may also include a second therapeutic agent. In some embodiments, the kit comprises the compound of this disclosure and a second therapeutic agent as separate pharmaceutical compositions.

[0835] IV. Biomarkers

[0836] In another embodiment, this disclosure provides a method for treating a subject with cancer such as multiple myeloma, the method comprising (a) determining the presence of a biomarker in a biological sample taken from the subject; and (b) if the biomarker is present in the biological sample, administering to the subject a therapeutically effective amount of the disclosed compound and optionally a second therapeutic agent. See, for example, 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, Neoplasia 50:31-40 (2003).

[0837] Biomarkers include, but are not limited to, cancers (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 another embodiment, the measurable aspect of a biomarker is its mutation status.

[0838] In one embodiment, the biomarker is WHSC1 / NSD2 / MMSET expression, which is differentially present in subjects with another phenotypic state (e.g., subjects with blood cancers) compared to subjects with one phenotypic state (e.g., normal, disease-free subjects or cancer patients who do not overexpress WHSC1 / NSD2 / MMSET). In another embodiment, the biomarker is overexpression of WHSC1 / NSD2 / MMSET.

[0839] Biomarker criteria can be predetermined, determined concurrently, or determined after obtaining biological samples from subjects. Biomarker criteria used with the methods described herein may, for example, include data from samples from subjects without cancer; data from samples from subjects with non-metastatic cancer (breast cancer); and data from samples from subjects with metastatic cancer (e.g., breast cancer). Comparisons can be made to establish predetermined threshold biomarker criteria for different categories of subjects (e.g., subjects with and without cancer). These criteria can be run in the same assay or can be known criteria from previously assayed studies.

[0840] If the mean or median expression or mutation level of a biomarker is found to be different between groups—that is, higher or lower—then the biomarker exists differentially between different phenotypic state groups. Therefore, biomarkers provide an indication of whether a subject (e.g., a cancer patient) belongs to one phenotypic state or another.

[0841] Any of the many 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 specific protein in a patient or biological sample and / or detecting WHSC1 / NSD2 / MMSET expression and / or chromosomal translocations, or the expression or mutation level of any other biomarker, can be used in the methods disclosed herein. Examples include, but are not limited to: PCR (polymerase chain reaction), or RT-PCR, flow cytometry, RNA blotting, Western blotting, ELISA (enzyme-linked immunosorbent assay), RIA (radioimmunoassay), gene chip analysis of RNA expression, immunohistochemistry, or immunofluorescence. See, for example, Slagle et al., Cancer 83:1401 (1998); Hudlebusch et al., Clin Cancer Res 17:2919-2933 (2011). Some embodiments of this disclosure include methods for determining the expression (transcription) of a biomarker RNA. Other embodiments of this disclosure include methods for determining protein expression in a biological sample. See, for example, 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 RNA blotting or RT-PCR analysis, RNA is isolated from tumor tissue samples using RNase-free techniques. Such techniques are well known in the art.

[0842] In one embodiment of this disclosure, a biological sample is obtained from a patient and the biological sample is measured to determine the expression or mutation status of a biomarker.

[0843] In one embodiment, this disclosure provides a method for treating a subject with cancer such as multiple myeloma, the method comprising: (a) determining whether a chromosomal translocation is present in a biological sample taken from the subject; and (b) if a chromosomal translocation is present in the biological sample, administering to the subject a therapeutically effective amount of the disclosed compound and optionally a second therapeutic agent.

[0844] In another embodiment, this disclosure provides a method for treating a subject with cancer such as multiple myeloma, the method comprising administering a therapeutically effective amount of the disclosed compound and optionally a second therapeutic agent to the subject having a chromosomal translocation.

[0845] In another embodiment, this disclosure provides a method comprising administering a therapeutically effective amount of the disclosed compound and an optional second therapeutic agent to a subject in need, wherein: (a) the subject has multiple myeloma; and (b) the multiple myeloma is characterized by having a chromosomal translocation.

[0846] In any of the above implementation schemes, the chromosomal translocation is a t(4;14) translocation.

[0847] In one embodiment, this disclosure provides a method for treating a subject with multiple myeloma, the method comprising: (a) determining whether overexpression of WHSC1 / NSD2 / MMSET is present in a biological sample taken from the subject; and (b) if overexpression of WHSC1 / NSD2 / MMSET is present in the biological sample, administering to the subject a therapeutically effective amount of the disclosed compound and optionally a second therapeutic agent.

[0848] In one embodiment, this disclosure provides a method for treating a subject with multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of the disclosed compound and, optionally, a second therapeutic agent, if overexpression of WHSC1 / NSD2 / MMSET is present in the subject.

[0849] In another embodiment, this disclosure provides a method comprising administering a therapeutically effective amount of the disclosed compound and an optional second therapeutic agent to a subject in need, wherein: (a) the subject has multiple myeloma; and (b) the multiple myeloma is characterized by overexpression of WHSC1 / NSD2 / MMSET.

[0850] V. Definition

[0851] The term "halogen" as used in this article, either on its own or as part of another group, refers to -Cl, -F, -Br, or -I.

[0852] The term "nitro" as used in this article, either on its own or as part of another group, refers to -NO2.

[0853] The term "cyano" as used herein, either on its own or as part of another group, refers to -CN.

[0854] The term "hydroxyl" as used in this article, either on its own or as part of another group, refers to -OH.

[0855] As used herein, the term "alkyl" either on its own or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing 1 to 12 carbon atoms, i.e., C1-C2. 12 Alkyl, or a specified number of carbon atoms, for example, C1 alkyl such as methyl, C2 alkyl such as ethyl, etc. In one embodiment, the alkyl group is C1-C2. 10 Alkyl group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C 12 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0856] As used herein, the term "optionally substituted alkyl" refers, either on its own or as part of another group, 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, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carbamate, carboxyl, alkoxycarbonyl, carboxylalkyl, -N(R 56a )C(=O)R 56b -N(R) 56c )S(=O)2R 56d -C(=O)R 57 -S(=O)R 56e -S(=O)2R 58 -N(R) 56a )C(=NR 60 )R 61 -N(R) 56a )C(=C-NO2)R 64 -C(=NR) 60 )R 61 or -C(=C-NO2)R 64 ;

[0857] in:

[0858] R 56a It is hydrogen or alkyl;

[0859] R 56bAlkyl, 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 heterocyclic, optionally substituted C6-C 10 Aryl, or optionally substituted heteroaryl;

[0860] R 56c It is hydrogen or alkyl;

[0861] R 56d 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 heterocyclic, optionally substituted C6-C 10 Aryl, or optionally substituted heteroaryl;

[0862] R 56e 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 heterocyclic, optionally substituted C6-C 10 Aryl, or optionally substituted heteroaryl;

[0863] R 57 It is a 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 heterocyclic, optionally substituted heteroaryl, (C3-C6 cycloalkyl)oxy, or (4- to 8-membered heterocyclic)oxy;

[0864] R 58 It is a 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 heterocyclic or optionally substituted heteroaryl.

[0865] R 60 Selected from cyano, nitro, hydroxy, C1-C6 alkoxy, -C(=O)R 62 and -S(=O)2R 62 ;

[0866] R 61Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[0867] R 62 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[0868] R 63a Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0869] R 63b Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or

[0870] R 63a and R 63b Together with the nitrogen atoms attached to them, they form 4- to 6-membered, optionally substituted heterocyclic groups;

[0871] R 64 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63c R 63d ;and

[0872] R 63c Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0873] R 63d Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or

[0874] R 63c and R 63d Together with the nitrogen atoms attached to them, they form 4- to 6-membered, optionally substituted heterocyclic groups.

[0875] In one embodiment, the optionally substituted alkyl group is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carbamate, carboxyl, alkoxycarbonyl, carboxylalkyl, -N(R 56a )C(=O)R 56b -N(R) 56c )S(=O)2R 56d -C(=O)R 57 -S(=O)R 56e , or -S(=O)2R 58 .

[0876] In another embodiment, the optionally substituted alkyl group has two substituents. In another embodiment, the optionally substituted alkyl group has one substituent. In another embodiment, the optionally substituted alkyl group is an optionally substituted C1-C6 alkyl group. In another embodiment, the optionally substituted alkyl group is an optionally substituted C1-C4 alkyl group. In one embodiment, the optionally substituted alkyl group is an optionally substituted C1 or C2 alkyl group. Non-limiting exemplary optionally substituted alkyl groups include -CH(CO2Me)CH2CO2Me and -CH(CH3)CH2N(H)C(=O)O(CH3)3.

[0877] As used herein, the term "alkenyl" refers, either on its own or as part of another group, to an alkyl group comprising one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is a C2-C6 alkenyl group. In another embodiment, the alkenyl group is a C2-C4 alkenyl group. In yet another embodiment, the alkenyl group has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0878] As used herein, the term "optionally substituted alkenyl" refers, either alone or as part of another group, to an alkenyl group that is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently a halogen, nitro, cyano, hydroxyl, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carboxyl, carboxylalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic. Non-limiting exemplary optionally substituted alkenyl groups include -CH=CHPh.

[0879] As used herein, the term "alkynyl" refers, either on its own or as part of another group, to an alkyl group comprising one, two, or three carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In another embodiment, the alkynyl group is a C1-C6 alkynyl group. In another embodiment, the alkynyl group is a C2-C4 alkynyl group. In yet another embodiment, the alkynyl group has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentyynyl, and hexynyl groups.

[0880] As used herein, the term "optionally substituted alkynyl" refers, either alone or as part of another group, to an alkynyl group that is unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently a halogen, nitro, cyano, hydroxyl, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carboxyl, carboxylalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic. Non-limiting exemplary optionally substituted alkynyl groups include -CH≡CHPh.

[0881] As used herein, the term "haloalkyl" refers, either on its own or as part of another group, to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two, or three fluorine atoms. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another 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 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.

[0882] As used herein, the term "hydroxyalkyl" or "(hydroxy)alkyl" refers, either on its own or as part of another group, to an alkyl group substituted with one, two, or three hydroxyl groups. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the hydroxyalkyl group 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-dihydroxypropyl-2-yl.

[0883] As used herein, the term "alkoxy" refers, either on its own or as part of another group, to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy groups.

[0884] The term "haloalkoxy" as used herein, either alone or as part of another group, refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6 alkyl group. In another embodiment, the haloalkyl group is a C1-C4 haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0885] As used herein, the term "alkyl thio" refers, either on its own or as part of another group, to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary alkyl thio groups include -SCH3 and -SCH2CH3.

[0886] As used herein, the term "alkoxyalkyl" or "(alkoxy)alkyl" refers, either on its own or as part of another group, to an alkyl group that substituted for an alkoxy group. In one embodiment, the alkoxy group is a C1-C6 alkoxy group. In another embodiment, the alkoxy group is a C1-C4 alkoxy group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl 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 pentyloxymethyl.

[0887] As used herein, the term "heteroalkyl" itself or part of another group refers to a stable straight-chain or branched hydrocarbon group containing 1 to 10 carbon atoms and at least two identical or different heteroatoms selected from O, N, or S, wherein the sulfur atom may optionally be oxidized. Heteratoms may be located at any internal position of the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule. In one embodiment, the heteroalkyl group contains two oxygen atoms. In another embodiment, the heteroalkyl group contains one oxygen atom and one nitrogen atom. In yet another embodiment, the heteroalkyl group contains two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -OCH2CH2NH2, -NHCH2CH2OCH3, and -OCH2CH2OCH3.

[0888] 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., C3- 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 another embodiment, the cycloalkyl is C3-8 cycloalkyl. In yet another embodiment, the cycloalkyl is C... 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].

[0889] 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 )R61 or -C(=C-NO2)R 64 ;where R 56a R 56b R 56c R 56d R 56e R 57 R 58 R 60 R 61 and R 64 As defined by the term "optionally substituted alkyl" and R 59 It is a (hydroxy)alkyl or (amino)alkyl group. Non-limiting exemplary substituted cycloalkyl groups include 3-(4-acetylpiperazin-1-yl)cyclohexyl, 3-(3-(N-methylacetamido)pyrrolidine-1-yl)cyclohexyl, 3-morpholinocyclohexyl, and 3-(pyrimidin-5-yl)cyclohexyl. In one embodiment, the optionally substituted cycloalkyl group is unsubstituted or substituted with 1, 2, or 3 substituents, wherein each substituent is 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 and -OR 59 .

[0890] As used herein, the term "heterocyclic group" refers, either directly or as part of another group, to saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic groups containing 3–14 ring members, i.e., 3–14-membered heterocycles containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to sulfoxide, i.e., S(=O), or sulfone, i.e., S(=O)2.

[0891] The term heterocyclic includes groups in which one or more -CH2- groups are replaced by one or more -C(=O)- groups, including cyclic urea groups such as imidazolidin-2-one, cyclic amide groups such as pyrrolidine-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidin-2-one.

[0892] The term heterocyclic also includes groups having fused optional substituted aryl or optional substituted heteroaryl groups, such as indoline, indoline-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H-benzo[d]azirate-heptadiene, or 1,3,4,5-tetrahydro-2H-benzo[d]azirate-heptadiene-2-one.

[0893] In one embodiment, the heterocyclic group is a 4-8 membered cyclic group containing one ring and one or two oxygen atoms, such as tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, such as pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, such as morpholine, and optionally, a -CH2- group is replaced by a -C(=O)- group, such as pyrrolidine-2-one or piperazine-2-one. In another embodiment, the heterocyclic group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, a -CH2- group is replaced by a -C(=O)- group. In another embodiment, the heterocyclic group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, a -CH2- group is replaced by a -C(=O)- group. In another embodiment, the heterocyclic group is an 8- to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocycle can be attached to the remainder of the molecule by any available carbon or nitrogen atom. Non-limiting exemplary heterocyclic groups include:

[0894]

[0895]

[0896]

[0897]

[0898] As used herein, the term "optionally substituted heterocycle" refers, either itself or as part of another group, to a heterocyclic group that is unsubstituted or substituted with one to four 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 ;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". Substitution can occur on any available carbon or nitrogen atom of the heterocyclic group. In one embodiment, the optionally substituted heterocycle is unsubstituted or substituted with 1 to 4 substituents, wherein each substituent is 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 -OR 59 .

[0899] Non-limiting exemplary alternatively substituted heterocyclic groups include:

[0900]

[0901] .

[0902] The term "aryl" as used alone or as part of another group in this article refers to an aromatic ring system having 6 to 14 carbon atoms, i.e., C6-C6. 14 Aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthraceneyl, indene, azulel, biphenyl, biphenylenyl, and fluorenyl. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0903] As used herein, the term "optionally substituted aryl" refers, either alone or as part of another group, to an aryl group that is unsubstituted or substituted with 1 to 5 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 ;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 aryl group is unsubstituted or substituted with 1 to 5 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 -OR 59 .

[0904] 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 yet another embodiment, the optionally substituted phenyl group has one substituent. Non-limiting exemplary 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 an aryl group having a fused optional substituted cycloalkyl group and a fused optional substituted heterocyclic group. Non-limiting examples include: 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphth-1-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azacycloheptanetrien-2-yl, 1,2,3,4-tetrahydroisoquinoline-1-yl and 2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azacycloheptanetrien-1-yl.

[0905] As used herein, the term "heteroaryl" refers, either on its own or as part of another group, to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members, i.e., 5- to 14-membered heteroaryls containing 1, 2, 3, or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, such as a thiophene group, a 5-membered heteroaryl having 4 carbon atoms and 1 sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, such as a pyridyl group, a 6-membered heteroaryl having 5 carbon atoms and 1 nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianyl, furanyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazinoneyl, chromenyl, xanthonyl, 2H-pyrroleyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, inzolyl, purinel, isoquinolinyl, quinolinyl, phthalazinyl, naphridinyl, cinolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbazolyl, phenanthridineyl, acridineyl, pyrimidinyl, phenanthridineyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazinyl, and phenothiazinyl. 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-imidazo-2-yl and 2H-imidazo-4-yl), pyrazolel (e.g., 1H-pyrazole-3-yl, 1H-pyrazole-4-yl and 1H-pyrazole-5-yl), and pyridyl (e.g., pyridin-2-yl, pyridine). The terms heteroaryl also include N-oxides. A non-limiting exemplary N-oxide is a pyrimidinyl N-oxide.

[0906] 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 1 to 4 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 -OR 59 .

[0907] 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.

[0908] As used herein, the term "aryloxy group" refers, either on its own or as part of another group, to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0909] The term "heteroaryloxy" as used herein, either on its own or as part of another group, refers to an optionally substituted heteroaryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is pyridinyl-O-.

[0910] As used herein, the term "aralkyloxy" refers, either on its own or as part of another group, to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.

[0911] As used herein, the term "(cycloalkyl)oxy" refers, either on its own or as part of another group, to a cycloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary cycloalkyloxy groups include:

[0912] .

[0913] As used herein, the term "(heterocyclic)oxy group" refers, either on its own or as part of another group, to a heterocyclic group attached to a terminal oxygen atom. Non-limiting exemplary (heterocyclic)oxy groups include:

[0914] .

[0915] As used herein, the term "(cyano)alkyl" refers, either on its own or as part of another group, 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-C6 alkyl group. In yet another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0916] As used herein, the term "(cycloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has been substituted with an optionally substituted cycloalkyl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl. In another embodiment, the alkyl group is a C1-C6 alkyl. In another embodiment, the alkyl group is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. Non-limiting exemplary (cycloalkyl)alkyl groups include:

[0917]

[0918] The term "sulfonamide group" as used herein, either on its own or as part of another group, refers to the formula -SO2NR. 50a R 50b The group, wherein R 50a and R 50b Each of the following groups is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R50a and R50b together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary sulfonamide groups include -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.

[0919] As used herein, the term "alkyl carbonyl" refers, either on its own or as part of another group, to a carbonyl group, i.e., -C(=O)-, which is substituted with an alkyl group. In one embodiment, the alkyl group is a C1-C4 alkyl group. A non-limiting exemplary alkyl carbonyl group is -COCH3.

[0920] As used herein, the term "aryl carbonyl" refers, either on its own or as part of another group, to a carbonyl group, i.e., -C(=O)-, which is optionally substituted with an aryl group. A non-limiting exemplary aryl carbonyl group is -COPh.

[0921] As used herein, the term "alkylsulfonyl" refers, either on its own or as part of another group, to a sulfonyl group, i.e., -SO2-, which is substituted with an alkyl group. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.

[0922] As used herein, the term "arylsulfonyl" refers, either on its own or as part of another group, to a sulfonyl group, i.e., -SO2-, which is optionally substituted with an aryl group. A non-limiting exemplary arylsulfonyl group is -SO2Ph.

[0923] The term "mercaptoalkyl" as used in this article, either on its own or as part of another group, refers to an alkyl group that has been substituted with –SH.

[0924] The term "carboxyl group" as used in this article, either on its own or as part of another group, refers to a group of the formula -C(=O)OH.

[0925] As used herein, the term "ureido" itself, or as part of another group, refers to a group of the formula -NR51a-C(=O)-NR51bR51c, wherein R51a is hydrogen or alkyl; and R51b and R51c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl, or R51b and R51c together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary ureido groups include -NH-C(C=O)-NH2 and -NH-C(C=O)-NHCH3.

[0926] As used herein, the term "guanidinyl" itself, or as part of another group, refers to a group of the formula -NR52a-C(=NR53)-NR52bR52c, wherein R52a is hydrogen or alkyl; R52b and R53c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; or R52b and R52c together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclic group; and R53 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, formamido, or sulfonamide. Non-limiting exemplary guanidinyl groups include -NH-C(C=NH)-NH2, -NH-C(C=NCN)-NH2, and -NH-C(C=NH)-NHCH3.

[0927] As used herein, the term "(heterocyclic)alkyl" refers, either on its own or as part of another group, to an alkyl group substituted with one, two, or three optionally substituted heterocyclic groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 8-membered heterocyclic group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In yet another embodiment, the alkyl group is a C1-C4 alkyl group. The heterocyclic group may be attached to the alkyl group via a carbon or nitrogen atom. Non-limiting exemplary (heterocyclic)alkyl groups include:

[0928]

[0929] As used herein, the term "carbamate group" refers, either on its own or as part of another group, to a group of the formula -NR54a-C(=O)-OR54b, wherein R54a is hydrogen or alkyl, and R54b is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting exemplary carbamate group is -NH-(C=O)-OtBu.

[0930] As used herein, the term "(heteroaryl)alkyl" refers, either on its own or as part of another group, to an alkyl group that is 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 C1-C6 alkyl. In another embodiment, the alkyl group is C1-C4 alkyl. In another embodiment, the alkyl group is C1 or C2 alkyl. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0931] .

[0932] As used herein, the term "(heteroaryl)(aryl)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted heteroaryl group and an optionally substituted aryl group. In one embodiment, the heteroaryl group is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl group is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the aryl group is an optionally substituted phenyl group or an optionally substituted naphthyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another 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 (heteroaryl)(aryl)alkyl groups include:

[0933]

[0934] As used herein, the term "(heteroaryl)(heterocyclic)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted heteroaryl group and an optionally substituted heterocyclic group. In one embodiment, the heteroaryl group is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl group is an optionally substituted 5- or 6-membered heteroaryl 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 alkyl group is a C1-C6 alkyl group. In another 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 (heteroaryl)(heterocyclic)alkyl groups are:

[0935] .

[0936] As used herein, the term "(heteroaryl)(formamido)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted heteroaryl group and a formamido group. In one embodiment, the heteroaryl group is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl group is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group. Non-limiting exemplary (heteroaryl)(formamido)alkyl groups include:

[0937] .

[0938] As used herein, the term "formamido" refers, either on its own or as part of another group, to a group of the formula -C(=O)NR55aR55b, wherein R55a and R55b 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 heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclic)alkyl, or (heteroaryl)alkyl; or R55a and R55b together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclic group. Non-limiting exemplary formamide groups include: morpholine-4-carbonyl, N,N-dimethylaminocarbonyl, N-(1-methylpiperidin-4-yl)aminocarbonyl, 4-methylpiperazin-1-carbonyl, N-(3-aminocyclopentyl)aminocarbonyl, N-(pyridin-3-yl)aminocarbonyl, and N-(tetrahydrofuran-3-yl)aminocarbonyl.

[0939] As used herein, the term "(heteroaryl)(cycloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted heteroaryl group and an optionally substituted cycloalkyl group. In one embodiment, the heteroaryl group is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl group is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group. Non-limiting exemplary (heteroaryl)(C3-C6 cycloalkyl)alkyl groups are:

[0940] .

[0941] As used herein, the term "(aryl)(alkoxycarbonyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted aryl group and an alkoxycarbonyl 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-C6 alkyl group. In another 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 (aryl)(alkoxycarbonyl)alkyl groups are:

[0942] .

[0943] As used herein, the term "alkoxycarbonyl" refers, either on its own or as part of another group, to a carbonyl group, i.e., -C(=O)-, which is substituted with a C1-C6 alkoxy group. In one embodiment, the alkoxy group is a C1-C4 alkoxy group. In another embodiment, the alkoxy group is a C1-C3 alkoxy group. Non-limiting exemplary alkoxycarbonyl groups include -CO2-Me and -CO2Et.

[0944] As used herein, the term "(heteroaryl)(amino)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one optionally substituted heteroaryl group and one amino group. In one embodiment, the heteroaryl group is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl group is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another 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 (heteroaryl)(amino)alkyl groups are:

[0945] .

[0946] As used herein, the term "(cycloalkyl)(alkoxycarbonyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one optionally substituted cycloalkyl group and one alkoxycarbonyl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In yet another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (cycloalkyl)(alkoxycarbonyl)alkyl groups are:

[0947] .

[0948] As used herein, the term "(heteroaryl)(alkoxycarbonyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted heteroaryl group and an alkoxycarbonyl group. In one embodiment, the heteroaryl group is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl group is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another 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 (heteroaryl)(alkoxycarbonyl)alkyl groups include:

[0949] and .

[0950] As used herein, the term "(heterocyclic)(cycloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for an optionally substituted heterocyclic group and an 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 (heterocyclic)(cycloalkyl)alkyl groups are:

[0951] .

[0952] As used herein, the term "(aryl)(cycloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one optionally substituted aryl group and one optionally substituted cycloalkyl 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 cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another 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 (aryl)(cycloalkyl)alkyl groups are:

[0953] .

[0954] As used herein, the term "arylalkyl" or "(aryl)alkyl" refers, either alone or as part of another group, to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted aryl group. In another embodiment, the alkyl group is substituted with two optionally substituted aryl groups. In one embodiment, the aryl group is an optionally substituted phenyl 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-C6 alkyl group. In another 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 (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0955] As used herein, the term "(aryl)(hydroxy)alkyl" refers, either on its own or as part of another group, to an alkyl group that is substituted with an optionally substituted aryl group and a hydroxyl 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-C6 alkyl group. In another 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 (aryl)(hydroxy)alkyl groups include:

[0956] and

[0957] As used herein, the term "(cycloalkyl)(hydroxy)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one optionally substituted cycloalkyl group and one hydroxyl group. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In yet another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (cycloalkyl)(hydroxy)alkyl groups are:

[0958] .

[0959] As used herein, the term "(alkoxycarbonyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that substitutes for one or two alkoxycarbonyl groups. 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)alkyl groups are:

[0960] .

[0961] As used herein, the term "(aryl)(haloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that is substituted with an optionally substituted aryl group and a haloalkyl group. In one embodiment, the aryl group is an optionally substituted 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-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 (aryl)(haloalkyl)alkyl groups are:

[0962] .

[0963] As used herein, the term "(cycloalkyl)(haloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has 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:

[0964] .

[0965] As used herein, the term "(hydroxy)(haloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one hydroxyl group and one haloalkyl group substituted. In one embodiment, the haloalkyl group is a C1-C4 haloalkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In yet another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (hydroxy)(haloalkyl)alkyl groups are:

[0966] .

[0967] As used herein, the term "(alkoxycarbonyl)(haloalkyl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one alkoxycarbonyl group and one haloalkyl group substituted. In one embodiment, the haloalkyl group is a C1-C4 haloalkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In yet another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (alkoxycarbonyl)(haloalkyl)alkyl groups are:

[0968] .

[0969] As used herein, the term "(formamido)alkyl" refers, either on its own or as part of another group, to an alkyl group substituted with a formamido 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 (formamido)alkyl groups include -CH2C(=O)NH2, -C(H)(CH3)C(=O)NH2, -CH2C(=O)N(H)CH3, and -CH2C(=O)N(CH3)2.

[0970] As used herein, the term "(carboxy)alkyl" refers, either on its own or as part of another group, to an alkyl group substituted with -C(=O)OH. 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. A non-limiting exemplary (carboxy)alkyl group is -CH2CO2H.

[0971] As used herein, the term "(amino)(hydroxy)alkyl" refers, either on its own or as part of another group, to an alkyl group that has one hydroxyl group and one amino group substituted for it. In one embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary "(amino)(hydroxy)alkyl" groups include:

[0972] .

[0973] As used herein, the term "(amino)(aryl)alkyl" refers, either on its own or as part of another group, to an alkyl group that has an amino group and an optionally substituted aryl group. In one embodiment, the amino group is -NH2, an alkylamino, or a dialkylamino. In one embodiment, the aryl group is an optionally substituted phenyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. Non-limiting exemplary (amino)(aryl)alkyl groups include:

[0974]

[0975] As used herein, the term "amino" itself or as part of another group refers to the group of formula -NR55aR55b, wherein R55a and R55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclic)alkyl, or (heteroaryl)alkyl.

[0976] In one embodiment, the amino group is -NH2.

[0977] In another embodiment, the amino group is an "alkylamino group", that is, the following amino group, wherein R 55a C1-6 alkyl and R 55b It is hydrogen. In one implementation, R 55a It is a C1-C4 alkyl group. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0978] In another embodiment, the amino group is a "dialkylamino", that is, the following amino group, wherein R 55a and R55b Each is independently a C1-6 alkyl group. In one embodiment, R 55a and R 55b Each is independently a C1-C4 alkyl group. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0979] In another embodiment, the amino group is a "hydroxyalkylamino group", that is, the following amino group, wherein R 55a (hydroxy)alkyl and R 55b It is hydrogen or C1-C4 alkyl.

[0980] In another embodiment, the amino group is a "cycloalkylamino group", that is, the following amino group, wherein R 55a Optionally substituted cycloalkyl and R 55b It is hydrogen or C1-C4 alkyl.

[0981] In another embodiment, the amino group is an "arylamino group", that is, the following amino group, wherein R 55a Aryl and R 55b It is hydrogen or C1-C4 alkyl. Non-limiting exemplary aryl alkyl amino groups include -N(H)CH2Ph, -N(H)CHPh2 and -N(CH3)CH2Ph.

[0982] In another embodiment, the amino group is "(cycloalkyl)alkylamino", that is, the following amino group, wherein R 55a (Cycloalkyl)alkyl and R 55b It is hydrogen or C1-C4 alkyl. Non-limiting exemplary (cycloalkyl) alkylamino groups include:

[0983] and .

[0984] In another embodiment, the amino group is a "(heterocyclic)alkylamino" group, that is, the following amino groups, wherein R 55a (Heterocyclic)alkyl and R 55b It is hydrogen or C1-C4 alkyl. Non-limiting exemplary (heterocyclic) alkylamino groups include:

[0985] and .

[0986] As used herein, the term "(amino)alkyl" refers, either on its own or as part of another group, to an alkyl group that has been substituted with an amino group. In one embodiment, the amino group is -NH2. In one embodiment, the amino group is an alkylamino group. In another embodiment, the amino group is a dialkylamino group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. 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).

[0987] This disclosure includes any of the compounds disclosed herein that are isotopically labeled (i.e., radiolabeled), which is achieved by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that may be included in the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, for example, 3H, 11C, and 14C. In one embodiment, a composition is provided in which substantially all atoms at positions within the compounds disclosed herein 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 at positions within the compounds disclosed herein are replaced, i.e., the compounds disclosed are enriched at positions of atoms having different atomic masses or mass numbers. The isotopically labeled compounds of this disclosure can be prepared by methods known in the art.

[0988] The compounds disclosed herein may contain one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomers. This disclosure covers all such possible forms, as well as their racemic and resolved forms and the use of mixtures thereof. In view of this disclosure, individual enantiomers can be isolated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise indicated, it is intended that they include both E and Z geometric isomers. This disclosure covers all tautomers.

[0989] As used herein, the term "stereoisomer" is a general term for all isomers of a single molecule that differ only in the spatial orientation of their atoms. It includes enantiomers and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).

[0990] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom that is attached to four different groups.

[0991] The terms “enantiomer” and “enantiomer” refer to molecules that cannot be superimposed on their mirror image and are therefore optically active, wherein the enantiomer rotates the plane of polarization in one direction and its mirror compound rotates the plane of polarization in the opposite direction.

[0992] The term "racemic" refers to a mixture of equal parts of enantiomers that is optically inactive. In one embodiment, the compound disclosed herein is racemic.

[0993] The term "absolute configuration" refers to the spatial arrangement (e.g., R or S) of the atoms of a chiral molecular entity (or group) and their stereochemical description.

[0994] Stereochemical terms and conventions used in this specification are intended to be consistent with Pure & Appl. Chem 68:2193 (1996) unless otherwise stated.

[0995] The term "enantiomer excess" or "ee" refers to a measure of the amount of one enantiomer present compared to another. For a mixture of R and S enantiomers, the enantiomer excess percentage is defined as |R - S| * 100, where R and S are each the molar or weight fraction of the enantiomers in the mixture such that R + S = 1. By knowing the optical rotation of the chiral substance, the enantiomer excess percentage is defined as ([α]obs / [α]max) * 100, where [α]obs is the optical rotation of the enantiomer mixture, and [α]max is the optical rotation of the pure enantiomer. Enantiomer excess can be determined using various analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarization.

[0996] In one embodiment, the disclosed compound having one or more chiral centers is enriched in enantiomers, for example, 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%.

[0997] The term "a" or "an" refers to one or more or more types of things.

[0998] As used in this article, the term "about" includes ±10% of the listed values. Therefore, "about 10" means 9 to 11.

[0999] As used herein, the terms "treat," "treating," or "treatment" refer to the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treating a disease or condition does not require the complete elimination of the disease, condition, or its associated symptoms. As used herein, the terms "treat," "treating," or "treatment" may include "preventive treatment," which refers to reducing the likelihood of the recurrence of a disease or condition or a previously controlled disease or condition in a subject who does not have a disease or condition but is at risk of recurrence or a relapse of such a disease or condition. The term "treat" and its synonyms are considered in relation to the administration of a therapeutically effective amount of the compound disclosed herein to an individual in need of such treatment.

[1000] Within the meaning of this disclosure, "treatment" also includes relapse prevention or stage prevention, as well as treatment of acute or chronic signs, symptoms, and / or dysfunctions. For example, treatment can be symptom-oriented, thereby suppressing symptoms. It can be achieved over a short period, oriented for a moderate period, or, for example, be long-term treatment in the context of maintenance therapy.

[1001] As used herein, the terms "therapeutic effective amount" or "effective dose" refer to the amount of one or more active ingredients sufficient, when administered by the methods disclosed herein, to effectively deliver one or more active ingredients for treating a condition or disease of interest to an individual in need. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent may reduce (i.e., slow down and preferably stop) undesirable cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and preferably stop) tumor metastasis; inhibit tumor growth to some extent; regulate protein methylation in target cells; and / or alleviate one or more symptoms associated with cancer to some extent. The administered compound or composition may be cytoseptic and / or cytotoxic, providing some degree of protection against the growth of existing cancer cells and / or killing existing cancer cells.

[1002] The term "container" refers to any container and closure suitable for storing, transporting, dispensing and / or handling pharmaceuticals.

[1003] The term "instructions for use" refers to the information accompanying a pharmaceutical product that provides instructions on how to administer the product, along with safety and efficacy data necessary for physicians, pharmacists, and patients to make informed decisions regarding the use of the product. Instructions for use are often considered the "label" for pharmaceutical products.

[1004] The terms "disease," "symptom," or "disorder" refer to disturbances and / or abnormalities that are generally considered to be in a pathological state or function and can manifest themselves in the form of specific signs, symptoms, and / or functional impairments. The compounds disclosed herein inhibit the SETD2 protein and can be used to treat diseases and conditions, such as proliferative disorders, where inhibition of the SETD2 protein provides benefit. See, for example, US Patent Publication No. 62 / 545,353.

[1005] In some embodiments, the compounds disclosed herein can be used to treat “SETD2 protein-mediated disorders.” SETD2 protein-mediated disorders are any pathological conditions in which the SETD2 protein is known to play a role. In some embodiments, the SETD2-mediated disorder is a proliferative disorder.

[1006] In some embodiments, inhibition of the SETD2 protein is the inhibition of one or more activities of the SETD2 protein. In some embodiments, the activity of the SETD2 protein is the ability of the SETD2 protein to transfer methyl groups to a target protein (e.g., histone). It should be understood that the activity of SETD2 can be inhibited in vitro or in vivo. Exemplary levels of SETD2 activity inhibition 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.

[1007] As used herein, the term "biological sample" refers to any tissue or fluid from a subject suitable for detecting chromosomal translocations. Examples of useful biological samples include, but are not limited to, biopsy tissues and / or cells (e.g., solid tumors, lymph nodes, inflamed tissue, tissues and / or cells related to a condition or disease), blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebrospinal fluid, etc. Other suitable biological samples will be familiar to those skilled in the art. Chromosomal translocations in biological samples can be analyzed 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 cytoplasmic light chain immunofluorescence (cIg-FISH) combined with fluorescence in situ hybridization. Biological samples can be obtained using techniques entirely within the scope of clinical common sense. In one embodiment of this disclosure, the biological sample comprises blood cells.

[1008] The phrase "combination" in relation to the administration of the compounds and second therapeutic agents of the present invention to a subject means that the compounds and second therapeutic agents of the present invention may be administered to a subject together, for example, as part of a single pharmaceutical composition or formulation, or separately, for example, as part of two or more separate pharmaceutical compositions or formulations. Therefore, the phrase "combination" in relation to the administration of the compounds and second therapeutic agents of the present invention to a subject is intended to include sequential administration of the compounds and second therapeutic agents of the present invention, wherein the compounds and second therapeutic agents of the present invention are administered to the subject at different times, and simultaneously or substantially simultaneously. For example, simultaneous administration can be achieved by administering a single capsule containing a fixed proportion of each compound and second therapeutic agent of the present invention to the subject, or by administering multiple single capsules for each compound and second therapeutic agent of the present invention. Sequential or substantially simultaneous administration of the compounds and second therapeutic agents of the present invention can be achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The compounds and second therapeutic agents of the present invention can be administered via the same or different routes. For example, the combined second therapeutic agent can be administered intravenously, while the combined compounds of the present disclosure can be administered orally. Alternatively, for example, both the compounds and second therapeutic agents of the present invention can be administered orally, or both can be administered intravenously. The compound and the second therapeutic agent of the present invention can also be administered alternately. In one embodiment, the compound and the second therapeutic agent of the present invention are given to the subject separately, for example, as part of two or more separate pharmaceutical compositions or formulations.

[1009] General synthesis of compounds

[1010] The compounds of this disclosure are prepared using the methods disclosed in PCT / US2019 / 046569 or by the illustrative methods shown in the following general scheme. In the general scheme, R1d, R2b, R2d, R2e, A1, A2, R11a, R14a, R14b, R19, R20, G, Z4, and q are as defined with respect to formulas II, III, IV, V, or VI, unless otherwise indicated. In any general scheme, suitable protecting groups may be used in the synthesis, for example when Z is an (amino)alkyl group or any other group that may require protection, or when R... 8 When it is an amino, (amino)alkyl, or any other group that may require protection. (See Wuts PGM and TWGreene, “Greene’s Protective Groups in Organic Synthesis,” 4th ed., J. Wiley & Sons, NY, 2007), unless otherwise indicated.

[1011] In general scheme 1, an arylhydrazine having formula (1) is reacted with ethyl 2-oxopropionate 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 indole-2-carboxylic acid having formula (4). In step 4, the compound having formula (4) is reacted with G under standard coupling conditions. 1 The NH2 reaction yields a compound having formula II.

[1012] General Solution 1

[1013]

[1014] In General Scheme 2, the compound of formula (5) reacts with R2b-H, where R2b is a heterocyclic group, for example, R2b-H is piperidine or an amine, for example, R2b-H is dimethylamine, to give the compound of formula (6). The nitro group of the compound of formula (6) is reduced to give the compound of formula (7). In step 3, the compound of formula (7) reacts with the compound of formula (4) under standard coupling conditions, see General Scheme 1, to give the compound of formula III, where A1 and A2 are CH, and R2b is an optionally substituted heterocyclic group or an amino group.

[1015] General Solution 2

[1016]

[1017] (where A) 1 and A 2 It is CH; and R 2b (Optionally substituted heterocyclic or amino groups)

[1018] In general scheme 3, the compound of formula (8) and R 2b -H reaction, where R 2b It is a heterocyclic group, for example, R 2b -H is piperidine or amine, for example, R 2b -H is dimethylamine, yielding the compound of formula (9). In step 2, the compound of formula (9) reacts with the compound of formula (10) to yield the compound of formula III, wherein A 1 and / or A 2 It is N, R 2b It can be an optionally substituted heterocyclic group or amino group.

[1019] General Solution 3

[1020]

[1021] (where A) 1 and / or A 2 Let N be the number of elements and R be the number of elements. 2b(Optionally substituted heterocyclic or amino groups)

[1022] In general scheme 4, the compound of formula (11) and R 11a -H reaction, where R 11a It is a heterocyclic group, such as R 11a -H is piperidine, yielding the compound of formula (12). In step 2, the Cbz group is removed to yield the compound of formula (13). The compound of formula (13) is coupled with the compound of formula (4) to yield the compound of formula IV, wherein R 11a It is an optional substituted heterocyclic group, Z 5 It is -CH2-.

[1023] General Solution 4

[1024]

[1025] (where R) 11a The heterocyclic group is optionally substituted; and Z 5 (for CH2)

[1026] In step 1 of general scheme 5, the nitrile of formula (14) is reacted with the Grignard reagent (R). 14a The product is reacted with MgBr and reduced to give the compound of formula (15). The compound of formula (15) is coupled with the compound of formula (4) to give the compound of formula V, where p is 0.

[1027] General Solution 5

[1028]

[1029] In general scheme 6, the aldehyde of formula (16) reacts with the ester of formula (17) to give the compound of formula (18). In step 2, the compound of formula (18) is hydrolyzed to give the compound of formula (19). In step 3, the compound of formula (19) is converted into the isocyanate of formula (20). The compound of formula (20) reacts with benzyl alcohol to give the compound of formula (21). The compound of formula (21) is hydrogenated and the Cbz group is removed to give the amine of formula (23). The compound of formula (23) is coupled with the compound of formula (4) to give the compound of formula V, where p is 1.

[1030] General Solution 6

[1031]

[1032] Formula V

[1033] (where p is 1)

[1034] In general scheme 7, the nitrile of formula (24) is reduced to obtain the amine of formula (25). The compound of formula (25) is coupled with the compound of formula (4) to obtain the compound of formula VI.

[1035] General Solution 7

[1036]

[1037] Style VI Example

[1038] Example 1

[1039] Synthesis of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole-2-carboxamide (compound number 15)

[1040] Step 1. Synthesis of ethyl (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazine-1-yl]propionate

[1041]

[1042] A solution of (5-fluoro-2-methylphenyl)hydrazine hydrochloride (100 g, 572.73 mmol, 1.00 equivalent) in ethanol (400 mL), ethyl 2-oxopropionate (66 g, 1.20 equivalent), and sulfuric acid (10 mL) were added to a 1000 mL round-bottom flask. 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. It yielded 120 g (yield = 88%) of (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazine-1-yl]propionate as a yellow solid. LCMS (Method A: ESI): RT = 1.399 min, m / z = 239.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 11.96 (d, J = 2.0 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.

[1043] Step 2. Synthesis of ethyl 4-fluoro-7-methyl-1H-indole-2-carboxylate

[1044]

[1045] A solution of ethyl (2E)-2-[2-(5-fluoro-2-methylphenyl)hydrazide-1-yl]propionate (40 g, 167.89 mmol, 1.00 equivalent) in toluene (400 mL) and 4-methylbenzene-1-sulfonic acid (50 g, 290.36 mmol, 1.70 equivalent) were added to a 1000 mL round-bottom flask. The resulting solution was stirred at 100 °C for 18 h. The reaction progress was monitored by LCMS. The resulting solution was concentrated under vacuum, and the residue was dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 3 x 200 mL saturated NaHCO3 aqueous solution. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:5). The resulting mixture was concentrated under vacuum. The solid was purified by recrystallization from ethanol. It gave 9.1 g (yield = 24%) of ethyl 4-fluoro-7-methyl-1H-indole-2-carboxylate as a yellow solid. LCMS (Method A, ESI): RT = 1.354 min, m / z = 222.0 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 12.07 (s, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.00 (m, 1H), 6.77 (m, 7.8Hz, 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.

[1046] Step 3. Synthesis of 4-fluoro-7-methyl-1H-indole-2-carboxylic acid

[1047]

[1048] A solution of ethyl 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (9.1 g, 41.13 mmol, 1.00 equivalent) in tetrahydrofuran (150 mL), sodium hydroxide (8 g, 200.00 mmol, 5.00 equivalent), water (50 mL), and methanol (2 mL) was added to a 500 mL round-bottom flask. The resulting solution was stirred at 25 °C for 6 h. The mixture was concentrated under vacuum. The residue was diluted with 50 mL of water and then adjusted to pH 5 with hydrogen chloride (3.0 mol / L). The resulting solution was extracted with 3 x 50 mL ethyl acetate. The solid was collected by filtration. It gave 8.0 g (yield = 81%) of 4-fluoro-7-methyl-1H-indole-2-carboxylic acid as a brown solid. LCMS (Method C, ESI): RT = 0.989 min, m / z = 192.0 [MH] + . 1H 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.

[1049] Step 4. Synthesis of N-[3-(4-acetylpiperazin-1-yl)cyclohexyl]tert-butyl carbamate

[1050]

[1051] N-(3-oxocyclohexyl)carbamate tert-butyl ester (800 mg, 3.75 mmol, 1.00 equivalent), 1-(piperazin-1-yl)ethyl-1-one (800 mg, 6.24 mmol, 1.66 equivalent), methanol (10 mL), and Pd / C (0.2 g) were added to a 100 mL round-bottom flask, and hydrogen gas was introduced into the mixture. The resulting solution was stirred at 25 °C for 2 h. The reaction progress was monitored by LCMS. The solids were filtered off. The resulting mixture was concentrated under vacuum. The crude product (900 mg) was purified by Flash-Prep-HPLC under the following conditions: column, C18 silica gel; mobile phase; detector, UV 254 / 220 nm. It yielded 700 mg (yield = 57%) of N-[3-(4-acetylpiperazin-1-yl)cyclohexyl]carbamate tert-butyl ester as a colorless oil. LCMS (Method A, ESI): RT = 1.361 minutes, m / z = 325.9 [M+H]+.

[1052] Step 5. Synthesis of 1-[4-(3-aminocyclohexyl)piperazin-1-yl]acetoone

[1053]

[1054] N-[3-(4-acetylpiperazin-1-yl)cyclohexyl]tert-butyl carbamate (700 mg, 2.15 mmol, 1.00 equivalent) and dichloromethane (3 mL) were added dropwise to a 100 mL round-bottom flask, followed by the addition of trifluoroacetic acid (2 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. It yielded 700 mg of 1-[4-(3-aminocyclohexyl)piperazin-1-yl]ethyl-1-one as a brown oil. LCMS (Method A, ES): RT = 0.647 min, m / z = 225.95 [M+H]+.

[1055] Step 6. Synthesis of N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide (as TFA salt)

[1056]

[1057] Compound number 15

[1058] Add 4-fluoro-7-methyl-1H-indole-2-carboxylic acid (100 mg, 0.52 mmol, 1.00 equivalent), 1-[4-(3-aminocyclohexyl)piperazin-1-yl]ethyl-1-one (110 mg, 0.49 mmol, 0.94 equivalent), N,N-dimethylformamide (4 mL), DIEA (200 mg, 1.55 mmol, 2.99 equivalent), and HATU (260 mg, 0.68 mmol, 1.32 equivalent) in portions to a 100-mL round-bottom flask. Stir the resulting solution at 25°C for 2 h. Monitor the reaction progress using LCMS, and quench the reaction solution with 10 mL of water. Extract the resulting solution with 3 × 15 mL of ethyl acetate, combine the organic layers, and concentrate under vacuum. Plugging the residue onto a silica gel column containing ethyl acetate / petroleum ether (1:1). The crude product was purified by Chiral-Prep-HPLC under the following conditions: column, (R, R)-WHELK-014.6*50 mm, 3.5 µm: 1-78220-30056749; mobile phase, hexane (0.1% DEA): EtOH = 85:15; detector, UV 254 nm / 220 nm. The obtained product was further purified by preparative HPLC under the following conditions: column, XBridge Prep Phenyl OBD column, 5 m, 19 × 150 mm; mobile phase, water containing 10 mmol TFA and MeCN (20.0% MeCN increased to 30.0% in 10 min, increased to 95.0% in 1 min, remained at 95.0% in 1 min, and decreased to 20.0% in 2 min); detector, UV 254 / 220 nm. It yielded 30.5 mg (yield = 11%) N-[(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl]-4-fluoro-7-methyl-1H-indole-2-carboxamide trifluoroacetate, as a white solid. LCMS (Method B, ES): RT = 1.138 min, m / z = 401.0 [M-TFA]+. 1H 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.

[1059] Example 2

[1060] Combinatorial research

[1061] Log-linear growth rate multiple myeloma (MM) and mantle cell lymphoma (MCL) cell line cultures were treated with a combination of compound number 15 and its conjugate according to a common treatment modality. Analytically ready plates were prepared by dispensing the compounds onto 384-well white opaque plates (CulturPlate-384, white opaque 384-well microculture plates, sterile and tissue culture treated) using an HP-D300 nanoliter dispenser (Tecan, Mannedorf, Switzerland) to achieve 2- or 3-fold serial dilutions within the concentration range near the IC50 of compound number 15 and its conjugate. Concentrations were matrixed in an 8x9 array (8 concentrations of compound number 15 and 9 concentrations of its conjugate). Each combination was tested in quadruplicated wells. The final concentration of DMSO (carrier) in the assay was 0.1% v / v. 50 μL of cell line suspension was dispensed directly onto the assay-ready plate using an automated multichannel dispenser on the 384-well assay-ready plate. The assay plates were cultured for 7 days at 37°C in humid air with 5% CO2. The effect of a single reagent or combination on cell viability was quantified by measuring cellular adenosine triphosphate (ATP) using the CellTiter-Glo® (Promega, Madison, WI) chemiluminescence cell viability assay. Chemiluminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). Concentration-response plots were generated in GraphPad Prismversion 7.0 for Windows, GraphPad Software (La Jolla, California), and curves were fitted with a four-parameter logistic model with a variable slope. The percentage of inhibition for each treatment concentration was calculated. Synergistic effects were quantified using the Loewe additive model, and Loewe volume (VLoewe) was calculated using CHALICE software (Horizon Discovery, Cambridge, UK) (Lehar 2007) (VLoewe > 1: synergistic effect, between 1 and -1: additive effect, and < -1: antagonistic effect; if neither drug or combination of drugs achieved 50% inhibition of proliferation, it was considered "ineffective". See Loewe, Arzneimittelforschung 3(6):285-290 (1953) and Lehar et al., MolSyst 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 the American Type Culture Collection (ATCC, Manassas VA); KMS-11, KMS34, and KMS-28-BM were purchased from the Japanese Collection of Research Bioresources (JCRB, Osaka, Japan); and L-363 and GRANTA519 were purchased from the Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures.

[1062] The results of these combinations are summarized in Tables A and B (multiple myeloma cell lines) and Tables C and D (mantle cell lymphoma cell lines).

[1063] For example, Figure 3 The study showed that the combination of compound 15 and pomalidomide in KMS-11 cells exhibited synergistic antiproliferative activity during a 7-day co-treatment study. Figure 4 Loewe model analysis of the study of compound 15 / pomalidomide combination in KMS-11 cells is shown.

[1064] Diffuse large B-cell lymphoma cells were seeded into flasks and pretreated with either compound #15 or DMSO at several concentrations. Cells were then separated, adjusted to initial density, re-plated, and co-treated for an additional 3 days in tissue culture-treated solid white 384-well plates using compound #15 and a second reagent of interest (DMSO) via an HP D300 digital dispenser (Tecan Group, Mannedorf, Switzerland). Both reagents were serially diluted and combined in a matrix, diagonally passing through the plates at a constant ratio, with a final DMSO concentration of 0.11% (v / v). After 3 days of co-treatment, cell viability was measured by ATP content using a CellTiter-Glo® (Promega, Madison, WI) and luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA).

[1065] Example 3

[1066] Combinatorial research

[1067] Cultures of a log-linear growth rate diffuse large B-cell lymphoma (DLBCL) cell line were treated with a combination of compound #15 and its co-conjugates according to a pretreatment model. Cells were first seeded into eight flasks and pretreated for four days with seven different concentrations of compound #15 (concentrations around the IC50 of compound #15, in 3-fold dilution ranges) and DMSO. On day 4, assay-ready plates were prepared by dispensing the compound into 384-well white opaque plates (CulturPlate-384, white opaque 384-well microplates, sterile and tissue culture treated) using an HP-D300 nanoliter dispenser (Tecan, Mannedorf, Switzerland) to achieve 3-fold serial dilutions around the IC50 of the co-conjugates. Cells were harvested from each flask and reseeded in three replicates into corresponding 384-well plates with the same concentration of compound #15 and nine concentrations of its co-conjugates. The final concentration of DMSO (carrier) in the experiment was 0.1% v / v. 50 μL of cell line suspension was directly dispensed onto 384-well analyzer-ready plates using an automated multichannel dispenser. The plates were incubated for three days at 37°C in humidified air with 5% CO2. The effect of a single reagent or combination on cell viability was quantified using CellTiter-Glo® (Promega, Madison, WI) by measuring cellular adenosine triphosphate (ATP). Luminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). Concentration-response plots were generated in GraphPadPrism version 8.0 for Windows, GraphPad Software (La Jolla, California), and curves were fitted with a four-parameter logistic model with a variable slope. The percentage of inhibition for each treatment concentration was calculated. The synergistic effect was quantified using the Loewe additive model and the Loewe volume (VLoewe) was calculated using CHALICE software (Horizon Discovery, Cambridge, UK) (Lehar 2007) (VLoewe > 1: synergistic effect, between 1 and -1: additive effect, and < -1: antagonistic effect; if neither drug or the combination of drugs achieved 50% inhibition, it was considered ineffective. 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 the American Type Culture Collection (ATCC, Manassas VA). WSUDLCL2 was purchased from the 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).

[1068] Table A

[1069]

[1070] Table B

[1071]

[1072] Table C

[1073]

[1074] Table D

[1075]

[1076] Table E

[1077]

[1078] Example 4

[1079] Combinatorial research

[1080] Long-term KMS-11 proliferation assay: Cells exhibiting log-linear growth were treated for a total of 14 days with compound number 15 (500 nM) and the combination of tandem tazestat (100 nM) and / or lenalidomide (1000 nM). For each of these reagents, the concentration used on day 14 was close to the IC50 value. On day 0, exponentially growing cells were partitioned into three 96-well plates in six replicates. Cell cultures were incubated for 4 and 7 days in the presence of DMSO, a single reagent, or a combination of the above reagents in either a dual or triple combination at 37°C in a humid environment containing 5% CO2. These plates were developed on days 0, 4, and 7, and the effect of single reagents and combinations on cell viability was quantified by measuring cellular adenosine triphosphate (ATP) using a CellTiter-Glo® (Promega, Madison, WI). Bioluminescence was detected using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, CA). In addition, on day 0, cells with log-linear growth rate were seeded into three 6-well plates and treated with DMSO, a single reagent, and dual or triple combinations of the corresponding reagents. These 6-well plates were incubated at 37°C in a humidified atmosphere of 5% CO2 for 7 days. On day 7, cells from each treatment were trypsinized, counted, and divided back to the original plate density, then placed into three 96-well plates with six replicate wells for analysis on days 7, 11, and 14. These re-platened cells were treated in the same way as on day 0. These plates were then developed using CellTiter-Glo® (Promega, Madison, WI) on days 7, 11, and 14. 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 of triplet combinations compared to each binary combination was performed using one-way ANOVA and Tukey multiple comparisons (p < 0.0001). Figure 1 and Figure 2 The results of a long-term KMS-11 proliferation assay are shown.

[1081] This invention provides the following technical solution:

[1082] 1. A method for treating a subject in need, the method comprising administering to the subject a therapeutically effective dose of:

[1083] (a) Compounds of Formula I:

[1084]

[1085] in:

[1086] R1a is selected from halogens, alkyl groups, alkoxy groups, cycloalkyl groups, (hydroxy)alkyl groups, and (cycloalkyl)alkyl groups;

[1087] Q 1 Selected from -C(R) 1b = and –N=;

[1088] Q 2 Selected from -C(R) 1c = and –N=;

[1089] Q 3 Selected from -C(R) 1d = and –N=;

[1090] The condition is that at least one of Q1, Q2, or Q3 is -C(R1b)=, -C(R1c)=, or -C(R1d)=;

[1091] R1b, R1c, and R1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy.

[1092] R1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[1093] It can be a single bond or a double bond;

[1094] G1 is selected from: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclic)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclic)alkyl; (heteroaryl)(formamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclic)(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

[1095] G2 is selected from hydrogen and alkyl groups; or

[1096] G1 and G2, together with the nitrogen atoms they are attached to, form optionally substituted heterocyclic groups.

[1097] 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,

[1098] Or its pharmaceutically acceptable salts or solvates; and

[1099] (b) A second therapeutic agent, wherein:

[1100] 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.

[1101] 2.1 The method thereof, wherein the compound is a compound of formula II:

[1102]

[1103] Or its pharmaceutically acceptable salts or solvates.

[1104] 3.1 or 2, wherein G1 is 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- to C8 cycloalkyl; (5- to 9-membered heteroaryl)C1- to C6 alkyl; (5- to 9-membered heteroaryl)(C6- 10 Aryl)C1-C4 alkyl; (5- to 9-membered heteroarylheteroaryl)(C3-C6 cycloalkyl)C1-C4 alkyl; and (C3-C6 cycloalkyl)C1-C4 alkyl, or pharmaceutically acceptable salts or solvates thereof.

[1105] 4.3 The method thereof, wherein the compound is a compound of formula IV:

[1106]

[1107] in:

[1108] Z4 is selected from -O-, -C(R28a)(R28b)-, and -N(R23)-; or Z4 does not exist;

[1109] Z 5 Selected from -CH2- and -CH2CH2-;

[1110] R11a is selected from optionally substituted alkyl groups, optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, and -N(R12b)C(=O)R13c;

[1111] R12b is selected from hydrogen, alkyl, cycloalkyl and heterocyclic groups, (C1-C4 alkoxy)C1-C4 alkyl and (hydroxy)C1-C4 alkyl; and

[1112] R13c is selected from alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclic, amino, (amino)alkyl, (C3-C6 cycloalkyl)oxy and (4- to 8-membered heterocyclic)oxy.

[1113] R 23 Selected from hydrogen and C1-C4 alkyl groups; and

[1114] R28a and R28b are independently selected from hydrogen, alkyl, and halogen;

[1115] Or its pharmaceutically acceptable salts or solvates.

[1116] 5.4 The method thereof, wherein the compound is a compound of formula IV-A:

[1117]

[1118] Or its pharmaceutically acceptable salts or solvates.

[1119] 6.4 The method thereof, wherein the compound is a compound of formula IV-B:

[1120]

[1121] Or its pharmaceutically acceptable salts or solvates.

[1122] 7.4 The method thereof, wherein the compound is a compound of formula IV-C:

[1123]

[1124] Or its pharmaceutically acceptable salts or solvates.

[1125] 8.4 The method thereof, wherein the compound is a compound of formula IV-D:

[1126]

[1127] Or its pharmaceutically acceptable salts or solvates.

[1128] 9. The method described in any one of 4-8, wherein:

[1129] R11a is selected from:

[1130] (A) Unsubstituted 4- to 14-membered heterocycles;

[1131] (B) Substituted 4- to 14-membered heterocyclic groups having 1, 2, or 3 independent substituents selected from the following:

[1132] (i) -N(R 12a )C(=O)R 13a (ii) -C(=O)R 13b (iii) C1-C4 alkyl; (iv) (C1-C4 alkoxy)C1-C4 alkyl; (v) (hydroxy)C1-C4 alkyl; (vi) C1-C4 haloalkyl; (vii) amino; (vii) hydroxy; (viii) -N(R 12a )S(=O)2R 24 ;(ix) -S(=O)2R 24 (x) Unsubstituted C3-C6 cycloalkyl; (xi) Substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; (xii) Unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; (xiii) -C(=NR) 60 )R 61 ; and (xiv) -C(=C-NO2)R 64 ;

[1133] (C) Unsubstituted 5- to 10-membered heteroaryl groups;

[1134] (D) A substituted 5- or 6-membered heteroaryl group having 1, 2, 3 or 4 independent substituents selected from the following: halogens and C1-C4 alkyl groups;

[1135] (E) C1-C6 alkyl; and

[1136] (F) -N(R12b)C(=O)R13c;

[1137] R12a and R12b are each independently selected from hydrogen, C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl;

[1138] R13a, R13b, and R13c are each 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-C6 cycloalkyl. 10 Aryl; (I) substituted C6-C 10 aryl group having 1, 2, 3, or 4 independently selected substituents 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 independently selected substituents 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 independently selected substituents from: 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

[1139] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[1140] R 60 Selected from cyano, nitro, hydroxy, C1-C6 alkoxy, -C(=O)R 62 and -S(=O)2R 62 ;

[1141] R 61 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[1142] R 62 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ;

[1143] R 63a Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[1144] R 63b Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or

[1145] R63a and R63b together with the nitrogen atom to which they are attached form 4- to 6-membered, optionally substituted heterocyclic groups;

[1146] R 64Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -NR 63c R 63d ;

[1147] R 63c Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[1148] R 63d Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or

[1149] R63c and R63d, together with the nitrogen atom to which they are attached, form 4- to 6-membered optionally substituted heterocycles, or pharmaceutically acceptable salts or solvates thereof.

[1150] 10.9 The method thereof, wherein R11a is a substituted 4- to 14-membered heterocyclic group selected from:

[1151]

[1152]

[1153] R 12a Selected from hydrogen, C1-C3 alkyl, (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl;

[1154] R 13a Selected from C1-C4 alkyl; amino; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from the following: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic group; and substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: amino, hydroxy and C1-C4 alkyl;

[1155] R 13b Selected from C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclic)oxy;

[1156] R 21Selected from hydrogen, -C(=O)R 13b C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted 4- to 14-membered heterocyclic groups and -S(=O)2R 24 ;

[1157] R 22 It is a C1-C4 alkyl; an unsubstituted C3-C6 cycloalkyl; a substituted C3-C6 cycloalkyl having one or two independent substituents selected from the following: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; an unsubstituted 4- to 14-membered heterocyclic group; and a substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: amino, hydroxyl and C1-C4 alkyl;

[1158] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl;

[1159] R 25 Selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;

[1160] R 25b and R 25c Independently selected from C1-C4 alkyl and C1-C4 haloalkyl;

[1161] R26 is selected from unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; and

[1162] R21a and R25a, together with the atoms they are attached to, form optionally substituted 4- to 8-membered heterocyclic groups.

[1163] Or its pharmaceutically acceptable salts or solvates.

[1164] 11.9 The method thereof, wherein R11a is a substituted 4- to 14-membered heterocyclic group selected from:

[1165]

[1166]

[1167]

[1168] R27a and R27b are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl;

[1169] R 27c Selected from hydrogen; -C(=O)R 13bC1-C4 alkyl; C1-C4 haloalkyl; unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; and -S(=O)2R 24 ;

[1170] R 27d Selected from hydrogen; C1-C4 alkyl; and C1-C4 haloalkyl;

[1171] R 13b Selected from C1-C4 alkyl; amino-C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic groups; substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclic)oxy; and

[1172] R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl,

[1173] Or its pharmaceutically acceptable salts or solvates.

[1174] 12.11 The method thereof, wherein R11a is a substituted 4- to 14-membered heterocyclic group selected from:

[1175]

[1176]

[1177]

[1178]

[1179] Or its pharmaceutically acceptable salts or solvates.

[1180] 13.9 The method thereof, wherein R11a is a substituted 4- to 14-membered heterocyclic group selected from:

[1181]

[1182] Or its pharmaceutically acceptable salts or solvates.

[1183] 14. The method described in any one of 4-13, wherein Z 4It is -CH2-, or a pharmaceutically acceptable salt or solvate thereof.

[1184] 15. The method of any one of 1-14, wherein R1d is fluorine, or a pharmaceutically acceptable salt or solvate thereof.

[1185] 16.1 The method wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[1186] 17.1 The method wherein the compound is a compound of Table 1B, or a pharmaceutically acceptable salt or solvate thereof.

[1187] 18. The method of any one of 1-17, wherein the second therapeutic agent comprises a glucocorticoid receptor agonist.

[1188] 19.18 The method thereof, wherein the glucocorticoid receptor agonist is dexamethasone.

[1189] 20. The method of any one of 1-19, wherein the second therapeutic agent comprises an immunomodulatory drug.

[1190] 21.20 The method wherein the immunomodulatory drug is pomalidomide or lenalidomide.

[1191] 22. The method of any one of 1-21, wherein the second therapeutic agent comprises a proteasome inhibitor.

[1192] 23.22 The method thereof, wherein the proteasome inhibitor is bortezomib.

[1193] 24. The method of any one of 1-23, wherein the second therapeutic agent comprises a Bcl-2 inhibitor.

[1194] 25.24 The method thereof, wherein the Bcl-2 inhibitor is venetum.

[1195] 26. The method of any one of 1-25, wherein the second therapeutic agent comprises a pleiotropic modulator.

[1196] 27. The method of 26, wherein the pleiotropic pathway modulator is CC-122.

[1197] 28. The method of any one of 1-27, wherein the second therapeutic agent comprises an XPO1 inhibitor.

[1198] 29.28 The method thereof, wherein the XPO1 inhibitor is celiniso.

[1199] 30. The method of any one of 1-29, wherein the second therapeutic agent comprises a histone deacetylase inhibitor.

[1200] 31. The method of 30, wherein the histone deacetylase inhibitor is palbistat.

[1201] 32. The method of any one of 1-31, wherein the second therapeutic agent is an EZH2 inhibitor.

[1202] 33.32 The method thereof, wherein the EZH2 inhibitor is tazetine.

[1203] 34. The method of any one of 1-33, wherein the compound of formula I and the second therapeutic agent are administered separately to the subject.

[1204] 35. The method of any one of 1-34, wherein the desired subject has cancer.

[1205] 36.35 The method thereof, wherein the cancer is any one or more of the cancers listed in Table 2.

[1206] 37. 38 The method thereof, wherein the cancer is a blood cancer.

[1207] 38. The method described in 37, wherein the blood cancer is any one or more of the cancers listed in Table 3.

[1208] 39. A reagent kit comprising:

[1209] (a) Compounds of Formula I:

[1210]

[1211] in:

[1212] R1a is selected from halogens, alkyl groups, alkoxy groups, cycloalkyl groups, (hydroxy)alkyl groups, and (cycloalkyl)alkyl groups;

[1213] Q1 is selected from -C(R1b) and –N;

[1214] Q2 is selected from -C(R1c) and –N;

[1215] Q3 is selected from -C(R1d) and –N.

[1216] The condition is that at least one of Q1, Q2, or Q3 is -C(R1b)=, -C(R1c)=, or -C(R1d)=;

[1217] R1b, R1c, and R1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy.

[1218] R1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl;

[1219] It can be a single bond or a double bond;

[1220] G1 is selected from: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclic)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclic)alkyl; (heteroaryl)(formamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclic)alkyl (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

[1221] G2 is selected from hydrogen and alkyl groups; or

[1222] G1 and G2, together with the nitrogen atoms they are attached to, form optionally substituted heterocyclic groups.

[1223] 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,

[1224] Or its pharmaceutically acceptable salts or solvates; and

[1225] (b) A second therapeutic agent, wherein:

[1226] 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.

[1227] The kit of 40.39 also includes instructions for administering the Formula I compound and the second therapeutic agent to a subject with cancer.

[1228] 41. A compound selected from:

[1229] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[1230] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aS,6aS)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[1231] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aR,6aR)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[1232] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aR,6aR)-1-methyl-2-oxohexahydropyrrolo[3,4-b]pyrrolo-5(1H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[1233] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[1234] 4-Fluoro-7-methyl-N-((1R,3S)-3-((3aR,6aR)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide;

[1235] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aS,6aS)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide; and

[1236] 4-Fluoro-7-methyl-N-((1R,3R)-3-((3aR,6aR)-4-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrolo-1(2H)-yl)cyclohexyl)-1H-indole-2-carboxamide,

[1237] Or its pharmaceutically acceptable salts or solvates.

[1238] 42. A pharmaceutical composition comprising the compound described in 41, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[1239] 43. A method of treating a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound described in 41, or a pharmaceutically acceptable salt or solvate thereof.

[1240] 44. The method of 43, wherein the desired subject has cancer.

[1241] 45. The method described in 44, wherein the cancer is any one or more of the cancers listed in Table 2.

[1242] 46. ​​The method of 44, wherein the cancer is a blood cancer.

[1243] 47. The method of 46, wherein the blood cancer is any one or more of the cancers listed in Table 3.

[1244] 48. The pharmaceutical composition described in 43, used to treat a subject.

[1245] 49. The pharmaceutical composition described in 48, wherein the subject has cancer.

[1246] 50. The pharmaceutical composition of 49, wherein the cancer is any one or more of the cancers listed in Table 2.

[1247] 51. The pharmaceutical composition of 49, wherein the cancer is a blood cancer.

[1248] 52.51 The method wherein the blood cancer is any one or more of the cancers listed in Table 3.

[1249] 53. The compound described in 41, used to treat a subject.

[1250] 54. The compound used in 53, wherein the subject had cancer.

[1251] 55. The compound used in 54, wherein the cancer is any one or more of the cancers listed in Table 2.

[1252] 56. The compound used in 54, wherein the cancer is a hematologic cancer.

[1253] 57. The method of 56, wherein the blood cancer is any one or more of the cancers listed in Table 3.

[1254] Use of compound 58.21 in the preparation of a medicament for treating a subject.

[1255] 59. Use of 58, wherein the subject has cancer.

[1256] Use of 60.59, wherein the cancer is any one or more of the cancers listed in Table 2.

[1257] 61. 59, wherein the cancer described is a blood cancer.

[1258] 62. Use of 61, wherein the blood cancer is any one or more of the cancers listed in Table 3.

[1259] 63. A kit comprising the compound described in 41 and instructions for administering the compound to a subject.

[1260] 64. 63 kits, wherein the subject had cancer.

[1261] The invention has now been fully described, and those skilled in the art will understand that the same operation can be performed under broad and equivalent conditions, formulations and other parameters without affecting the scope of the invention or any of its embodiments.

[1262] Other embodiments of the invention will be apparent to those skilled in the art from the description and practice of the invention disclosed herein. The specification and examples are to be considered exemplary only, and the true scope and spirit of the invention are indicated by the appended claims.

[1263] All patents, patent applications (e.g., PCT / US2019 / 046569) and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A method for treating a subject in need, the method comprising administering to the subject a therapeutically effective dose of: (a) Compounds of Formula I: in: R1a is selected from halogens, alkyl groups, alkoxy groups, cycloalkyl groups, (hydroxy)alkyl groups, and (cycloalkyl)alkyl groups; Q 1 Selected from -C(R) 1b = and –N=; Q 2 Selected from -C(R) 1c = and –N=; Q 3 Selected from -C(R) 1d = and –N=; The condition is that at least one of Q1, Q2, or Q3 is -C(R1b)=, -C(R1c)=, or -C(R1d)=; R1b, R1c, and R1d are each independently selected from hydrogen, halogen, alkyl, alkenyl, (hydroxy)alkyl, and alkoxy. R1e is selected from hydrogen, halogen, alkyl, cycloalkyl, (hydroxy)alkyl, and (cycloalkyl)alkyl; It can be a single bond or a double bond; G 1 Selected from: optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted cycloalkyl; (aryl)alkyl; (heteroaryl)alkyl; (heterocyclic)alkyl; (amino)(aryl)alkyl; (heteroaryl)(aryl)alkyl; (heteroaryl)(heterocyclic)alkyl; (heteroaryl)(formamido)alkyl; (heteroaryl)(cycloalkyl)alkyl; (aryl)(alkoxycarbonyl)alkyl; (cycloalkyl)alkyl; (heteroaryl)(amino)alkyl; (cycloalkyl)(alkoxycarbonyl)alkyl; (heteroaryl)(alkoxycarbonyl)alkyl; (heterocyclic)alkyl)(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 G2 is selected from hydrogen and alkyl groups; or G1 and G2, together with the nitrogen atoms they are attached to, form optionally substituted heterocyclic groups. 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, Or its pharmaceutically acceptable salts or solvates; and (b) A second therapeutic agent, wherein: 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.

2. The method of claim 1, wherein the compound is a compound of formula II: Or its pharmaceutically acceptable salts or solvates.

3. The method of claim 1 or 2, wherein G1 is 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- to C8 cycloalkyl; (5- to 9-membered heteroaryl)C1- to C6 alkyl; (5- to 9-membered heteroaryl)(C6- 10 Aryl)C1-C4 alkyl; (5- to 9-membered heteroarylheteroaryl)(C3-C6 cycloalkyl)C1-C4 alkyl; and (C3-C6 cycloalkyl)C1-C4 alkyl, or pharmaceutically acceptable salts or solvates thereof.

4. The method of claim 3, wherein the compound is a compound of formula IV: in: Z4 is selected from -O-, -C(R28a)(R28b)-, and -N(R23)-; or Z4 does not exist; Z 5 Selected from -CH2- and -CH2CH2-; R11a is selected from optionally substituted alkyl groups, optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, and -N(R12b)C(=O)R13c; R12b is selected from hydrogen, alkyl, cycloalkyl and heterocyclic groups, (C1-C4 alkoxy)C1-C4 alkyl and (hydroxy)C1-C4 alkyl; and R13c is selected from alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocyclic, amino, (amino)alkyl, (C3-C6 cycloalkyl)oxy and (4- to 8-membered heterocyclic)oxy. R 23 Selected from hydrogen and C1-C4 alkyl groups; and R28a and R28b are independently selected from hydrogen, alkyl, and halogen; Or its pharmaceutically acceptable salts or solvates.

5. The method of claim 4, wherein the compound is a compound of formula IV-A: Or its pharmaceutically acceptable salts or solvates.

6. The method of claim 4, wherein the compound is a compound of formula IV-B: Or its pharmaceutically acceptable salts or solvates.

7. The method of claim 4, wherein the compound is a compound of formula IV-C: Or its pharmaceutically acceptable salts or solvates.

8. The method of claim 4, wherein the compound is a compound of formula IV-D: Or its pharmaceutically acceptable salts or solvates.

9. The method according to any one of claims 4-8, wherein: R11a is selected from: (A) Unsubstituted 4- to 14-membered heterocycles; (B) Substituted 4- to 14-membered heterocyclic groups having 1, 2, or 3 independent substituents selected from the following: (i) -N(R 12a )C(=O)R 13a (ii) -C(=O)R 13b (iii) C1-C4 alkyl; (iv) (C1-C4 alkoxy)C1-C4 alkyl; (v) (hydroxy)C1-C4 alkyl; (vi) C1-C4 haloalkyl; (vii) amino; (vii) hydroxy; (viii) -N(R 12a )S(=O)2R 24 ;(ix) -S(=O)2R 24 (x) Unsubstituted C3-C6 cycloalkyl; (xi) Substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino, and (amino)C1-C4 alkyl; (xii) Unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; (xiii) -C(=NR) 60 )R 61 ; and (xiv) -C(=C-NO2)R 64 ; (C) Unsubstituted 5- to 10-membered heteroaryl groups; (D) A substituted 5- or 6-membered heteroaryl group having 1, 2, 3 or 4 independent substituents selected from the following: halogens and C1-C4 alkyl groups; (E) C1-C6 alkyl; and (F) -N(R12b)C(=O)R13c; R12a and R12b are each independently selected from hydrogen, C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (hydroxy)C1-C4 alkyl; R13a, R13b, and R13c are each 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-C6 cycloalkyl. 10 Aryl; (I) substituted C6-C 10 aryl group having 1, 2, 3, or 4 independently selected substituents 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 independently selected substituents 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 independently selected substituents from: 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 R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl; R 60 Selected from cyano, nitro, hydroxy, C1-C6 alkoxy, -C(=O)R 62 and -S(=O)2R 62 ; R 61 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ; R 62 Selected from C1-C6 alkyl, C3-C6 cycloalkyl and -NR 63a R 63b ; R 63a Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; R 63b Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or R63a and R63b together with the nitrogen atom to which they are attached form 4- to 6-membered, optionally substituted heterocyclic groups; R 64 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, and -NR 63c R 63d ; R 63c Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; R 63d Selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; or R63c and R63d, together with the nitrogen atom to which they are attached, form 4- to 6-membered optionally substituted heterocycles, or pharmaceutically acceptable salts or solvates thereof.

10. The method of claim 9, wherein R11a is a substituted 4- to 14-membered heterocyclic group selected from: R 12a Selected from hydrogen, C1-C3 alkyl, (C1-C4 alkoxy)C1-C4 alkyl; and (hydroxy)C1-C4 alkyl; R 13a Selected from C1-C4 alkyl; amino; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from the following: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (hydroxy)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic group; and substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: amino, hydroxy and C1-C4 alkyl; R 13b Selected from C1-C4 alkyl; amino; C1-C4 haloalkyl; C1-C4 alkoxy; (hydroxy)C1-C4 alkyl; (C1-C4 alkoxy)C1-C4 alkyl; (amino)alkyl; unsubstituted C3-C6 cycloalkyl; substituted C3-C6 cycloalkyl having one or two independent substituents selected from: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl and C1-C4 alkyl; (C3-C6 cycloalkyl)oxy; and (4- to 8-membered heterocyclic)oxy; R 21 Selected from hydrogen, -C(=O)R 13b C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted 4- to 14-membered heterocyclic groups and -S(=O)2R 24 ; R 22 It is a C1-C4 alkyl; an unsubstituted C3-C6 cycloalkyl; a substituted C3-C6 cycloalkyl having one or two independent substituents selected from the following: halogen, hydroxyl, C1-C4 alkyl, amino and (amino)C1-C4 alkyl; an unsubstituted 4- to 14-membered heterocyclic group; and a substituted 4- to 14-membered heterocyclic group having one or two independent substituents selected from the following: amino, hydroxyl and C1-C4 alkyl; R 24 Selected from C1-C4 alkyl and (hydroxy)C1-C4 alkyl; R 25 Selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R 25b and R 25c Independently selected from C1-C4 alkyl and C1-C4 haloalkyl; R26 is selected from unsubstituted 4- to 14-membered heterocyclic groups; and substituted 4- to 14-membered heterocyclic groups having one or two independent substituents selected from: amino, hydroxyl, and C1-C4 alkyl; and R21a and R25a, together with the atoms they are attached to, form optionally substituted 4- to 8-membered heterocyclic groups. Or its pharmaceutically acceptable salts or solvates.

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