Modified proteins and protein binding agents

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for binding or modulating DDB1 and CUL4 associated factor 1 (DCAF1) proteins. Also provided herein are ligand-DCAF1 complexes or DCAF1 proteins modified in vivo.

Description

[0001] Cross-references

[0002] This application claims the benefit of PCT application No. PCT / CN2021 / 081117, filed on March 16, 2021, which is incorporated herein by reference in its entirety. Background Technology

[0003] There is a need for ligands used to bind or modify proteins. In the pharmaceutical field, there is a need for selective regulation of proteins. Summary of the Invention

[0004] This article describes modified proteins and protein-ligand complexes. Some embodiments of modified proteins and protein-ligand complexes can be used in biotechnological applications such as the selective regulation of proteins.

[0005] This article describes ligands that can bind to DDB1 and CUL4-associated factor 1 (DCAF1). DCAF1-binding ligands can be used in biotechnological applications such as the selective regulation of DCAF1.

[0006] In one aspect, this paper provides compounds of formula Ia:

[0007]

[0008] Or its pharmaceutically acceptable salt, wherein:

[0009] Is it a single bond or a double bond?

[0010] R 1 Selected from H, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Halogenated alkyl and C 1-10 Heteroalkyl;

[0011] Each R 2 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0012] n is 0, 1, 2, 3 or 4;

[0013] The condition is that the compound of formula Ia is not

[0014] In another respect, this article provides compounds selected from the following:

[0015]

[0016] Or its pharmaceutically acceptable salt.

[0017] In another respect, this paper provides a method for binding or modulating DDB1 and CUL4-associated factor 1 (DCAF1) in desired subjects, the method comprising administering a therapeutically effective amount of a compound of formula I:

[0018]

[0019] Or its pharmaceutically acceptable salt, wherein:

[0020] Is it a single bond or a double bond?

[0021] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10 -C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C 2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0022] R 2 Selected from C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic and 3 to 10-membered heterocyclic groups, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic and heterocyclic group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0023] Each R 3 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0024] n is 0, 1, 2, 3 or 4.

[0025] In another respect, this paper provides compounds of formula IIa:

[0026]

[0027] Or its pharmaceutically acceptable salt, wherein:

[0028] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl;

[0029] R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl;

[0030] Each R 4 and each R 5 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0031] n is 0, 1, 2, or 3; and

[0032] m can be 0, 1, 2, 3, or 4.

[0033] In another respect, this article provides compounds selected from the following:

[0034]

[0035] Or its pharmaceutically acceptable salt.

[0036] In another respect, this paper provides a method for binding or modulating DDB1 and CUL4-associated factor 1 (DCAF1) in a desired object, the method comprising administering a therapeutically effective amount of a compound of formula II:

[0037]

[0038] Or its pharmaceutically acceptable salt, wherein:

[0039] R 1 Selected from H, C1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl;

[0040] R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10 -C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C 2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10 Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0041] Each R 4 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0042] n is 0, 1, 2, 3 or 4.

[0043] In another respect, this article provides compounds selected from the following:

[0044]

[0045] Or its pharmaceutically acceptable salt.

[0046] In another respect, this paper provides a method for binding or modulating DDB1 and CUL4-associated factor 1 (DCAF1) in desired subjects, the method comprising administering a therapeutically effective amount of a compound of formula III:

[0047]

[0048] Or its pharmaceutically acceptable salt, wherein:

[0049] Ring A is selected from none, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0050] X is selected from N and CR. 7 ;

[0051] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0052] R 2 R 3 and R 7 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0053] R 4 and R 5 Independently selected from H, halogen, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0054] R 4 and R 5 Together they form oxygen;

[0055] Each R 6 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0056] n is 0, 1, 2, 3, 4, 5, or 6.

[0057] In another respect, this paper provides a method comprising contacting the compounds provided herein with the DDB1 and CUL4-associated factor 1 (DCAF1) protein.

[0058] In some embodiments, contacting the compound with the DCAF1 protein includes applying the compound to cells.

[0059] In some implementations, contacting the compound with the DCAF1 protein includes applying the compound to the target.

[0060] In some embodiments, contacting the compound with the DCAF1 protein includes contacting the compound with a binding region on the DCAF1 protein, the binding region comprising a WD40 domain. In some embodiments, the binding region on the DCAF1 protein comprises one or more of the following DCAF1 residues: THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329, or PHE1355.

[0061] In some embodiments, the compound binds nonvalently to the DCAF1 protein. In some embodiments, the compound uses K... d ≤40 μM binds to DCAF1 protein. In some embodiments, the compound is in K... d The compound binds to DCAF1 protein at concentrations >40 μM and ≤70 μM. In some embodiments, the compound is expressed as K... d The compound binds to DCAF1 protein at concentrations >70 μM and ≤100 μM. In some embodiments, the compound is expressed as K... d >100μM binds to DCAF1 protein.

[0062] In another respect, this article provides an in vivo modified protein comprising a DCAF1 protein that directly binds to a ligand at a binding region on a DDB1 and CUL4-associated factor 1 (DCAF1) protein, the binding region containing a WD40 domain.

[0063] In some implementations, the binding region on the DCAF1 protein contains one or more of the following DCAF1 residues: THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329, or PHE1355.

[0064] In some embodiments, the ligand binds nonvalently to the DCAF1 protein. In some embodiments, the ligand uses K... d ≤40 μM binds to DCAF1 protein. In some embodiments, the ligand is K... d Binding to DCAF1 protein at concentrations >40 μM and ≤70 μM. In some embodiments, the ligand is K... d Binding to DCAF1 protein at concentrations >70 μM and ≤100 μM. In some embodiments, the ligand is K...d >100μM binds to DCAF1 protein.

[0065] In some implementations, the ligand is synthetic.

[0066] In some implementations, the ligand is a small molecule.

[0067] In some implementations, the ligands include compounds provided herein.

[0068] Incorporation

[0069] For the specific purposes identified herein, all publications, patents and patent applications mentioned in this specification are incorporated herein by reference. Attached Figure Description

[0070] Figure 1 Examples of compounds that bind to the binding region of the DCAF1 protein are shown.

[0071] Figures 2A-2F Binding data for some of the compounds described herein are shown. Detailed Implementation

[0072] The ubiquitin pathway plays a crucial role in regulating most cellular processes via an enzyme cascade, in which E1 and E2 enzymes catalyze the activation and conjugation of ubiquitin, and E3 confers response specificity through substrate recruitment (Hershko and Ciechanover, 1998; Pickart, 2004). C ullin R ING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases. In the CRL ligase complex, cullins act as a scaffold to bind small ring finger proteins ROC1 or ROC2 (RBX1 or RBX2) via their C-terminal domain and directly to adaptor-substrate receptor dimers or substrate receptors via their N-terminal domain. Mammalian cells express nine different cullins, including two cullin 4 (CUL4) proteins: CUL4A and CUL4B, which use DNA damage-binding protein 1 (DDB1) as an adaptor. DDB1 provides a link between CUL4 and DDB1 binding to a subclass of WD40 repeat proteins (DWD or DCAF targeting DDB1 cullin-associated factors). These DCAF proteins act as substrate receptors to target specific substrates to the CRL4 E3 complex (Jackson and Xiong, 2009). One of the most abundant DCAF proteins is DCAF1 (also known as VprBP).

[0073] DCAF1 is evolutionarily conserved in mammals, *Drosophila*, *Xenopus*, *C. elegans*, and *Arabidopsis*, but has no dominant homolog in yeast (Nakagawa et al., 2013; Schabla et al., 2019). It is universally expressed in all tissues and organs examined (Zhang et al., 2001). Genetic analysis revealed the essential function of DCAF1 during embryonic development in plants, flies, and mammals, leading to developmental arrest at the globular stage in *Arabidopsis* (Zhang et al., 2008), the postpupal stage in *Drosophila* (Tamori et al., 2010), and early embryonic lethality in mice (McCall et al., 2008), respectively.

[0074] DCAF1 was first identified as a binding protein to HIV-1 helper viral protein R (Vpr) (Zhang et al., 2001; Zhao et al., 1994), and was subsequently shown to associate with DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4) (Angers et al., 2006; He et al., 2006; Jin et al., 2006). DCAF1 contains multiple functional domains, including a putative protein kinase-like domain (Kim et al., 2013), a chromosome domain (acting as a substrate recognition pocket for monomethylation (Lee et al., 2012)), a putative LisH motif required for dimerization and interaction with the H3 tail (Ahn et al., 2011; Kim et al., 2012), a mixed α-helical motif H-box required for DDB1 binding (Fischer et al., 2011; Li et al., 2010), a WD40 repeat region required for DDB1 binding, and an acidic domain providing interaction with additional proteins (Huang and Chen, 2008; Wang et al., 2016). DCAF1 ligands have the potential to be used as antiviral agents.

[0075] This article provides compounds, pharmaceutical compositions, and methods for binding to or regulating the DDB1 and CUL4-associated factor 1 (DCAF1) protein. This article also provides ligand-DCAF1 complexes or in vivo modified DCAF1 protein.

[0076] The DCAF1 protein can be a mammalian DCAF1 protein. The DCAF1 protein can be a human DCAF1 protein. The DCAF1 protein can be encoded by a DCAF1 gene such as NCBI Gene ID:9730 (updated January 29, 2021). The DCAF1 protein can contain an amino acid sequence. Examples of DCAF1 amino acid sequences are included in UniProt ref. Q9Y4B6 (last revised sequence May 15, 2007). In some embodiments, the DCAF1 protein contains 1507 amino acids or has a mass of 169 kDa.

[0077] Modified proteins and ligand-protein complexes

[0078] In some embodiments, modified proteins are disclosed herein. In some embodiments, the modified proteins include in vivo modified proteins. In some embodiments, the modified proteins include in vitro modified proteins. In some embodiments, the modified proteins include DDB1 and CUL4-associated factor 1 (DCAF1) proteins. In some embodiments, the modified proteins include in vivo modified DCAF1 proteins. In some embodiments, the DCAF1 protein binds to a ligand. The ligand may be a compound described herein, such as a compound of formula Ia, I, IIa, II, or III as listed in Table 1. In some embodiments, the DCAF1 protein binds to a compound described herein. In some embodiments, the DCAF1 protein binds directly to a compound. In some embodiments, the binding between the DCAF1 protein and the compound is non-covalent. In some embodiments, the binding between the DCAF1 protein and the compound is covalent. The modified protein may be used in the methods described herein. In some embodiments, the ligand binds to a DCAF1 fragment. In some embodiments, the ligand binds to the full-length DCAF1 protein.

[0079] In some embodiments, ligand-protein complexes are disclosed herein. In some embodiments, the ligand-protein complex comprises the DCAF1 protein. In some embodiments of the ligand-protein complex, the DCAF1 protein binds to a ligand. The ligand may be a compound described herein, such as a compound of formula Ia, I, IIa, II, or III as listed in Table 1. In some embodiments, the DCAF1 protein binds directly to the compound. In some embodiments, the binding between the DCAF1 protein and the compound is non-covalent. In some embodiments, the binding between the DCAF1 protein and the compound is covalent. The ligand-protein complex can be formed in vivo. The ligand-protein complex can be formed in vitro. The ligand-protein complex can be used in the methods described herein. In some embodiments, the ligand binds to a DCAF1 fragment. In some embodiments, the ligand binds to the full-length DCAF1 protein.

[0080] In some embodiments, this document discloses modified proteins or ligand-protein complexes comprising compounds described herein that bind to the DCAF1 protein. In some embodiments, the DCAF1 protein includes a binding region. In some embodiments, the compound binds to the binding region of the DCAF1 protein. In some embodiments, the binding region includes a WD40 domain. In some embodiments, the DCAF1 fragment includes a WD40 domain.

[0081] In some embodiments, the binding region of the DCAF1 protein contains alanine. In some embodiments, the binding region of the DCAF1 protein contains arginine. In some embodiments, the binding region of the DCAF1 protein contains cysteine. In some embodiments, the binding region of the DCAF1 protein contains histidine. In some embodiments, the binding region of the DCAF1 protein contains lysine. In some embodiments, the binding region of the DCAF1 protein contains proline. In some embodiments, the binding region of the DCAF1 protein contains threonine. In some embodiments, the binding region of the DCAF1 protein contains tyrosine. In some embodiments, the binding region of the DCAF1 protein contains valine.

[0082] In some embodiments, the binding region of the DCAF1 protein comprises one or more amino acids following amino acid positions 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 of the DCAF1 protein. In some embodiments, the binding region of the DCAF1 protein comprises one or more amino acids preceding amino acid positions 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 of the DCAF1 protein. In some embodiments, the binding region of the DCAF1 protein comprises one or more amino acids between amino acid positions 1095 and 1355 of the DCAF1 protein.

[0083] In some embodiments, the binding region of the DCAF1 protein includes one or more of the following DCAF1 residues: THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329, or PHE1355. The binding region may include THR1097, ALA1137, THR1139, HIS1140, THR1155, HIS1180, TYR1181, ARG1225, CYS1227, ILE1262, VAL1265, ARG1298, VAL1299, VAL1300, LYS1327, PRO1329, or PHE1355. In some embodiments, the binding region of the DCAF1 protein includes THR1097. In some embodiments, the binding region of the DCAF1 protein includes ALA1137. In some embodiments, the binding region of the DCAF1 protein includes THR1139. In some embodiments, the binding region of the DCAF1 protein includes HIS1140. In some embodiments, the binding region of the DCAF1 protein includes THR1155. In some embodiments, the binding region of the DCAF1 protein includes HIS1180. In some embodiments, the binding region of the DCAF1 protein includes TYR1181. In some embodiments, the binding region of the DCAF1 protein includes ARG1225. In some embodiments, the binding region of the DCAF1 protein includes CYS1227. In some embodiments, the binding region of the DCAF1 protein includes ILE1262. In some embodiments, the binding region of the DCAF1 protein includes VAL1265. In some embodiments, the binding region of the DCAF1 protein includes ARG1298. In some embodiments, the binding region of the DCAF1 protein includes VAL1299. In some embodiments, the binding region of the DCAF1 protein includes VAL1300. In some embodiments, the binding region of the DCAF1 protein includes LYS1327. In some embodiments, the binding region of the DCAF1 protein includes PRO1329. In some embodiments, the binding region of the DCAF1 protein includes PHE1355. In some embodiments, one or more DCAF1 residues are non-covalently bound to the compound. Figure 1 A docking model of an exemplary compound (compound A8) that can bind to the said binding region of the DCAF1 protein is shown.

[0084] In some embodiments, the binding between the DCAF1 protein and the compound includes one or more of salt bridges, hydrogen bonds, stereoelectronic interactions, and dispersed contacts. In some embodiments, the binding between the DCAF1 protein and the compound includes a salt bridge. In some embodiments, the binding between the DCAF1 protein and the compound includes one or more hydrogen bonds. In some embodiments, the binding between the DCAF1 protein and the compound includes stereoelectronic interactions. In some embodiments, the binding between the DCAF1 protein and the compound includes dispersed contacts.

[0085] In some embodiments, the binding between the DCAF1 protein and the ligand involves a binding affinity having an equilibrium dissociation constant (K0) below 1500 μM. d K below 1250 μM d K below 1000 μM d K below 750 μM d K below 500 μM d K below 450 μM d K below 400 μM d K below 350 μM d K below 300 μM d K below 250 μM d K below 200 μM d K below 150 μM d K below 100 μM d K below 90 μM d K below 80 μM d K below 70 μM d K below 60 μM d Km below 50 μM, below 45 μM d K below 40 μM d K below 35 μM d K below 30 μM d K below 25 μM d or below 20 μM K d In some implementations, K d It is 100 μM or smaller. In some implementations, K d It is 70 μM or smaller. In some implementations, K d It is 40 μM or smaller. In some implementations, K d It is approximately 100 μM or smaller. In some implementations, K d It is approximately 70 μM or smaller. In some implementations, K d It is approximately 40 μM or smaller.

[0086] In some embodiments, the binding between the DCAF1 protein and the ligand includes a binding affinity having a K+ value greater than 1250 μM. d K higher than 1000 μM d K higher than 750 μM d K higher than 500 μM d K higher than 450 μM d K higher than 400 μM d K higher than 350 μM d K higher than 300 μM d K higher than 250 μM d K higher than 200 μM d K higher than 150 μM d K higher than 100 μM d K higher than 90 μM d K higher than 80 μM d K higher than 70 μM d K higher than 60 μM d K higher than 50 μM d K higher than 45 μM d K higher than 40 μM d K higher than 35 μM d K higher than 30 μM d K higher than 25 μM d K higher than 20 μM d or higher than 15 μM K d In some implementations, K d Greater than 100. In some implementations, K d Greater than 70. In some implementations, K d Greater than 40. In some implementations, K d Greater than approximately 100. In some implementations, K d Greater than approximately 70. In some implementations, K d Greater than approximately 40.

[0087] In some embodiments, the binding between the DCAF1 protein and the compound includes a binding affinity having a K0... d ≤40uM, K d >40uM and ≤70uM, K d >70uM and ≤100uM, or K d >100 μM. In some embodiments, the binding between the DCAF1 protein and the compound includes having K dBinding affinity ≤40 μM. In some embodiments, the binding between the DCAF1 protein and the compound includes a K-type binding affinity. d Binding affinity >40 μM and ≤70 μM. In some embodiments, the binding between the DCAF1 protein and the compound includes a K-type affinity. d Binding affinity >70 μM and ≤100 μM. In some embodiments, the binding between the DCAF1 protein and the compound includes a K-type affinity. d Binding affinity >100µM.

[0088] compound

[0089] In one aspect, this paper provides compounds of formula Ia:

[0090]

[0091] Or its pharmaceutically acceptable salt, wherein:

[0092] Is it a single bond or a double bond?

[0093] R 1 Selected from H, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Halogenated alkyl and C 1-10 Heteroalkyl;

[0094] Each R 2 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0095] n is 0, 1, 2, 3 or 4;

[0096] The condition is that the compound of formula Ia is not

[0097] In some implementation schemes, R 1 Selected from H, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Halogenated alkyl and C 1-10 Heteroalkyl. In some embodiments, R 1Selected from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Halogenated alkyl and C 1-10 Heteroalkyl. In some embodiments, R 1 Selected from C 1-10 Halogenated alkyl and C 1-10 Heteroalkyl. In some embodiments, R 1 It is H. In some implementations, R 1 It is C 1-10 Alkyl group. In some embodiments, R 1 It is C 2-10 Alkenyl. In some embodiments, R 1 It is C 2-10 Alkyne group. In some embodiments, R 1 It is C 1-10 Halogenated alkyl groups. In some embodiments, R 1 It is C 1-10 Heteroalkyl groups.

[0098] In some implementations, each R 2 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 2 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl groups. In some embodiments, each R 2 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl groups. In some embodiments, each R 2 Independently selected from H, halogen, hydroxyl, amino, cyano, and nitro groups. In some embodiments, each R... 2 Independently, it is H. In some implementations, each R... 2 Independently, it is halogenated. In some implementations, each R...2 Independently, it is a hydroxyl group. In some embodiments, each R... 2 Independently, it is an amino group. In some embodiments, each R... 2 It is independently a cyano group. In some embodiments, each R... 2 It is independently a nitro group. In some implementations, each R... 2 C is independent 1-8 Alkyl group. In some embodiments, each R 2 C is independent 2-8 Alkenyl. In some embodiments, each R 2 C is independent 2-8 Alkyne group. In some implementations, each R 2 C is independent 1-8 Halogenated alkyl groups. In some embodiments, each R... 2 C is independent 1-8 Heteroalkyl. In some embodiments, each R 2 C is independent 1-8 Alkyl groups. In some embodiments, each R 2 C is independent 3-10 Carbocyclic group. In some embodiments, each R 2 Independently, it is a 3- to 10-membered heterocyclic group. In some implementations, each R 2 C is independent 6-10 Aryl. In some implementations, each R 2 Independently, it consists of 5 to 10 heteroaryl groups.

[0099] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0100] In another respect, this article provides compounds selected from the following:

[0101]

[0102]

[0103] Or its pharmaceutically acceptable salt.

[0104] In another respect, this paper provides a method for binding or modulating DDB1 and CUL4-associated factor 1 (DCAF1) in desired subjects, the method comprising administering a therapeutically effective amount of a compound of formula I:

[0105]

[0106] Or its pharmaceutically acceptable salt, wherein:

[0107] Is it a single bond or a double bond?

[0108] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10 -C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C 2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10 Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0109] R 2 Selected from C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic and 3 to 10-membered heterocyclic groups, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic and heterocyclic group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0110] Each R 3 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0111] n is 0, 1, 2, 3 or 4.

[0112] In some implementation schemes, R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10 -C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10 Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C 2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl groups) and -SO2 (C 1-8 (heteroalkyl), wherein each alkyl, alkenyl, ynyl, haloalkyl and heteroalkyl group is independently and optionally substituted by one or more substituents, which are independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl group. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8Heteroalkyl, -C(O)(C 1-8 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -SO2(C 1-8 alkyl), -SO2(C 1-8 Halogenated alkyl groups) and -SO2 (C 1-8 (heteroalkyl), wherein each alkyl group, haloalkyl group, and heteroalkyl group is independently and optionally substituted by one or more substituents, the one or more substituents being independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl group. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl, wherein each alkyl group, haloalkyl group and heteroalkyl group is independently and optionally substituted by one or more substituents, the one or more substituents being independently selected from halogen, hydroxyl, oxo, amino, cyano and nitro groups.

[0113] In some implementation schemes, R 2 Selected from C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl, C 3-10 Carbocyclic and 3 to 10-membered heterocyclic groups, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic and heterocyclic group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10Carbocyclic and 3 to 10-membered heterocyclic groups, wherein each alkyl, haloalkyl, heteroalkyl, carbocyclic and heterocyclic group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl group. In some embodiments, R 2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 The group comprises a carbocyclic group and a 3- to 10-membered heterocyclic group, wherein each alkyl, haloalkyl, heteroalkyl, carbocyclic, and heterocyclic group is independently and optionally substituted by one or more substituents selected independently from halogen, hydroxyl, oxo, amino, cyano, and nitro groups.

[0114] In some implementations, each R 3 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 3 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl groups. In some embodiments, each R 3 The group is independently selected from halogen, hydroxyl, amino, cyano, and nitro groups. In some embodiments, each R... 3 Independently, it is halogenated. In some implementations, each R... 3 Independently, it is a hydroxyl group. In some embodiments, each R... 3Independently, it is an amino group. In some embodiments, each R... 3 It is independently a cyano group. In some embodiments, each R... 3 It is independently a nitro group. In some implementations, each R... 3 C is independent 1-8 Alkyl group. In some embodiments, each R 3 C is independent 2-8 Alkenyl. In some embodiments, each R 3 C is independent 2-8 Alkyne group. In some implementations, each R 3 C is independent 1-8 Halogenated alkyl groups. In some embodiments, each R... 3 C is independent 1-8 Heteroalkyl. In some embodiments, each R 3 C is independent 1-8 Alkyl groups. In some embodiments, each R 3 Independently in some implementation schemes, each R 3 C is independent 3-10 Carbocyclic group. In some embodiments, each R 3 Independently, it is a 3- to 10-membered heterocyclic group. In some implementations, each R 3 C is independent 6-10 Aryl. In some implementations, each R 3 Independently, it consists of 5 to 10 heteroaryl groups.

[0115] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0116] In another respect, this paper provides compounds of formula IIa:

[0117]

[0118] Or its pharmaceutically acceptable salt, wherein:

[0119] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl;

[0120] R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl;

[0121] Each R 4 and each R 5 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0122] n is 0, 1, 2, or 3; and

[0123] m can be 0, 1, 2, 3, or 4.

[0124] In some implementation schemes, R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 1 Selected from H and C 1-8 Alkyl group. In some embodiments, R 1 It is H. In some implementations, R 1 It is C 1-8 Alkyl group. In some embodiments, R 1 It is C 2-8 Alkenyl. In some embodiments, R 1 It is C 2-8 Alkyne group. In some embodiments, R 1 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 1 It is C 1-8 Heteroalkyl groups.

[0125] In some implementation schemes, R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 2-8 alkenyl, C 2-8alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 2 and R 3 Independently selected from H and C 1-8 Alkyl group. In some embodiments, R 2 It is H. In some implementations, R 2 It is C 1-8 Alkyl group. In some embodiments, R 2 It is C 2-8 Alkenyl. In some embodiments, R 2 It is C 2-8 Alkyne group. In some embodiments, R 2 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 2 It is C 1-8 Heteroalkyl. In some embodiments, R 3 It is H. In some implementations, R 3 It is C 1-8 Alkyl group. In some embodiments, R 3 It is C 2-8 Alkenyl. In some embodiments, R 3 It is C 2-8 Alkyne group. In some embodiments, R 3 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 3 It is C 1-8 Heteroalkyl groups.

[0126] In some implementations, each R 4 and each R 5 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 and each R 5 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 4 and each R 5 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl groups. In some embodiments, each R 4 and each R 5 Independently selected from H, halogen, hydroxyl, amino, cyano, and nitro groups. In some embodiments, each R... 4 Independently, it is H. In some implementations, each R... 4 Independently, it is halogenated. In some implementations, each R... 4 Independently, it is a hydroxyl group. In some embodiments, each R... 4 Independently, it is an amino group. In some embodiments, each R... 4 It is independently a cyano group. In some embodiments, each R... 4 It is independently a nitro group. In some implementations, each R... 4 C is independent 1-8 Alkyl group. In some embodiments, each R 4 C is independent 2-8 Alkenyl. In some embodiments, each R 4 C is independent 2-8 Alkyne group. In some implementations, each R 4 C is independent 1-8 Halogenated alkyl groups. In some embodiments, each R... 4 C is independent 1-8 Heteroalkyl. In some embodiments, each R 4 C is independent 1-8 Alkyl groups. In some embodiments, each R 4 C is independent 3-10 Carbocyclic group. In some embodiments, each R 4 Independently, it is a 3- to 10-membered heterocyclic group. In some implementations, each R 4 C is independent 6-10 Aryl. In some implementations, each R 4 It is independently a 5- to 10-membered heteroaryl group. In some implementations, each R 5 Independently, it is H. In some implementations, each R... 5Independently, it is halogenated. In some implementations, each R... 5 Independently, it is a hydroxyl group. In some embodiments, each R... 5 Independently, it is an amino group. In some embodiments, each R... 5 It is independently a cyano group. In some embodiments, each R... 5 It is independently a nitro group. In some implementations, each R... 5 C is independent 1-8 Alkyl group. In some embodiments, each R 5 C is independent 2-8 Alkenyl. In some embodiments, each R 5 C is independent 2-8 Alkyne group. In some implementations, each R 5 C is independent 1-8 Halogenated alkyl groups. In some embodiments, each R... 5 C is independent 1-8 Heteroalkyl. In some embodiments, each R 5 C is independent 1-8 Alkyl groups. In some embodiments, each R 5 C is independent 3-10 Carbocyclic group. In some embodiments, each R 5 Independently, it is a 3- to 10-membered heterocyclic group. In some implementations, each R 5 C is independent 6-10 Aryl. In some implementations, each R 5 Independently, it consists of 5 to 10 heteroaryl groups.

[0127] In some implementations, n is 0, 1, 2, or 3. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0128] In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4.

[0129] In another respect, this article provides compounds selected from the following:

[0130]

[0131] Or its pharmaceutically acceptable salt.

[0132] In another respect, this paper provides a method for binding or modulating DDB1 and CUL4-associated factor 1 (DCAF1) in a desired object, the method comprising administering a therapeutically effective amount of a compound of formula II:

[0133]

[0134] Or its pharmaceutically acceptable salt, wherein:

[0135] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl;

[0136] R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10 -C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C 2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10 Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0137] Each R 4 Independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0138] n is 0, 1, 2, 3 or 4.

[0139] In some implementation schemes, R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 1 Selected from H and C 1-8 Alkyl group. In some embodiments, R 1 It is H. In some implementations, R 1 It is C 1-8 Alkyl group. In some embodiments, R 1 It is C 2-8 Alkenyl. In some embodiments, R 1 It is C 2-8 Alkyne group. In some embodiments, R 1 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 1 It is C 1-8 Heteroalkyl groups.

[0140] In some implementation schemes, R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 2-8 alkenyl, C2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 2-8 alkenyl), -C(O)(C 2-8 ynyl group), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10 -C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 2-8 alkenyl), -SO2(C 2-8 alkynyl group), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10 Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -C(O)(C 1-8 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -C(O)(C 3-10-C(O) (3 to 10 membered heterocyclic groups), -C(O) (C 6-10 aryl), -C(O) (5 to 10 heteroaryl), -SO2(C 1-8 alkyl), -SO2(C 1-8 Halogenated alkyl), -SO2(C 1-8 heteroalkyl), -SO2(C 3-10 -Carbocyclic group), -SO2 (3 to 10-membered heterocyclic group), -SO2 (C 6-10 Aryl) and -SO2 (5 to 10-membered heteroaryl), wherein each alkyl, haloalkyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently and optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -C(O)(C 1-8 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 1-8 heteroalkyl), -SO2(C 1-8 alkyl), -SO2(C 1-8 Halogenated alkyl groups) and -SO2 (C 1-8 (heteroalkyl), wherein each alkyl group, haloalkyl group, and heteroalkyl group is independently and optionally substituted by one or more substituents, the one or more substituents being independently selected from halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl group. In some embodiments, R 2 and R 3 Independently selected from H and C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl, wherein each alkyl group, haloalkyl group, and heteroalkyl group is independently and optionally substituted with one or more substituents, the one or more substituents being independently selected from halogen, hydroxyl, oxo, amino, cyano, and nitro groups. In some embodiments, R 2 and R 3Independently selected from H and C 1-8 alkyl.

[0141] In some implementations, each R 4 Independently, it is halogenated. In some implementations, each R... 4 Independently, it is a hydroxyl group. In some embodiments, each R... 4 Independently, it is an amino group. In some embodiments, each R... 4 It is independently a cyano group. In some embodiments, each R... 4 It is independently a nitro group. In some implementations, each R... 4 C is independent 1-8 Alkyl group. In some embodiments, each R 4 C is independent 2-8 Alkenyl. In some embodiments, each R 4 C is independent 2-8 Alkyne group. In some implementations, each R 4 C is independent 1-8 Halogenated alkyl groups. In some embodiments, each R... 4 C is independent 1-8 Heteroalkyl. In some embodiments, each R 4 C is independent 1-8 Alkyl groups. In some embodiments, each R 4 C is independent 3-10 Carbocyclic group. In some embodiments, each R 4 Independently, it is a 3- to 10-membered heterocyclic group. In some implementations, each R 4 C is independent 6-10 Aryl. In some implementations, each R 4 Independently, it consists of 5 to 10 heteroaryl groups.

[0142] In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0143] In another respect, this article provides compounds selected from the following:

[0144]

[0145]

[0146] Or its pharmaceutically acceptable salt.

[0147] In another respect, this paper provides a method for binding or modulating DDB1 and CUL4-associated factor 1 (DCAF1) in desired subjects, the method comprising administering a therapeutically effective amount of a compound of formula III:

[0148]

[0149] Or its pharmaceutically acceptable salt, wherein:

[0150] Ring A is selected from none, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0151] X is selected from N and CR. 7 ;

[0152] R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0153] R 2 R 3 and R 7 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups;

[0154] R 4 and R 5 Independently selected from H, halogen, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 aryl and 5- to 10-membered heteroaryl; or

[0155] R 4 and R 5 Together they form oxygen;

[0156] Each R 6 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups; and

[0157] n is 0, 1, 2, 3, 4, 5, or 6.

[0158] In some implementation schemes, ring A is selected from none, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, ring A is absent. In some embodiments, ring A is C. 3-10 Carbocyclic group. In some embodiments, ring A is a 3- to 10-membered heterocyclic group. In some embodiments, ring A is C 6-10 Aryl. In some embodiments, ring A is a 5- to 10-membered heteroaryl group.

[0159] In some implementations, X is selected from N and CR. 7 In some implementations, X is N. In some implementations, X is CR. 7 .

[0160] In some implementation schemes, R 1 Selected from H, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 1 Selected from H, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 1It is H. In some implementations, R 1 It is C 1-8 Alkyl group. In some embodiments, R 1 It is C 2-8 Alkenyl. In some embodiments, R 1 It is C 2-8 Alkyne group. In some embodiments, R 1 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 1 It is C 1-8 Heteroalkyl. In some embodiments, R 1 It is C 3-10 Carbocyclic group. In some embodiments, R 1 It is a 3- to 10-membered heterocyclic group. In some implementations, R 1 It is C 6-10 Aryl. In some implementations, R 1 It consists of 5 to 10 aryl compounds.

[0161] In some implementation schemes, R 2 R 3 and R 7 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 2 R 3 and R 7 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 2 R 3 and R 7 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C 1-8 Alkyl group. In some embodiments, R 2 R3 and R 7 Independently selected from H, halogen, hydroxyl, amino, cyano, and nitro groups. In some embodiments, R 2 It is H. In some implementations, R 2 It is halogenated. In some implementations, R 2 It is a hydroxyl group. In some embodiments, R 2 It is an amino group. In some embodiments, R 2 It is cyano. In some implementations, R 2 It is a nitro group. In some implementations, R 2 It is C 1-8 Alkyl group. In some embodiments, R 2 It is C 2-8 Alkenyl. In some embodiments, R 2 It is C 2-8 Alkyne group. In some embodiments, R 2 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 2 It is C 1-8 Heteroalkyl. In some embodiments, R 2 It is C 1-8 Alkyl group. In some embodiments, R 2 It is C 3-10 Carbocyclic group. In some embodiments, R 2 It is a 3- to 10-membered heterocyclic group. In some implementations, R 2 It is C 6-10 Aryl. In some implementations, R 2 It is a 5- to 10-membered heteroaryl group. In some implementations, R 3 It is H. In some implementations, R 3 It is halogenated. In some implementations, R 3 It is a hydroxyl group. In some embodiments, R 3 It is an amino group. In some embodiments, R 3 It is cyano. In some implementations, R 3 It is a nitro group. In some implementations, R 3 It is C 1-8 Alkyl group. In some embodiments, R 3 It is C 2-8 Alkenyl. In some embodiments, R 3 It is C 2-8 Alkyne group. In some embodiments, R 3 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 3 It is C 1-8 Heteroalkyl. In some embodiments, R 3It is C 1-8 Alkyl group. In some embodiments, R 3 It is C 3-10 Carbocyclic group. In some embodiments, R 3 It is a 3- to 10-membered heterocyclic group. In some implementations, R 3 It is C 6-10 Aryl. In some implementations, R 3 It is a 5- to 10-membered heteroaryl group. In some implementations, R 7 It is H. In some implementations, R 7 It is halogenated. In some implementations, R 7 It is a hydroxyl group. In some embodiments, R 7 It is an amino group. In some embodiments, R 7 It is cyano. In some implementations, R 7 It is a nitro group. In some implementations, R 7 It is C 1-8 Alkyl group. In some embodiments, R 7 It is C 2-8 Alkenyl. In some embodiments, R 7 It is C 2-8 Alkyne group. In some embodiments, R 7 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 7 It is C 1-8 Heteroalkyl. In some embodiments, R 7 It is C 1-8 Alkyl group. In some embodiments, R 7 It is C 3-10 Carbocyclic group. In some embodiments, R 7 It is a 3- to 10-membered heterocyclic group. In some implementations, R 7 It is C 6-10 Aryl. In some implementations, R 7 It consists of 5 to 10 aryl compounds.

[0162] In some implementation schemes, R 4 and R 5 Independently selected from H, halogen, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 aryl and 5 to 10-membered heteroaryl; or R 4 and R 5 Together they form an oxygen atom. In some implementations, R4 and R 5 Together they form an oxygen atom. In some implementations, R 4 and R 5 Independently selected from H, halogen, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Independently selected from H, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, R 4 and R 5 Independently selected from H, halogen, cyano, nitro, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 1-8 Heteroalkyl. In some embodiments, R 4 and R 5 Independently selected from H, halogen, cyano, and nitro groups. In some embodiments, R 4 It is H. In some implementations, R 4 It is halogenated. In some implementations, R 4 It is cyano. In some implementations, R 4 It is a nitro group. In some implementations, R 4 It is C 1-8 Alkyl group. In some embodiments, R 4 It is C 2-8 Alkenyl. In some embodiments, R 4 It is C 2-8 Alkyne group. In some embodiments, R 4 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 4 It is C 1-8 Heteroalkyl. In some embodiments, R 4 It is C 3-10 Carbocyclic group. In some embodiments, R 4 It is a 3- to 10-membered heterocyclic group. In some implementations, R 4 It is C 6-10 Aryl. In some implementations, R4 It is a 5- to 10-membered heteroaryl group. In some implementations, R 5 It is H. In some implementations, R 5 It is halogenated. In some implementations, R 5 It is cyano. In some implementations, R 5 It is a nitro group. In some implementations, R 5 It is C 1-8 Alkyl group. In some embodiments, R 5 It is C 2-8 Alkenyl. In some embodiments, R 5 It is C 2-8 Alkyne group. In some embodiments, R 5 It is C 1-8 Halogenated alkyl groups. In some embodiments, R 5 It is C 1-8 Heteroalkyl. In some embodiments, R 5 It is C 3-10 Carbocyclic group. In some embodiments, R 5 It is a 3- to 10-membered heterocyclic group. In some implementations, R 5 It is C 6-10 Aryl. In some implementations, R 5 It consists of 5 to 10 aryl compounds.

[0163] In some implementations, each R 6 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 6 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, C 1-8 Alkoxy, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl groups. In some embodiments, each R 6 Independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl and C1-8 Alkyl groups. In some embodiments, each R 6 Independently selected from H, halogen, hydroxyl, amino, cyano, and nitro groups. In some embodiments, each R... 6 Independently, it is H. In some implementations, each R... 6 Independently, it is halogenated. In some implementations, each R... 6 Independently, it is a hydroxyl group. In some embodiments, each R... 6 Independently, it is an amino group. In some embodiments, each R... 6 It is independently a cyano group. In some embodiments, each R... 6 It is independently a nitro group. In some implementations, each R... 6 C is independent 1-8 Alkyl group. In some embodiments, each R 6 C is independent 2-8 Alkenyl. In some embodiments, each R 6 C is independent 2-8 Alkyne group. In some implementations, each R 6 C is independent 1-8 Halogenated alkyl groups. In some embodiments, each R... 6 C is independent 1-8 Heteroalkyl. In some embodiments, each R 6 C is independent 1-8 Alkyl groups. In some embodiments, each R 6 C is independent 3-10 Carbocyclic group. In some embodiments, each R 6 Independently, it is a 3- to 10-membered heterocyclic group. In some implementations, each R 6 C is independent 6-10 Aryl. In some implementations, each R 6 Independently, it consists of 5 to 10 heteroaryl groups.

[0164] In some implementations, n is 0, 1, 2, 3, 4, 5, or 6. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 5. In some implementations, n is 6.

[0165] In some embodiments, the compounds shown in Table 1 are provided herein.

[0166] Table 1. Exemplary Compounds

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184] Preparation of compounds

[0185] The compounds used in the chemical reactions described herein can be prepared from commercially available chemicals and / or compounds described in chemical literature, based on organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Paris Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0186] Suitable references and papers that detail the synthesis of reactants used to prepare the compounds described herein or provide citations to articles describing such preparations include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SRSandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," 2nd ed., WABenjamin, Inc., Menlo Park, Calif., 1972; TL Gilchrist, "Heterocyclic Chemistry," 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," 4th ed., Wiley-Interscience, New York, 1992. Additional suitable references and papers that detail the synthesis of reactants used to prepare the compounds described herein or provide citations to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G., “Organic Synthesis: Concepts, Methods, Starting Materials”, Second Revised and Supplemented Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC., “Comprehensive Organic Transformations: A Guide to Functional Group Preparations”, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J., “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 4th Edition (1992) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., “Organic Chemistry: Concepts, Methods, Starting Materials”, Second Revised and Supplemented Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., “Organic Chemistry: Concepts, Methods, Starting Materials”, Second Revised Edition (19 ... Wiley-VCH ISBN: Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann'sEncyclopedia"(1999)John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942–2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups," John Wiley & Sons, 73 volumes.

[0187] Alternatively, specific and similar reactants can be found through an index of known chemicals and reactions compiled by the American Chemical Society's Chemical Abstracts Service (available in most public and university libraries) and through online databases (for more details, please contact the American Chemical Society in Washington, D.C.). Chemicals known in the catalog but not commercially available may optionally be prepared by custom chemical synthesis companies, many of which are standard chemical suppliers (such as those listed above) that offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PHStahl & C.G. Wermuth, “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.

[0188] The compounds described herein can be prepared using general methods in the field of organic synthesis, as described in the Examples section. Alternative synthetic methods are also available for producing the compounds described herein.

[0189] Characterization of exemplary compounds

[0190] The binding affinity of specific exemplary compounds to DCAF1(1058-1396) (which is a fragment of the DCAF1 protein containing amino acid residues A1058 to E1396) was determined by surface plasmon resonance (SPR) assay. Briefly, purified DCAF1(1058-1396) protein was immobilized on a CM5 sensor chip at a density of 9,000–11,000 resonance units (RU). Sensing maps were recorded at different compound concentrations in a multi-cycle kinetic manner. The data were analyzed using Biacore evaluation software based on a steady-state affinity model to provide the equivalent dissociation constant (K0). d Data shows that the exemplary compounds bind to DCAF1 in a concentration-dependent manner, and some binding affinities (K... d The range is from 15 μM to 65 μM. Figures 2A-2F (Table 2).

[0191] Methods of combining or modulating DCAF1

[0192] In some embodiments, the compounds described herein are used to bind the DCAF1 protein. The compounds may include those listed in Table 1 or of formulas Ia, I, IIa, II, or III. In some embodiments, the compounds described herein are used to regulate the DCAF1 protein. In some embodiments, the compounds described herein are used to inhibit the DCAF1 protein. Some embodiments include contacting the DCAF1 protein with the compounds described herein. This contact may include applying the compound to a subject containing the DCAF1 protein. This contact may include applying the compound to cells containing the DCAF1 protein. This contact may include applying the compound to a sample containing the DCAF1 protein. This contact may include applying the compound to a solution containing the DCAF1 protein. This contact may be in vivo. This contact may be in vitro. The compounds may bind to the DCAF1 protein with the binding affinity described herein.

[0193] In some embodiments, the compounds described herein bind to DCAF1 proteins, such as the full-length DCAF1 protein. In some embodiments, the compounds described herein bind to DCAF1 fragments.

[0194] Treatment methods and pharmaceutical compositions

[0195] In some embodiments, the compounds described herein are used to treat a subject. Some embodiments include administering the compounds described herein to a subject, such as any compound from Table 1 or formula Ia, I, IIa, II, or III. Some embodiments include administering the compounds described herein to a subject in need. Some embodiments include administering a pharmaceutical composition comprising the compound to a subject. Some embodiments include providing the compounds or pharmaceutical compositions described herein to a subject.

[0196] In some embodiments, the modified proteins disclosed herein are formed in vivo upon administration of the compound or pharmaceutical composition to a subject. In some embodiments, the ligand-protein complexes disclosed herein are formed by administration of the compound or pharmaceutical composition to a subject.

[0197] In some embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, based on the chosen route of administration and standard pharmaceutical practice, such as that described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)), the compounds described herein are combined with a selected pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier). One embodiment provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0198] This document provides a pharmaceutical composition comprising at least one compound described herein or a stereoisomer thereof, a pharmaceutically acceptable salt or N-oxide, and one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is harmless to the recipient of the composition (i.e., the subject or patient). In some embodiments, the excipient comprises a buffer or solution. In some embodiments, the pharmaceutical composition is sterile.

[0199] In some embodiments, the compound described herein is substantially pure, i.e., it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts, for example, generated in one or more steps of the synthetic method.

[0200] Some embodiments include the use of the compound described herein, the use of a ligand-DCAF1 complex, or the use of a modified DCAF1 protein in vivo. In some embodiments, the use includes administering the compound to a subject. In some embodiments, the use includes contacting a sample with the compound.

[0201] Examples of objects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the object is a mammal. In some embodiments, the object is a human.

[0202] In some embodiments, administering the compound to the subject comprises administering an effective amount of the compound. In some embodiments, the administration is intravenous. In some embodiments, the administration comprises injection. In some embodiments, the administration is local. In some embodiments, the administration is systemic.

[0203] In some embodiments, the sample is a biological sample. In some embodiments, the biological sample includes tissue, cells, or biological fluid. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo.

[0204] definition

[0205] As used herein and in the appended claims, unless the context clearly specifies otherwise, the singular forms “an,” “a,” and “the” include the plural referents. Thus, for example, reference to “an agent” includes multiple such agents, and reference to “the cell” includes reference to one or more cells (or multiple cells) and their equivalents known to those skilled in the art. When the scope is used herein for physical properties such as molecular weight or chemical properties such as a chemical formula, it is intended to include all combinations and sub-combinations of the scope and specific embodiments thereof. When referring to a numerical value or range of values, the term “about” means that the referred numerical value or range of values ​​is an approximation within experimental variability (or within statistical experimental error), and thus, in some instances, the numerical value or range of values ​​will vary from 1% to 15% of the stated numerical value or range of values. The term “comprising” (and related terms such as “including,” “containing,” or “having”) is not intended to exclude, in certain other embodiments, such as embodiments of any composition, composition, method, or process described herein, from being “consisting of” or “substantially composed of” the stated features.

[0206] As used in the specification and appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0207] "Amino" refers to the –NH2 group.

[0208] "Cyano" refers to the -CN group.

[0209] "Nitro" refers to the -NO2 group.

[0210] "O-" refers to the -O- group.

[0211] "Oxo" refers to the =O group.

[0212] "Thio" refers to the =S group.

[0213] "Imine" refers to the =NH group.

[0214] "Oxime group" refers to the =N-OH group.

[0215] "Hydrazine" refers to the =N-NH2 group.

[0216] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, and having one to fifteen carbon atoms (e.g., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises one to thirteen carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halogroup, cyanogroup, nitrogroup, oxogroup, thiogroup, iminogroup, oxime group, trimethylsilyl group, R group. a -OR a -SR a -OC(O)-Ra -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0217] "Alkoxy" refers to a group of the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0218] "Halogenated alkyl" refers to an alkyl group substituted with one or more halogens. Exemplary halogenated alkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0219] “Heteroalkyl,” “heteroalkenyl,” and “heteroyneyl” refer to substituted or unsubstituted alkyl, alkenyl, and ynyl groups, each having one or more main chain atoms selected from atoms other than carbon. Exemplary main chain atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, wherein nitrogen, phosphorus, and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. If specified, numerical ranges refer to the total chain length. For example, 3- to 8-membered heteroalkyl groups have chain lengths of 3 to 8 atoms. Connection to the remainder of the molecule can be via heteroatoms or carbon atoms in the heteroalkyl, heteroalkenyl, or heteroyneyl chain. Unless otherwise expressly stated in this specification, heteroalkyl, heteroalkenyl, or heteroyne groups are optionally substituted with one or more substituents such as those described herein.

[0220] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In some embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is attached to the rest of the molecule by a single bond, such as vinyl, propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, pentenyl, 1,4-dienyl, etc. Unless otherwise specifically stated in this specification, the alkenyl group may optionally be substituted by one or more of the following substituents: halogroup, cyanogroup, nitrogroup, oxogroup, thiogroup, iminogroup, oxime group, trimethylsilyl group, R group. a -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0221] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In some embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group contains two to six carbon atoms. In still other embodiments, the alkynyl group contains two to four carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Unless otherwise specifically stated in this specification, the alkynyl group may optionally be substituted by one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, R a -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0222] "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, without any unsaturation, and having one to twelve carbon atoms, with the remainder of the molecule attached to a group. Examples include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the remainder of the molecule and to the group via single bonds. The attachment points of the alkylene chain to the remainder of the molecule and to the group are through one carbon atom or any two carbon atoms in the chain. In some embodiments, the alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in this specification, the alkylene chain may optionally be substituted with one or more of the following substituents: halogroup, cyanogroup, nitrogroup, oxogroup, thiogroup, iminogroup, oximegroup, trimethylsilyl group, R group. a -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)ORa -OC(O)-N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0223] "Aryl" refers to a group derived from aromatic monocyclic or polycyclic hydrocarbon ring systems by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon, ranging from five to eighteen carbon atoms, wherein at least one ring in the ring system is fully unsaturated, meaning it contains a cyclic, delocalized (4n+2)π-electron system conforming to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene. Unless otherwise specified in this specification, the term "aryl" or the prefix "aromatic" (such as in "arylalkyl") refers to an aryl group that is optionally substituted with one or more substituents, which are independently selected from alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a -R b -OR a -R b -OC(O)-R a -Rb -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0224] "Aryl group" refers to the formula -R c -aryl groups, where R c It is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group may optionally be substituted, as described above for the alkylene chain. The aryl portion of the aralkyl group may optionally be substituted, as described above for the aryl group.

[0225] A "carbocyclic group" is a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems, having three to fifteen carbon atoms. In some embodiments, the carbocyclic group contains three to ten carbon atoms. In other embodiments, the carbocyclic group contains five to seven carbon atoms. The carbocyclic group is attached to the rest of the molecule by a single bond. The carbocyclic group is either saturated (i.e., containing only C-C single bonds) or unsaturated (i.e., containing one or more double or triple bonds). A fully saturated carbocyclic group is also called a "carbocyclic group". Examples of monocyclic carbocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic groups are also called "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclic [2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethylbicyclic [2.2.1]heptyl, etc. Unless otherwise specifically stated in this specification, the term "carbocyclic" is intended to include carbocyclic groups optionally substituted with one or more substituents, which are independently selected from alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b-OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0226] "Carbocycloalkyl" refers to the formula -R c - A carbocyclic group, wherein R c It is an alkylene chain as defined above. The alkylene chain and carbocyclic group are optionally substituted as defined above.

[0227] "Halogen" or "halogen" refers to a bromine, chlorine, fluorine, or iodine substituent.

[0228] "Fluoroalkyl" refers to an alkyl group as defined above, which is substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be substituted, as defined above for alkyl groups.

[0229] A "heterocyclic group" refers to a stable 3- to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in this specification, a heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused or bridged ring systems. The heteroatoms in the heterocyclic group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclic group is partially or fully saturated. The heterocyclic group is attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclic groups include, but are not limited to, dioxacyclopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiohexanealkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically stated in this specification, the term "heterocyclic" is intended to include heterocyclic groups as defined above, optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(Ra )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0230] "N-heterocyclic group" or "N-attached heterocyclic group" refers to a heterocyclic group as defined above containing at least one nitrogen atom, wherein the attachment point of the heterocyclic group to the rest of the molecule is through a nitrogen atom in the heterocyclic group. The N-heterocyclic group may optionally be substituted, as described above for heterocyclic groups. Examples of such N-heterocyclic groups include, but are not limited to, 1-morpholino, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolyl, imidazolinyl, and imidazolinyl.

[0231] A “C-heterocyclic group” or “C-attached heterocyclic group” refers to a heterocyclic group as defined above containing at least one heteroatom, wherein the attachment point of the heterocyclic group to the rest of the molecule is through a carbon atom in the heterocyclic group. The C-heterocyclic group may optionally be substituted, as described above for heterocyclic groups. Examples of such C-heterocyclic groups include, but are not limited to, 2-morpholino, 2-piperidinyl, or 3-piperidinyl, or 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl, etc.

[0232] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group, comprising two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system wherein at least one ring in the ring system is fully unsaturated, i.e., it comprises a cyclic, delocalized (4n+2)π-electron system conforming to Hückel's theory. Heteroaryls include fused-ring or bridged-ring systems. The heteroatoms in the heteroaryl are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl is attached to the remainder of the molecule via any atom of the ring. Examples of heteroaryls include, but are not limited to, nitrogen-containing heteroaryls. 1,3-benzodioxane-1, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxane Benz[b][1,4]oxazinyl, 1,4-benzodioxane, benzonaphthofuryl, benzoxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexadienyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophenyl, benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thiophene[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]pyrimidinyl, 6,7-dihydro-5H-benzyl [6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridyl, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, 5,8-methylbridged-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphridinoneyl, oxadiazolyl, 2-oxoazapyridine 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroleyl, quinazolinyl, quinoxalinyl, isoquinolinyl, tetrahydroquinazolinyl Linyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridino[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thienoyl. Unless otherwise specifically stated in this specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, haloalkenyl, haloynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a)C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise stated.

[0233] "N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the attachment point of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The N-heteroaryl group may optionally be substituted, as described above for heteroaryl groups.

[0234] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the attachment point of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The C-heteroaryl group may optionally be substituted, as described above for heteroaryl groups.

[0235] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers, defined in absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, all stereoisomers of the compounds disclosed herein are intended to be taken into account in this disclosure. When the compounds described herein contain an alkene double bond, unless otherwise stated, this disclosure is intended to include E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomers are also intended to be included. The term “geometric isomer” refers to the E or Z geometric isomer of the alkene double bond (e.g., cis or trans). The term “positional isomer” refers to a structural isomer surrounding a central ring, such as ortho, meta, and para isomers surrounding a benzene ring.

[0236] A "tautomer" is a molecule in which it is possible for a proton to transfer from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibria include:

[0237]

[0238] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, such as enriched isotopes. 2 H, 3 H, 11 C 13 C and / or 14 The content of C. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0239] Unless otherwise stated, the structures described herein are intended to include compounds distinguished solely by the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than C-enriched carbon substitutions, are within the scope of this disclosure.

[0240] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may be labeled with isotopes, such as deuterium (…). 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). Use 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br、 125 Isotopic substitutions are all considered. All isotopic variations of the compounds of this invention, whether or not they are radioactive, are covered within the scope of this invention.

[0241] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and the following synthetic methods are included only as non-limiting examples.

[0242] Deuterium-substituted compounds are synthesized using various methods, such as those described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0243] Deuterated starting materials are readily available and can be used to synthesize deuterium-containing compounds via the synthetic methods described herein. A wide range of deuterium-containing reagents and structural units are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0244] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. The term "pharmaceutically acceptable salt" for any compound described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0245] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, are not undesirable in biological or other respects, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. This also includes salts formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids, such as arginine salts, gluconates, and galacturons, are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 66:1-19 (1997)). In some implementations, an acid addition salt of a basic compound is prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt, according to methods and techniques familiar to those skilled in the art.

[0246] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the bioavailability and properties of the free acid and are not undesirable in biological or other respects. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following organic bases: primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., ibid.

[0247] Example

[0248] The following embodiments are provided to illustrate to those skilled in the art the principles and practices of the examples disclosed herein and should not be construed as limiting the scope of any claimed examples. Unless otherwise stated, all shares and percentages are based on weight.

[0249] The following are non-limiting examples of compound synthesis schemes.

[0250] Example 1: 1-(1-methyl-1H-pyrrolo-2-yl)-N-(pyridin-4-ylmethyl)methylamine (CPD-001)

[0251]

[0252] A mixture of 1-methyl-1H-pyrrolo-2-carboxaldehyde (218 mg, 2.0 mmol) and pyridin-4-ylmethylamine (216 mg, 2.0 mmol) in MeOH (5 mL) was stirred at room temperature (rt) for 16 h. Then, NaBH4 (91 mg, 2.4 mmol) was added and stirred at room temperature for 30 min. The mixture was concentrated, and the residue was diluted with DCM, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 10:1) to provide the title compound as a colorless oil (239 mg, yield: 59%). MS (ESI) m / z = 201.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.54(d,J=6.0Hz,2H),7.27(d,J=5.6Hz,2H),6.60(t,J=2.0Hz,1H),6.05–6.02(m,2H),3.83(s,2H),3.74(s,2H),3.65(s,3H).

[0253] Example 2: 1-(1-methyl-1H-pyrrolo-2-yl)-N-(pyridin-3-ylmethyl)methylamine (CPD-002)

[0254]

[0255] CPD-002 (235 mg, yield: 58%) was synthesized according to the standard procedure used for the preparation of CPD-001, as a colorless oil. MS (ESI) m / z = 202.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=1.6Hz,1H),8.50(dd,J=1.6,4.4Hz,1H),7.67(d,J=7.6Hz,1H),7 .27–7.24(m,1H),6.59(t,J=2.4Hz,1H),6.05–6.02(m,2H),3.83(s,2H),3.74(s,2H),3.63(s,3H).

[0256] Example 3: 1-(1-methyl-1H-pyrrolo-2-yl)-N-(pyridin-2-ylmethyl)methylamine (CPD-003)

[0257]

[0258] CPD-003 (263 mg, yield: 65%) was synthesized according to the standard procedure used for the preparation of CPD-001, as a colorless oil. MS (ESI) m / z = 202.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 1.6, 7.2 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H), 6.04 (d, J = 2.0 Hz, 2H), 3.93 (s, 2H), 3.78 (s, 2H), 3.65 (s, 3H).

[0259] Example 4: 1-(6-aminohexyl)-N-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxamide (CPD-004)

[0260]

[0261] Step 1. Synthesis of 6-((tert-Butoxycarbonyl)amino)hexyl methanesulfonate

[0262]

[0263] MsCl (1.76 g, 15.4 mmol) was added to a mixture of tert-butyl 6-hydroxyhexyl)carbamate (3.2 g, 14.7 mmol) and TEA (1.78 g, 17.64 mmol) in DCM (32 mL) in an ice bath. The mixture was stirred at room temperature for 5 h, then diluted with water (50 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, concentrated, and purified by silica gel chromatography (petroleum ether:EtOAc = 8:1) to provide the title compound (2.8 g, yield: 64%) as a yellow solid.

[0264] Step 2. Synthesis of 1-(6-((tert-Butoxycarbonyl)amino)hexyl)-1H-pyrrole-2-carboxylic acid

[0265]

[0266] NaH (60%, 160 mg, 4 mmol) was added to a mixture of methyl 1H-pyrrole-2-carboxylate (250 mg, 2 mmol) in THF (4 mL) at 10 °C. The reaction mixture was stirred for 30 min, and then 6-((tert-butoxycarbonyl)amino)hexyl methanesulfonate (592 mg, 2 mmol) was added at room temperature. The mixture was stirred at 50 °C for 18 h, and then the reaction was quenched with water (8 mL). The aqueous phase was extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine, concentrated, and purified by silica gel chromatography (petroleum ether:EtOAc = 1:2) to provide the title compound as a white solid (220 mg, yield: 84%).

[0267] Step 3. Synthesis of tert-butyl carbamate (6-(2-((pyridin-4-ylmethyl)carbamoyl)-1H-pyrrolo-1-yl)hexyl)carbamate

[0268]

[0269] A mixture of pyridin-4-ylmethylamine (80.6 mg, 0.746 mmol), 1-(6-((tert-butyloxycarbonyl)amino)hexyl)-1H-pyrrole-2-carboxylic acid (220 mg, 0.71 mmol), HATU (296.4 mg, 0.78 mmol), and DIEA (274.8 mg, 2.14 mmol) in DMF (4 mL) was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL), and the aqueous phase was then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, concentrated, and purified by silica gel chromatography (petroleum ether:EtOAc = 2:1) to provide the title compound (70 mg, yield: 67%) as a white solid. MS (ESI) m / z = 401.1 [M+H] + .

[0270] Step 4. Synthesis of 1-(6-aminohexyl)-N-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxamide

[0271]

[0272] HCl (3M, 1 mL in MeOH) was added to a solution of tert-butyl carbamate (70 mg, 0.175 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 4 h, and then the reaction mixture was concentrated and neutralized with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, concentrated, and purified by preparative HPLC (0.1% NH4HCO3 in H2O) to provide the title compound (48 mg, yield: 91%) as a clear oil. MS (ESI) m / z = 301.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.55(d,J=5.6Hz,2H),7.24(d,J=6.0Hz,2H),6.81(t,J=2.0Hz,1H),6.61(dd,J=2.0,4.0Hz,1H),6.40(t,J=5.6Hz,1H),6.11( dd,J=2.0,6.0Hz,1H),4.58(d,J=6.0Hz,2H),4.34(t,J=7.2Hz,2H),2.66( t,J=6.8Hz,2H),1.81–1.77(m,2H),1.44–1.39(m,2H),1.32–1.30(m,4H).

[0273] Example 5: 6-(2-(((pyridin-4-ylmethyl)amino)methyl)-1H-pyrrolo-1-yl)hex-1-amine (CPD-005)

[0274]

[0275] Step 1. Synthesis of tert-butyl (6-(2-formyl-1H-pyrrolo-1-yl)hexyl)carbamate

[0276]

[0277] In an ice bath, 60% NaH (252 mg, 6.30 mmol) was added in portions to a solution of 1H-pyrrole-2-carboxaldehyde (300 mg, 3.15 mmol) in DMF (6 mL). The mixture was stirred for 0.5 h, and then 6-((tert-butyloxycarbonyl)amino)hexyl methanesulfonate (1024 mg, 3.47 mmol) was added. The reaction mixture was stirred overnight at room temperature, and then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine and concentrated. The residue was purified by silica gel chromatography (petroleum ether:EtOAc = 50:1 to 15:1) to provide the title compound (650 mg, yield: 70%) as a colorless oil. MS (ESI) m / z = 295.2 [M+H] + .

[0278] Step 2. Synthesis of 1-(6-aminohexyl)-1H-pyrrole-2-carboxaldehyde

[0279]

[0280] A solution of tert-butyl carbamate (250 mg, 0.85 mmol) in HCl (3 M, 5 mL in EtOAc) was stirred at room temperature for 3 h. The solution was concentrated, and then DCM (10 mL) was added. The mixture was cooled to 0 °C in an ice bath, and then TEA (268 mg, 1.28 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to provide the title compound (240 mg, crude) as a brown oil, which was used directly in the next step without further purification. MS (ESI) m / z = 195.2 [M+H]+.

[0281] Step 3. Synthesis of 2,2,2-trifluoro-N-(6-(2-formyl-1H-pyrrolo-1-yl)hexyl)acetamide

[0282]

[0283] TEA (429 mg, 4.25 mmol) and TFAA (268 mg, 1.28 mmol) were added to a solution of 1-(6-aminohexyl)-1H-pyrrole-2-carboxaldehyde (240 mg, 0.85 mmol) in DCM (10 mL) in an ice bath. The reaction mixture was stirred at room temperature for 16 h, and then the mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine and concentrated. The residue was purified by preparative TLC (petroleum ether:EtOAc = 5:1) to provide the title compound as a colorless oil (46 mg, 2-step yield: 18%), MS (ESI) m / z = 289.1 [MH]. - .

[0284] Step 4. Synthesis of 2,2,2-trifluoro-N-(6-(2-(((pyridin-4-ylmethyl)amino)methyl)-1H-pyrrolo-1-yl)hexyl)acetamide

[0285]

[0286] A mixture of 2,2,2-trifluoro-N-(6-(2-formyl-1H-pyrrolo-1-yl)hexyl)acetamide (80 mg, 0.28 mmol) and pyridin-4-ylmethylamine (33 mg, 0.30 mmol) in MeOH (3 mL) was stirred at room temperature for 16 h. The mixture was cooled to 0 °C in an ice bath, and then NaBH4 (10.5 mg, 0.28 mmol) was added in portions. The reaction mixture was stirred for another 1 h, and then water (10 mL) was added. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine and concentrated. The residue was purified by preparative TLC to provide the title compound (50 mg, yield: 48%) as a colorless oil. MS (ESI) m / z = 381.1 [MH] - .

[0287] Step 5. Synthesis of 6-(2-(((pyridin-4-ylmethyl)amino)methyl)-1H-pyrrolo-1-yl)hexyl-1-amine

[0288]

[0289] K₂CO₃ (58 mg, 0.42 mmol) was added to a solution of 2,2,2-trifluoro-N-(6-(2-(((pyridin-4-ylmethyl)amino)methyl)-1H-pyrrolo-1-yl)hexyl)acetamide (45 mg, 0.12 mmol) in MeOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h, and then filtered. The filtrate was concentrated and the resulting residue was purified by preparative HPLC (0.1% NH₄HCO₃ in H₂O) to provide the title compound (26 mg, yield: 77%) as a pale yellow oil. MS (ESI) m / z = 287.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=6.0Hz,2H),7.33(d,J=5.6Hz,2H),6.66(t,J=2.0Hz,1H),5.88-5.86(m,2H ), 3.86 (t, J = 7.2Hz, 2H), 3.69 (s, 2H), 3.59 (s, 2H), 2.50–2.47 (m, 2H), 1.64–1.59 (m, 2H), 1.30–1.23 (m, 6H).

[0290] Example 6: 6-(2-(((pyridin-4-ylmethyl)amino)methyl)-1H-pyrrolo-1-yl)hex-1-amine (CPD-006)

[0291]

[0292] CPD-006 (16.6 mg, yield: 46%) was synthesized according to the standard procedure used for the preparation of CPD-005, as a pale yellow oil. MS (ESI) m / z = 363.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=5.6Hz,2H),7.34(d,J=5.2Hz,2H),6.71(s,1H),5.88–5.86(m,2H ), 4.06 (t, J = 5.6Hz, 2H), 3.69 (s, 2H), 3.65-3.62 (m, 4H), 3.46–3.36 (m, 10H), 2.64 (t, J = 5.2Hz, 2H).

[0293] Example 7: 3-Fluoro-N-((2-methyl-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)pyridine-2-amine (CPD-007)

[0294]

[0295] A solution of (2-methyl-1,2,3,4-tetrahydroisoquinoline-3-yl)methylamine (100 mg, 0.567 mmol), 2-chloro-3-fluoropyridine (75 mg, 0.567 mmol), Pd2(dba)3 (52 mg, 0.0567 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos) (33 mg, 0.0567 mmol), and t-BuONa (109 mg, 1.13 mmol) in toluene (10 mL) was stirred overnight at 100 °C under an argon atmosphere. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to give the title compound (21.0 mg, yield: 11.7%) as a colorless oil. 1 H NMR(400MHz, DMSO-d6)δ8.16(s,1H),7.81–7.80(m,1H),7.35–7.30(m,1H),7.13–7.04(m,4H),6.52–6.48(m,1H),6.46–6.44(m,1H) ),3.83–3.79(m,1H),3.65–3.56(m,2H),3.35–3.29(m,1H),3.06–3.00(m,1H),2.85–2.79(m,1H),2.73–2.67(m,1H),2.41(s,3H). MS(ESI)m / z=272.2[M+H] + .

[0296] Example 8: 2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-008)

[0297]

[0298] Step 1. Synthesis of tert-butyl 8-chloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid ester

[0299]

[0300] 4-O-piperidin-1-carboxylic acid tert-butyl ester (2.67 g, 13.4 mmol) was added to a solution of (4-chlorophenyl)hydrazine hydrochloride (2.00 g, 11.2 mmol) in AcOH (20 mL) at room temperature under an argon atmosphere. The mixture was heated to 60 °C for 16 h, then diluted with H₂O (30 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 3:1) to give the title compound (780 mg, 23.0% yield) as a yellow solid. MS (ESI) m / z = 307.4 [M+H] + .

[0301] Step 2. Synthesis of 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0302]

[0303] HCl / MeOH (10 mL, 3 M) was added to a solution of tert-butyl 8-chloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid (780 mg, 2.54 mmol) in MeOH (10 mL) at room temperature. The mixture was stirred at 40 °C for 2 h, and then the reaction mixture was concentrated to give a crude product (720 mg, 100% yield) as a yellow solid, which was used directly in the next step. MS (ESI) m / z = 207.4 [M+H]+.

[0304] Step 3. Synthesis of 2-(but-3-yn-1-yl)-8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0305]

[0306] Cs₂CO₃ (296 mg, 2.23 mmol) was added to a solution of 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (360 mg, 1.48 mmol) in DMF (10 mL). The reaction mixture was heated at 50 °C for 16 h, then cooled to room temperature, diluted with H₂O (20 mL), and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 3:1) to give the title compound (290 mg, 76.0% yield) as a yellow oil. MS (ESI) m / z = 259.1 [M+H] + .

[0307] Step 4. Synthesis of 2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0308]

[0309] CuSO4 (178 mg, 1.12 mmol), TMSN3 (129 mg, 1.12 mmol), and sodium ascorbate (221 mg, 1.12 mmol) were added to a solution of 2-(but-3-yn-1-yl)-8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (290 mg, 1.12 mmol) in t-BuOH / water (10 mL / 5 mL) at room temperature. The mixture was stirred at room temperature for 16 h, then the reaction mixture was diluted with H2O (20 mL) and filtered to give a crude product, which was further purified by preparative HPLC (0.1% TFA) to give the title compound (80 mg, 23.7% yield) as a yellow solid. MS (ESI) m / z = 302.4 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.46(s,1H),10.11(s,1H),7.80(br s,1H),7.56(d,J=1.6Hz,1H),7.38(d,J=8.4Hz,1H),7.10–7.12(m,1H),4.77–4.75(m,1H),4.53(br s,1H),3.85(brs,1H),3.58–3.60(m,3H),3.25–3.14(m,4H).

[0310] Example 9: 2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-009)

[0311]

[0312] CPD-009 (20 mg, yield: 4.3%) was synthesized according to the standard procedure used for the preparation of CPD-008, as a white solid. MS (ESI) m / z = 310.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),7.66(s,1H),7.17–7.15(m,2H),6.88(dd,J=1.6Hz,8.4Hz,1H),6.07(br s,1H),3.63(s,2H),2.96–2.75(m,9H),1.22(d,J=6.8Hz,6H).

[0313] Example 10: 2-(2-isopropyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetic acid (CPD-010)

[0314]

[0315] Step 1. Synthesis of tert-butyl 5-(2-ethoxy-2-oxoethyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid ester

[0316]

[0317] NaH (14.7 mg, 0.368 mmol) was added to a solution of 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (100 mg, 0.368 mmol) in DMF (2 mL) at room temperature under an argon atmosphere. The reaction was stirred at room temperature for 0.5 h, and then ethyl 2-bromoacetate (61.4 mg, 0.368 mmol) was added. The mixture was stirred at room temperature for 3 h, then diluted with H2O (20 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (110 mg, crude), which was used in the next step without further purification. MS (ESI) m / z = 359.5 [M+H] + .

[0318] Step 2. Synthesis of ethyl 2-(1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)

[0319]

[0320] At room temperature, tert-butyl hydrochloride (3 mL, 2 M) was added to a solution of 5-(2-ethoxy-2-oxoethyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (110 mg, crude) in MeOH (1 mL). The mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure to give the title compound (98 mg, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI) m / z = 259.2 [M+H] + .

[0321] Step 3. Synthesis of ethyl 2-(2-isopropyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)

[0322]

[0323] Acetone (2 mL) was added to a solution of ethyl 2-(1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetate (98 mg, crude) in MeOH (2 mL) at room temperature under an argon atmosphere. The reaction was stirred at room temperature for 0.5 h, and then NaBH3CN (29 mg, 0.456 mmol) was added. The resulting mixture was stirred at room temperature for 3 h, then diluted with H2O (10 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (108 mg, crude) as a brown solid, which was used in the next step without further purification. MS (ESI) m / z = 301.6 [M+H] + .

[0324] Step 4. Synthesis of 2-(2-isopropyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetic acid

[0325]

[0326] To a solution of ethyl 2-(2-isopropyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetate (108 mg, crude) in MeOH (10 mL), NaOH (10 N, 3 mL) was added. The mixture was stirred overnight at room temperature, and then the reaction mixture was purified by preparative HPLC (0.1% formic acid) to give the title compound as a white solid (65.8 mg, 65.7% in three-step yield). MS (ESI) m / z = 273.5 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.17(br s,1H),9.78(s,1H),7.54–7.44(m,2H),7.18–7.06(m,2H),5.07–4.95(m,2H),4.56–4.52(m,1 H),4.38–4.36(m,1H),3.84–3.69(m,2H),3.44–3.39(m,1H),3.10(s,2H),1.40–1.37(m,6H).

[0327] Example 11: 2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-(tert-butyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-011)

[0328]

[0329] CPD-011 (19 mg, yield: 3.9%) was synthesized according to the standard procedure used for the preparation of CPD-008, as a white solid. MS (ESI) m / z = 324.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.14(s,1H),7.67(s,1H),7.30(d,J=1.2Hz,1H),7.17(d,J=8.4Hz,1H),7. 08(dd,J=8.4Hz,2.0Hz,1H),3.74(s,2H),2.99–2.96(m,2H),2.92–2.90(m,4H),2.80–2.78(m,2H),1.31(s,9H).

[0330] Example 12: 2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-012)

[0331]

[0332] CPD-012 (27.6 mg, yield: 16.8%) was synthesized according to the standard procedure used for the preparation of CPD-008, as a white solid. MS (ESI) m / z = 286.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ14.82(br s,1H),11.34(s,1H),10.02(s,1H),8.02–7.74(m,1H),7.37–7.34(m,1H),7.28–7.25(m,1H),6.97–6.92(m, 1H),4.75–4.70(m,1H),4.36(s,1H),3.91–3.85(m,1H),3.60–3.32(m,3H),3.15–3.10(m,2H),3.08(s,2H).

[0333] Example 13: 2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-013)

[0334]

[0335] CPD-013 (6.7 mg, yield: 1.4%) was synthesized according to the standard procedure used for the preparation of CPD-008, as a white solid. MS (ESI) m / z = 282.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.17(s,1H),7.66(s,1H),7.13(d,J=8.0Hz,1H),7.10(s,1H),6. 81(d,J=8.0Hz,1H),3.64(s,2H),2.96–2.92(m,2H),2.88–2.83(m,4H),2.77–2.75(m,2H),2.34(s,3H).

[0336] Example 14: 6-(2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)hex-1-amine (CPD-014)

[0337]

[0338] Step 1. Synthesis of tert-butyl carbamate (6-(2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)hexyl)carbamate

[0339]

[0340] The title compound (176 mg, crude product) was synthesized according to the standard procedure used to prepare CPD-008. It was a brown oil and was used directly in the next step without further purification. MS (ESI) m / z = 442.5 [M+H] + .

[0341] Step 2. Synthesis of 6-(2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)hex-1-amine

[0342]

[0343] HCl / MeOH (4 mL, 3 M) was added to a solution of (176 mg, crude) tert-butyl carbamate in MeOH (2 mL) at room temperature. The mixture was stirred at room temperature for 5 h, and then purified by preparative HPLC (0.1% FA) to give the title compound (9.5 mg, 5.5% yield) as a white solid. MS (ESI) m / z = 385.5 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δ7.79(s,1H),7.42–7.38(m,1H),7.21–7.17(m,1H),7.00–6.95(m,1H),4.17–4.14(m,2H),3.74–3.7 0(m,2H),3.39–3.35(m,2H),3.29–3.22(m,8H),2.90–2.86(m,2H),1.80–1.77(m,2H),1.64–1.58(m,2H),1.40–1.36(m,4H).

[0344] Example 15: 6-Hydroxy-N-((2-Methyl-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)pyrazine-2-carboxamide (CPD-015)

[0345]

[0346] A solution of (2-methyl-1,2,3,4-tetrahydroisoquinoline-3-yl)methylamine (100 mg, crude), 6-hydroxypyrazin-2-carboxylic acid (80 mg, 0.568 mmol), HATU (432 mg, 1.14 mmol), and DIPEA (147 mg, 1.14 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The mixture was then purified by preparative HPLC (0.1% NH3·H2O) followed by preparative HPLC (0.1% FA) to give the title compound (3.91 mg, 2% yield) as a brown solid. MS (ESI) m / z = 299.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.35(s,1H),8.22(s,1H),7.13–7.15(m,4H),3.83–3.79(m,3H),2.91–2.69(m,4H),2.37(s,3H).

[0347] Example 16: 2-(2-(2-(2-(2-(1H-1,2,3-triazol-5-yl)ethyl)-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)ethoxy)ethoxy)ethoxy)ethyl-1-amine (CPD-016)

[0348]

[0349] CPD-016 (105 mg, yield: 41.5%) was synthesized according to the standard procedure used for the preparation of CPD-014, as a white solid. MS (ESI) m / z = 461.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.85(s,1H),10.27(s,1H),7.85–7.74(m,4H),7.54–7.50(m,1H),7.31–7.28(m,1H),7.03–6.98(m,1H),4. 76–4.72(m,1H),3.41–4.35(m,1H),4.30–4.27(m,2H),3.94–3.87(m,1H),3.66–3.46(m,15H),3.25–3.21(m,4H),2.96–2.95(m,2H).

[0350] Example 17: N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(((3-fluoropyridin-2-yl)amino)methyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine (CPD-017)

[0351]

[0352] A solution of N-((7-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)-3-fluoropyridin-2-amine (50 mg, 0.143 mmol), 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethyl-1-amine) (137 mg, 0.715 mmol), L-proline (16 mg, 0.143 mmol), CuI (27 mg, 0.143 mmol), and K3PO4 (60 mg, 0.143 mmol) in DMSO (1 mL) was stirred overnight at 100 °C under an argon atmosphere. The mixture was cooled to room temperature and then purified by preparative HPLC (0.1% TFA) to give the title compound (8.60 mg, yield: 10.5%) as a white solid. MS (ESI) m / z = 462.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.18–10.10(m,1H),7.86–7.85(m,4H),7.44–7.39(m,1H),6.97–6.95(m,2H),6.65–6.59(m ,2H),6.38(s,1H),4.60–4.44(m,1H),4.26–4.16(m,1H),3.76–3.48(m,15H),3.18–3.15(m,2H),2.99–2.82(m,7H).

[0353] Example 18: N1-(3-(((3-fluoropyridin-2-yl)amino)methyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)hexane-1,6-diamine (CPD-018)

[0354]

[0355] CPD-018 (8.2 mg, yield: 11.5%) was synthesized according to the standard procedure used for the preparation of CPD-017, as a white solid. MS (ESI) m / z = 386.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.86–7.85(m,1H),7.45–7.40(m,1H),6.96(d,J=8 .4Hz,1H),6.66–6.62(m,1H),6.58–6.56(m,1H),6.96(d,J=1.2Hz,1H),4.4 8–4.43(m,1H),4.24–4.14(m,1H),3.95–3.93(m,1H),3.78–3.60(m,3H),3 .04–2.91(m,4H),2.87–2.75(m,4H),1.57–1.47(m,4H),1.38–1.30(m,4H).

[0356] Example 19: 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-019)

[0357]

[0358] 1-Methylpiperidin-4-one (0.85 g, 7.75 mmol) was added to a solution of p-tolylhydrazine (1.00 g, 6.30 mmol) in AcOH (10 mL) at room temperature under an argon atmosphere. The mixture was stirred overnight at 65 °C, then diluted with H₂O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the title compound as a brown solid (534 mg, 42.4% yield). MS (ESI) m / z = 201.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.09(s,1H),7.24–7.22(m,1H),7.18(s,1H),6.94–6.91(m,1H) ,4.59–4.56(m,1H),4.26–4.23(m,1H),3.73–3.70(m,2H),3.11–3.06(m,2H),2.99(s,3H),2.36(s,3H).

[0359] Example 20: 2,2,5,8-Tetramethyl-2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole-2-cation (CPD-020)

[0360]

[0361] NaH (90 mg, 0.375 mmol) and MeI (50 mg, 0.30 mmol) were added to a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.25 mmol) in DMSO (3 mL) at room temperature under an argon atmosphere. The mixture was stirred at room temperature for 3 h, and then purified by preparative HPLC (0.1% TFA) to give the title compound (7.6 mg, 13.3% yield) as a white solid. MS (ESI) m / z = 229.5 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ7.29(d,J=8.4Hz,1H),7.22(s,1H),7.07–7.05(m,1H),4.68( s,2H),3.84–3.81(m,2H),3.69(s,3H),3.27–3.26(m,6H),3.24(s,2H),2.41(s,3H).

[0362] Example 21: 2,2,8-Trimethyl-2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole-2-cation (CPD-021)

[0363]

[0364] Na₂CO₃ (130 mg, 0.75 mmol) and MeI (50 mg, 0.50 mmol) were added to a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.50 mmol) in acetonitrile (3 mL) at room temperature under an argon atmosphere. The mixture was stirred at room temperature for 3 h, and then purified by preparative HPLC (0.1% TFA) to give the title compound as a brown solid (78.6 mg, 73.1% yield). MS (ESI) m / z = 215.6 [M+H]⁺. 1H NMR(400 MHz,DMSO-d6)δ11.20(s,1H),7.26–7.24(m,1H),7.16(s,1H),6.95–6.93(m,1H) ),4.63(s,2H),3.75–3.72(m,2H),3.19–3.16(m,6H),3.15(s,2H),2.36(s,3H).

[0365] Example 22: 2,5,8-Trimethyl-2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole (CPD-022)

[0366]

[0367] Formaldehyde / water (30%, 0.5 mL) and AcOH (1 drop) were added to a solution of tert-butyl 5,8-dimethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid (120 mg, crude) in MeOH (2 mL) under an argon atmosphere at room temperature. The reaction was stirred at room temperature for 30 min, and then NaBH3CN (130 mg, 2.10 mmol) was added. The mixture was stirred at room temperature for 3 h, then diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% TFA) to give the title compound (29.8 mg, 41.8% yield) as a brown solid. MS (ESI) m / z = 215.6 [M+H]+. 1H NMR(400 MHz, DMSO-d6)δ9.98–9.96(m,1H),7.36–7.34(m,1H),7.21(s,1H),7.01–7.99(m,1H),4.62–4.57(m,1H),4.27–4. 22(m,1H),3.81–3.80(m,1H),3.72–3.67(m,1H),3.64(s,3H),3.16–3.09(m,2H),2.99–2.98(m,2H),2.37(s,3H).

[0368] Example 23: Methyl (2-(3,4-dihydroisoquinoline-2(1H)-yl)ethyl)carbamate (CPD-023)

[0369]

[0370] Step 1. Synthesis of tert-butyl (2-(3,4-dihydroisoquinoline-2(1H)-yl)ethyl)carbamate

[0371]

[0372] At room temperature under an argon atmosphere, tert-butyl 2-oxoethyl carbamate (239 mg, 1.50 mmol) and AcOH (1 drop) were added to a solution of 1,2,3,4-tetrahydroisoquinoline (200 mg, 1.50 mmol) in MeOH (10 mL). The reaction was stirred at room temperature for 0.5 h, and then NaBH3CN (280 mg, 4.50 mmol) was added. The mixture was stirred at room temperature for another 3 h, then diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:H2O = 40:1) to give the title compound in oil (120 mg, 29.0% yield). MS (ESI) m / z = 277.1 [M+H]+.

[0373] Step 2. Synthesis of 2-(3,4-dihydroisoquinoline-2(1H)-yl)ethyl-1-amine

[0374]

[0375] TFA (2 mL) was added to a solution of tert-butyl carbamate (110 mg, 0.385 mmol) in DCM (4 mL) at room temperature. The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure to give the title compound (100 mg, crude) as a brown solid, which was used directly in the next step without further purification.

[0376] Step 3. Synthesis of methyl (2-(3,4-dihydroisoquinoline-2(1H)-yl)ethyl)carbamate

[0377]

[0378] TEA (1 mL) and methyl chloroformate (61 mg, 0.645 mmol) were added to a solution of 2-(3,4-dihydroisoquinoline-2(1H)-yl)ethyl-1-amine (100 mg, crude) in DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 2 h, and then the reaction mixture was purified by preparative HPLC (0.1% TFA) to give the title compound as a white solid (32.6 mg, 9.3% in three-step yield). MS (ESI) m / z = 235.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.32–7.25(m,3H),7.20–7.19(m,1H),4.61–4.43(m,2H),3.86–3.77(m,7H),3.65–3.58(m,2H),3.20(s,2H).

[0379] Example 24: N-((1H-imidazol-5-yl)methyl)-1-(5-methylfuran-2-yl)methylamine trifluoroacetate (CPD-024)

[0380]

[0381] A mixture of 1H-imidazol-5-carboxaldehyde (200 mg, 2.1 mmol) and (5-methylfuran-2-yl)methylamine (231 mg, 2.1 mmol) in MeOH (4 mL) was stirred at room temperature for 1 h, followed by the addition of NaBH4 (95 mg, 2.5 mmol). The reaction was stirred at room temperature for 30 min, and the mixture was then concentrated and purified by preparative HPLC (0.1% TFA in H2O) to provide the title compound (328 mg, yield: 82%) as a white solid. MS (ESI) m / z = 192 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.59(br s,1H),8.71(br s,1H),7.60(s,1H),6.50(d,J=2.8Hz,1H),6.14(t,J=2.0Hz,1H),4.24(s,2H),4.22(s,2H),2.28(s,3H).

[0382] Example 25: N-((1H-imidazol-5-yl)methyl)-1-(2-methoxypyridin-4-yl)methylamine (CPD-025)

[0383]

[0384] CPD-025 (243 mg, yield: 62%) was synthesized as a colorless oil according to the standard procedure used for the preparation of CPD-024. MS (ESI) m / z = 219.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.81(br s,1H),8.89(s,1H),8.23(d,J=5.2Hz,1H),7.67(s,1H),7.08(dd,J=1.2,5.2Hz,1H),6.95(s,1H),4.31(s,2H),4.21(s,2H),3.87(s,3H).

[0385] Example 26: 4-((((1H-imidazol-5-yl)methyl)amino)methyl)pyridine-2(1H)-keto hydrochloride (CPD-026)

[0386]

[0387] Concentrated HCl (12 M, 0.2 mL, 2.4 mmol) was added to a solution of N-((1H-imidazol-5-yl)methyl)-1-(2-methoxypyridin-4-yl)methylamine (CPD-025, 50 mg, 0.229 mmol) in EtOH (5 mL). The mixture was stirred under reflux for 18 h, and then concentrated and purified by preparative HPLC (0.1% HCl in H2O) to provide the title compound (63 mg, yield: 99%) as a white solid. MS (ESI) m / z = 205.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ14.83 (br s, 1H), 10.51 (br s, 2H), 9.17 (d, J = 0.8 Hz, 1H), 7.87 (s, 1H), 7.50 (d, J = 6.8 Hz, 1H), 6.95 (s, 1H), 6.50 (d, J = 6.8 Hz, 1H), 4.32 (s, 2H), 4.06 (s, 2H).

[0388] Example 27: N-((1H-imidazol-5-yl)methyl)-1-(5-methoxypyridin-3-yl)methylamine (CPD-027)

[0389]

[0390] Step 1. Synthesis of (5-methoxypyridin-3-yl)methanol

[0391]

[0392] NaBH4 (552 mg, 15 mmol) was added to a solution of 5-methoxynicotinaldehyde (1.0 g, 7.3 mmol) in THF (10 mL). The reaction was stirred at room temperature for 1 h, and then the mixture was concentrated. The residue was redissolved in EtOAc. The resulting solution was washed with H2O and brine, dried over Na2SO4, and concentrated to provide the title compound as a white solid (698 mg, yield: 70%). ¹H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.11 (s, 1H), 7.48 (s, 1H), 4.73 (s, 2H), 3.92 (s, 3H).

[0393] Step 2. Synthesis of 3-(azidomethyl)-5-methoxypyridine

[0394]

[0395] DPPA (825.6 mg, 3 mmol) was added to a mixture of (5-methoxypyridin-3-yl)methanol (350 mg, 2.5 mmol) and DBU (570 mg, 4.5 mmol) in THF (7 mL). The mixture was stirred overnight at 70 °C, then diluted in EtOAc, washed with H2O and brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether:EtOAc = 20:1) to provide the title compound as a clear oil (150 mg, yield: 36%). 1 HNMR (400 MHz, CDCl3) δ8.19(s,1H),8.16(s,1H),7.41(s,1H),4.49(s,2H),3.94(s,3H).

[0396] Step 3. Synthesis of (5-methoxypyridin-3-yl)methylamine

[0397]

[0398] A mixture of 3-(azidomethyl)-5-methoxypyridine (140 mg, 0.85 mmol) and 5% Pd / C (wet, 16 mg) in MeOH (6 mL) was stirred at room temperature under H2 for 3 h. The mixture was filtered and concentrated to provide the title compound as a clear oil (104 mg, yield: 88%). MS (ESI) m / z = 139.2 [M+H] + .

[0399] Step 4. Synthesis of N-((1H-imidazol-5-yl)methyl)-1-(5-methoxypyridin-3-yl)methylamine

[0400]

[0401] A mixture of 1H-imidazol-5-carboxaldehyde (50 mg, 0.52 mmol) and (5-ethylpyridin-3-yl)methylamine (86.4 mg, 0.625 mmol) in MeOH (3 mL) was stirred at room temperature for 2 h, followed by the addition of NaBH4 (29.5 mg, 0.78 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, and then concentrated and purified by preparative HPLC (0.1% NH3·H2O in H2O) to provide the title compound as a white solid (18.4 mg, yield: 16%). MS (ESI) m / z = 219.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ8.22 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 7.57 (s, 1H), 7.23 (s, 1H), 6.89 (s, 1H), 3.83 (s, 3H), 3.79 (s, 4H).

[0402] Example 28: N-((1H-imidazol-5-yl)methyl)-1-(3-methoxy-5-methylphenyl)methylamine (CPD-028)

[0403]

[0404] CPD-028 (20 mg, yield: 16%) was synthesized according to the standard procedure used for the preparation of CPD-027, as a white solid. MS (ESI) m / z = 232.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.61 (s, 1H), 6.55 (s, 1H), 3.67 (s, 3H), 3.64 (s, 2H), 3.60 (s, 2H), 2.20 (s, 3H).

[0405] Example 29: N-((1H-imidazol-5-yl)methyl)-1-(1H-indol-6-yl)methylamine (CPD-029)

[0406]

[0407] CPD-029 (38 mg, yield: 48%) was synthesized according to the standard procedure used to prepare CPD-001, as a white solid. MS (ESI) m / z = 227.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),7.54(s,1H),7.45(d,J=8.0Hz,1H),7.34(s,1H),7.28 (t,J=2.8Hz,1H),6.96(d,J=8.0Hz,1H),6.85(s,1H),6.37(s,1H),3.77(s,2H),3.61(s,2H).

[0408] Example 30: N-((1H-imidazol-5-yl)methyl)-1-(7-chlorobenzo[d][1,3]dioxacyclopenten-5-yl)methylamine (CPD-030)

[0409]

[0410] Step 1. Synthesis of (7-chlorobenzo[d][1,3]dioxacyclopenten-5-yl)methylamine hydrochloride

[0411]

[0412] SO₂Cl₂ (2.68 g, 19.8 mmol) was added dropwise to a solution of benzo[d][1,3]dioxane-5-ylmethylamine (2.0 g, 13.2 mmol) in AcOH (20 mL) in an ice bath. The mixture was stirred at room temperature for 2 h. The mixture was filtered and washed with ether to provide the title compound (1.8 g, yield: 61%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (br s, 3H), 7.27 (s, 1H), 7.17 (s, 1H), 6.11 (s, 2H), 4.01 (d, J = 4.4 Hz, 2H).

[0413] Step 2. Synthesis of N-((1H-imidazol-5-yl)methyl)-1-(7-chlorobenzo[d][1,3]dioxacyclopenten-5-yl)methylamine

[0414]

[0415] A mixture of (7-chlorobenzo[d][1,3]dioxacyclopenten-5-yl)methylamine hydrochloride (222 mg, 1 mmol), 1H-imidazolium-5-carboxaldehyde (96 mg, 1 mmol), and NaOAc (82 mg, 1 mmol) in MeOH (4 mL) was stirred at room temperature for 2 h, followed by the addition of NaBH4 (38 mg, 1 mmol). The mixture was stirred at room temperature for 1 h, then concentrated and purified by preparative TLC (DCM:MeOH:NH3·H2O = 10:1:0.1) to provide the title compound as a white solid (29.7 mg, yield: 11%). MS (ESI) m / z = 266.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.56(s,1H),7.12(s,1H),7.04(s,1H),6.90(s,1H),6.05(s,2H),3.71(s,2H),3.63(s,2H).

[0416] Example 31: 2-(4-((((1H-imidazol-4-yl)methyl)amino)methyl)phenoxy)ethanol-1-ol (CPD-031)

[0417]

[0418] Step 1. Synthesis of tert-butyl (4-hydroxybenzyl)carbamate

[0419]

[0420] A solution of NaHCO3 (1.02 g, 12.18 mmol) in H2O (10 mL) was added to a solution of 4-(aminomethyl)phenol (0.5 g, 4.06 mmol) in THF (10 mL), followed by the addition of Boc2O (975 mg, 4.47 mmol). The resulting mixture was stirred at room temperature for 1 h, then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (petroleum ether: EtOAc = 2:1) to provide the title compound (820 mg, yield: 91%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ9.25 (s, 1H), 7.25 (t, J = 6.0Hz, 1H), 7.02 (d, J = 8.4Hz, 2H), 6.68 (d, J = 8.4Hz, 2H), 3.99 (d, J = 6.0Hz, 2H), 1.38 (s, 9H).

[0421] Step 2. Synthesis of tert-butyl (4-(2-hydroxyethoxy)benzyl)carbamate

[0422]

[0423] 2-Bromoethanol (202 mg, 1.61 mmol) was added to a solution of tert-butyl 4-hydroxybenzylcarbamate (300 mg, 1.34 mmol) and K₂CO₃ (371 mg, 2.68 mmol) in DMF (5 mL). The mixture was stirred at 110 °C for 16 h, and then the yellow mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (petroleum ether: EtOAc = 2:1) to provide the title compound as a yellow oil (230 mg, yield: 64%). 1 HNMR (400MHz, DMSO-d6) δ7.31(t,J=6.0Hz,1H),7.13(d,J=8.0Hz,2H),6.89(d,J=8.0Hz,2H),4.8 5(t,J=6.0Hz,1H),4.04(d,J=6.4Hz,2H),3.94(t,J=4.8Hz,2H),3.71–3.67(m,2H),1.38(s,9H).

[0424] Step 3. Synthesis of 2-(4-(aminomethyl)phenoxy)ethane-1-ol

[0425]

[0426] TFA (1 mL) was added to a solution of (230 mg, 0.86 mmol) tert-butyl carbamate in DCM (2 mL). The resulting mixture was stirred at 20 °C for 2 h, then the yellow solution was diluted with water (2 mL), alkalized to pH 7–8 with saturated NaHCO3, and concentrated. The residue was ground with DCM:MeOH (10:1, 20 mL) and filtered. The filtrate was concentrated to provide the title compound (270 mg) as a yellow oil, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ7.25(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),4.85(br s,1H),4.15(br s,2H),3.97–3.94(m,2H),3.71(s,4H).

[0427] Step 4. Synthesis of 2-(4-((((1H-imidazol-4-yl)methyl)amino)methyl)phenoxy)ethanol-1-ol

[0428]

[0429] A mixture of 1H-imidazolium-5-carboxaldehyde (150 mg, 1.56 mmol) and 2-(4-(aminomethyl)phenoxy)ethanol-1-ol (260 mg, 2.1 mmol) in MeOH (2 mL) was stirred at room temperature for 1 h, followed by the addition of NaBH4 (60 mg, 1.56 mmol). The mixture was stirred at room temperature for 30 min, then concentrated and purified by preparative HPLC (0.1% NH4HCO3 in H2O) to provide the title compound (12.6 mg, yield: 5%) as a white solid. MS (ESI) m / z = 248.4 [M+H]+. 1H NMR (400MHz, CD3OD) δ7.54(s,1H),7.15(d,J=8.4Hz,2H),6.91(s,1H),6.83(d,J=8 .4Hz,2H),3.93(t,J=7.6Hz,2H),3.75(t,J=7.6Hz,2H),3.64(s,2H),3.61(s,2H).

[0430] Examples 32 & 33: trans-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-032) and cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-033)

[0431]

[0432] Step 1. Synthesis of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0433]

[0434] A solution of p-toluidine hydrochloride (10 g, 63 mmol) and 1-methylpiperidin-4-one (7.1 g, 63 mmol) in EtOH (200 mL) was added with 12N HCl (26 mL, 315 mmol). The reaction mixture was stirred overnight at 80 °C. The EtOH was removed, and the pH was adjusted to 12 with NaOH (12N). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (DCM / MeOH = 20:1 to 10:1) to give the title compound (10.1 g, 80% yield) as a white solid. MS (ESI) m / z = 201.1 [M+H]+ .

[0435] Step 2. Synthesis of 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0436]

[0437] A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3 g, 15 mmol) in THF (100 mL) was added at 0 °C with LiBH4 (2 M, 22.5 mL, 45 mmol) in THF, followed by the addition of BF3·Et2O (15.7 mL, 60 mmol). The reaction mixture was stirred at room temperature for 30 min, then at 70 °C for 6 h. HCl (6 N, 25 mL) was added. The reaction mixture was stirred at 100 °C for 1 h. The pH was adjusted to 10 with NaOH (6 N). The organic solvent was removed, and the residue was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine and dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (3.03 g, crude) as a yellow oil. MS (ESI) m / z = 203.2 [M+H] + .

[0438] Step 3. Synthesis of tert-butyl 2,8-dimethyl-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indole-5-carboxylic acid ester

[0439]

[0440] TEA (3.78 g, 37.5 mmol) and (Boc)₂O (4.9 g, 22.5 mmol) were added to a solution of 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (3.03 g, 15 mmol) in DCM (100 mL). The resulting mixture was stirred overnight at room temperature, and the reaction was then quenched with H₂O and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (DCM / MeOH = 20:1) to give the title compound (2.04 g, 44% yield) as a yellow oil. MS (ESI) m / z = 303.2 [M+H] + .

[0441] Step 4. Synthesis of trans-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole and cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0442]

[0443] TFA (5 mL) was added to a solution of tert-butyl 2,8-dimethyl-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indole-5-carboxylic acid (1.8 g, 5.96 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue was diluted with H2O (5 mL) and the pH was adjusted to pH 8 with an aqueous solution of NaHCO3. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography to obtain the major product, trans-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (1 g, 83% yield), as a white solid, and the minor product, cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (60 mg, 5% yield), as a yellow oil. Major product: 1 H NMR(400MHz, DMSO-d6)δ6.80(s,1H),6.76-6.73(m,1H),6.50(d,J=7.6Hz,1H),5.52(d,J=3.2Hz,1H),3.35-3.32(m,1H),2.87-2.78(m,2H), 2.61-2.54(m,1H),2.28(s,3H),2.17(s,3H),2.05-1.99(m,2H),1.92- 1.88(m,1H),1.76-1.69(m,1H).2.16(s,3H), MS(ESI)m / z=203.1[M+H] + Secondary products: 1H NMR (400MHz, DMSO-d6) δ6.83(s,1H),6.72(d,J=8.0Hz,1H),6.43(d,J=7.6Hz,1H),5.22(s,1H),3.61-3.57(m,1H),2.99-2.94(m,1H),2.4 9-2.47(m,1H),2.30-2.25(m,1H),2.22-2.19(m,1H),2.16(s,3H),2.10(s,3H),2.00-1.97(m,1H),1.80-1.73(m,1H),1.67-1.62(m,1H). MS(ESI)m / z=203.2[M+H] + .

[0444] Example 34: trans-2,5,8-trimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-034)

[0445]

[0446] To a solution of trans-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (250 mg, 1.24 mmol) and (HCHO)n (55 mg, 1.85 mmol) in MeOH (10 mL), MgSO4 (100 mg, 0.83 mmol) and AcOH (2 drops) were added. The reaction mixture was stirred overnight at 70 °C, and then NaBH3CN (155.5 mg, 2.47 mmol) was added. The resulting mixture was stirred for another 1 h at room temperature. The reaction was filtered, concentrated, and purified by preparative HPLC to give the title compound (29 mg, 11% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.86(d,J=7.6Hz,1H),6.83(s,1H),6.52(d,J=7.6Hz,1H),3.37-3.34(m,1H),2.95-2.92(m,1H ),2.67-2.60(m,1H),2.58(s,3H),2.29(s,3H),2.24-2.20(m,1H),2.19(s,3H),2.05-1.98(m,3H),1.69-1.62(m,1H). MS(ESI)m / z=217.2[M+H] + .

[0447] Example 35: (E)-1-(trans-2,8-dimethyl-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indol-5-yl)-3-(thiazolyl-2-yl)prop-2-en-1-one (CPD-035)

[0448]

[0449] Step 1. Synthesis of (E)-3-(thiazolyl-2-yl)acrylic acid

[0450]

[0451] Piperidine (1 drop) was added to a solution of thiazole-2-carboxaldehyde (1 g, 8.8 mmol) and malonic acid (0.92 g, 8.8 mmol) in pyridine (10 mL). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The solvent was removed, and the residue was diluted with water. The pH was adjusted to pH 5 with HCl (2N). The resulting mixture was filtered and the filter cake was dried to give the title compound as a white solid (1.37 g, 67% yield). 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),8.00(d,J=3.2Hz,1H),7.93(d,J=3.2Hz,1H),7.69(d,J=15.6Hz,1H),6.67(d,J=15.6Hz,1H).

[0452] Step 2. Synthesis of (E)-3-(thiazolyl-2-yl)acryloyl chloride

[0453]

[0454] SOCl2 (0.27 mL, 3.9 mmol) and DMF (2 drops) were added to a solution of (E)-3-(thiazolyl-2-yl)acrylic acid (200 mg, 1.3 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at 55 °C for 1 h and then concentrated under vacuum to give the title compound (223 mg, crude product) as a yellow oil.

[0455] Step 3. Synthesis of (E)-1-(trans-2,8-dimethyl-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indol-5-yl)-3-(thiazolyl-2-yl)prop-2-en-1-one

[0456]

[0457] TEA (0.53 mL, 3.9 mmol) was added to a solution of trans-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (260 mg, 1.3 mmol) in DCM (10 mL). Then, (E)-3-(thiazolyl-2-yl)acryloyl chloride (223 mg, 1.3 mmol) was added dropwise to DCM (5 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature, and then quenched with water (5 mL). The organic phase was dried and concentrated. The resulting residue was purified by preparative HPLC to provide the title compound as a yellow solid (32.4 mg, 7% yield). 1H NMR (400MHz, DMSO-d6) δ8.00(d,J=3.2Hz,1H),7.91(d,J=3.2Hz,1H),7.66(d ,J=15.2Hz,1H),7.37-7.28(m,2H),7.07(s,1H),7.03(d,J=8.0Hz,1H),3.62- 3.56(m,1H),3.46-3.43(m,1H),3.09-3.04(m,1H),3.00-2.97(m,1H),2.67- 2.61(m,1H),2.31(s,3H),2.28(s,3H),2.20-2.07(m,2H),2.01-1.92(m,1H). MS(ESI)m / z = 340.1[M+H] + .

[0458] Example 36: cis-2,5,8-trimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-036)

[0459]

[0460] CPD-036 (25 mg, 28% yield) was synthesized according to the standard procedure used for the preparation of CPD-034, as a colorless oil. 1 HNMR(400MHz,DMSO-d6)δ6.86-6.83(m,2H),6.46(d,J=7.6Hz,1H),3.08-3.01(m,2H),2.65-2.61(m,1H),2.58 (s,3H),2.46-2.43(m,1H),2.18(s,3H),2.11(s,3H),2.08-2.02(m,1H),1.92-1.88(m,1H),1.81-1.68(m,2H). MS(ESI)m / z=217.2[M+H]+.

[0461] Example 37: (E)-1-(cis-2,8-dimethyl-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indol-5-yl)-3-(thiazolyl-2-yl)prop-2-en-1-one (CPD-037)

[0462]

[0463] CPD-037 (35 mg, 58% yield) was synthesized according to the standard procedure used for the preparation of CPD-035, and was a yellow solid. 1 HNMR(400MHz, DMSO-d6)δ8.02-8.00(m,2H),7.92(d,J=2.8Hz,1H),7.78(d,J=15.2Hz,1H),7.36(d,J=15.2Hz,1H),7.16(s,1H),7.02(d,J=8.0Hz, 1H),4.80-4.79(m,1H),3.45-3.41(m,2H),2.58-2.56(m,1H),2.33-2.32 (m,1H),2.31(s,3H),2.19(s,3H),2.03-1.91(m,2H),1.42-1.34(m,1H). MS(ESI)m / z 340.1[M+H] + .

[0464] Example 38: 6-bromo-2,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CPD-038)

[0465]

[0466] Step 1. Synthesis of (2-bromo-5-methylphenyl)hydrazine

[0467]

[0468] NaNO₂ (3.8 g, 55.1 mmol) was added to a solution of 2-bromo-5-methylaniline (9.7 g, 52.14 mmol) in HCl (6 M, 160 mL) at 0 °C. The reaction was stirred at 0 °C for 1.5 h, and then SnCl₂·2H₂O (16.5 g, 73.0 mmol) in HCl (6 M, 100 mL) was added dropwise to the reaction mixture at 0 °C. The resulting mixture was stirred at 0 °C for another 1.5 h, and then the reaction was filtered. The pH of the filtrate was adjusted to pH = 12 with an aqueous solution of NaOH. The precipitate was collected by filtration, washed with H₂O, and dried to give the title compound (8.0 g, 77% yield) as a pale yellow solid. MS (ESI) m / z = 201.1 [M+H] +.

[0469] Step 2. Synthesis of 6-bromo-2,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0470]

[0471] The title compound (2.0 g, 29% yield) was synthesized as a yellow solid according to the standard procedure used to prepare CPD-032. 1 H NMR(400MHz, DMSO-d6)δ10.87(s,1H),7.04(d,J=8.0Hz,1H),6.62(d,J=8.0Hz,1H), 3.77(s,2H),2.78(t,J=4.8Hz,2H),2.69(t,J=4.8Hz,2H),2.47(s,3H),2.44(s,3H). MS(ESI)m / z=279.1[M+H] + .

[0472] Example 39: trans-2,9-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-039)

[0473]

[0474] Step 1. Synthesis of trans-6-bromo-2,9-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0475]

[0476] At 0 °C, a solution of 6-bromo-2,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 1.79 mmol) in THF (10 mL) was treated with LiBH4 (2 M, 4.5 mL, 9.0 mmol) in THF, followed by the addition of BF3·Et2O (3.2 mL, 12.5 mmol). The reaction mixture was stirred at room temperature for 30 min, then at 70 °C for 6 h. HCl (6 N, 3.5 mL) was added. The reaction mixture was stirred at 100 °C for 1 h. The pH was adjusted to 10 with NaOH (6 N). The organic solvent was removed, and the residue was then extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (DCM / MeOH = 20:1 to 10:1) to give the title compound (120 mg, 24%) as a white solid. MS (ESI) m / z = 281.1 [M+H]+ .

[0477] Step 2. Synthesis of trans-2,9-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0478]

[0479] Pd / C (40 mg) was added to a solution of trans-6-bromo-2,9-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (500 mg, 1.79 mmol) in MeOH (15 mL). The resulting mixture was stirred at room temperature under H2 for 4 h. The solution was then filtered and the filtrate was purified by preparative HPL to give the title compound (50 mg, yield: 14%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.82(t,J=7.6Hz,1H),6.43(d,J=7.6Hz,1H),6.37(d,J=7.6Hz,1H),5.65(d,J=2.8Hz,1H),3.53(dd=10.4,2.8 Hz,1H),2.87-2.81(m,2H),2.70-2.63(m,1H),2.29(s,3H),2.21-2.16(m,4H),2.7-2.00(m,1H),1.93-1.89(m,1H),1.75-1.67(m,1H). MS(ESI)m / z=203.1[M+H] + .

[0480] Example 40: trans-2,5,9-trimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-040)

[0481]

[0482] CPD-040 (40 mg, 31% yield) was synthesized according to the standard procedure used to prepare CPD-034, and was a yellow solid. 1HNMR (400MHz, DMSO-d6) δ6.93(t,J=8.0Hz,1H),6.46(d,J=8Hz,2H),3.56(dd,J=10.4,3.2Hz,1H),2.94-2.91(m,1H),2.75-2. 68(m,1H),2.60(s,3H),2.30(s,3H),2.28-2.22(m,1H),2.19(s,3H),2.18-2.13(m,1H),2.06-1.99(m,2H),1.68-1.58(m,1H). MS(ESI)m / z=217.2[M+H] + .

[0483] Example 41: cis-2,9-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-041)

[0484]

[0485] Step 1. Synthesis of 2,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0486]

[0487] Pd / C (50 mg) was added to a solution of 6-bromo-2,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (650 mg, 2.33 mmol) in MeOH (15 mL). The mixture was stirred at room temperature under H2 for 4 h, then filtered and concentrated to give the title compound (530 mg, crude) as a yellow solid, which was used directly in the next step. MS (ESI) m / z = 203.1 [M+H] + .

[0488] Step 2. Synthesis of cis-2,9-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0489]

[0490] The title compound (12.2 mg, 3% yield) was synthesized as a white solid according to the standard procedure used to prepare CPD-033. 1H NMR (400MHz, DMSO-d6) δ6.81(t,J=7.6Hz,1H),6.36(d,J=7.6Hz,2H),5.38(d,J=2.4Hz,1H),3.64(d=2.8Hz,1H),3.1 0-3.04(m,1H),2.73-2.68(m,1H),2.53-2.51(m,1H),2.15-2.08(m,7H),1.87-1.77(m,2H),1.51(t,J=11.2Hz,1H). MS(ESI)m / z=203.1[M+H] + .

[0491] Example 42: cis-2,5,9-trimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (CPD-042)

[0492]

[0493] CPD-042 (20 mg, 19% yield) was synthesized according to the standard procedure used to prepare CPD-034, and was a white solid. 1 HNMR (400MHz, DMSO-d6) δ6.94(t,J=7.6Hz,1H),6.47(d,J=7.6Hz,1H),6.42(d,J=7.6Hz,1H),3.20-3.14(m,1H),3.03-3.01(m,1H ),2.83-2.79(m,1H),2.64-2.59(m,4H),2.17(s,3H),2.15(s,3H),2.08-2.02(m,2H),1.89-1.78(m,1H),1.50(t,J=11.2Hz,1H). MS(ESI)m / z=217.2[M+H] + .

[0494] Example 43: Compound binding to DCAF1 ( Figures 2A-2F (Table 2).

[0495] The binding affinity of the compounds to DCAF1 was determined by surface plasmon resonance (SPR) assay. Purified DCAF1 (1058-1396) protein was immobilized on a CM5 sensor chip, and dose-range solutions of the compounds were injected using a multi-cycle kinetic approach. Steady-state modeling was used to analyze the data to provide the equivalent dissociation constant (K0). d The binding affinity (K) of the selected compound. d The values ​​are presented in Table 2. The data show that some compounds can bind to DCAF1 in a concentration-dependent manner.

[0496] Table 2. Binding Affinity

[0497]

[0498]

[0499] K d Value: A≤40μM; 40 <B≤70μM;70<C≤100μM;D> 100μM

[0500] Materials and methods

[0501] General chemical methods: Chemicals and reagents were purchased from commercial suppliers and used without further purification. LCMS spectra of compounds were obtained using a Waters LC-MS AcQuity HUPLC system. The Waters LC-MS AcQuity H UPLC system includes a pump with a degasser (quaternary solvent manager), an autosampler (FTN), a column oven (40°C unless otherwise specified), and a photodiode array PDA detector. Chromatography was performed on an AcQuity UPLC BEH C18 (1.7 μm, 2.1 x 50 mm) at a flow rate of 0.6 mL / min using water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B. The fluid from the column was split and directed to the MS spectrometer. The MS detector was equipped with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a MassLynx data system. Nuclear magnetic resonance spectra were recorded on a Bruker Avance III 400 spectrometer. Chemical shifts are expressed in parts per million (ppm) and reported as δ values ​​(chemical shift δ). Coupling constants are reported in Hertz (J value, Hz; integral and splitting modes: where s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet). Purification of intermediates or final products was performed on an Agilent Prep 1260 series with a UV detector set to 254 nm or 220 nm. Samples were injected at room temperature onto a Phenomenex Luna C18 column (5 μm, 30 x 75 mm). The flow rate was 40 mL / min. A linear gradient was used, with 10% or 50% MeOH in H₂O containing 0.1% TFA as solvent A and 100% MeOH as solvent B. Alternatively, the product was purified in… Purification was performed on a NextGen 300 system with the UV detector set to 254 nm, 220 nm, or 280 nm. The flow rate was 40 mL / min. A linear gradient was used, with H₂O containing 0.05% TFA as solvent A and 100% MeOH containing 0.05% TFA as solvent B. The compound showed >95% purity using the LCMS method described herein.

[0502] Protein Expression and Purification: The coding sequence of human DCAF1 (1058-1396) (UniPro:Q9Y4B6) was cloned into the pFastBacHT vector and expressed in Sf9 cells using the Bac-to-Bac baculovirus expression system (Thermo Fisher Scientific). The expression construct for DCAF1 (1058-1396) included an N-terminal His6-tag to facilitate purification. The DCAF1 (1058-1396) protein was obtained from the supernatant of cell lysates and purified by a combination of Ni affinity chromatography (Ni-NTA column, Bio-Rad), tag removal using TEV protease, and size exclusion chromatography (Superdex 200 column, GE Healthcare).

[0503] Surface plasmon resonance (SPR) binding assay: SPR studies were performed on a Biacore X100 plus or T200 instrument (GE Healthcare). Purified DCAF1 (1058-1396) was immobilized at 25°C using a CM5 sensor chip. The surface was pre-equilibrated in HBS-EP running buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% P2O) and then activated with EDC / NHS. DCAF1 (1058-1396) was immobilized on flow cell channel 2 (FC2) at a density of 9,000-12,000 resonance units (RU) by amino groups, while flow cell channel 1 (FC1) was used as a reference. The DCAF1-immobilized surface and the reference surface were inactivated with 1 M ethanolamine.

[0504] Interaction experiments were conducted at 25 °C. Compounds were prepared and serially diluted in HBS-EP running buffer containing a final 2% DMSO (6-point 2x serial dilutions, 100 μM–3.125 μM final compound concentration). Compound solutions were individually injected in a multi-cycle kinetic configuration without regeneration (flow rate 30 μL / min, association time 60 s, dissociation time 60 s). Sensing plots from the reference surface and blank injection were subtracted from the raw data (dual reference), and the data were solvent-corrected prior to analysis. The data were analyzed using Biacore evaluation software with a steady-state affinity model to provide the equivalent dissociation constant (K0). d ).

[0505] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Many changes, variations, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A compound of formula Ia: Formula Ia Or its pharmaceutically acceptable salt, wherein: It is a double bond; R 1 Selected from H, C 1-10 Alkyl and C 1-10 Heteroalkyl; Each R 2 Independently selected from H, halogen and C 1-4 Alkyl; and n is 0, 1, or 2; The condition is that the compound of formula Ia is not .

2. A compound selected from the group consisting of: , , , , , , , and , Or its pharmaceutically acceptable salt.

3. A compound of formula IIa: Formula IIa Or its pharmaceutically acceptable salt, wherein: R 1 Selected from H and C 1-4 alkyl; R 2 and R 3 Independently selected from H and C 1-8 Alkyl and C 1-8 Heteroalkyl; Each R 4 It is H, and each R 5 Independently selected from H and halogen groups; n is 0, 1, 2, or 3; and m is 0 or 1.

4. A compound having the following structure: and , Or its pharmaceutically acceptable salt.

5. A compound selected from the group consisting of: , , , , , and , Or its pharmaceutically acceptable salt.

6. A compound selected from the group consisting of: N -(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(((3-fluoropyridin-2-yl)amino)methyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine (CPD-017); trans -2,9-Dimethyl-2,3,4,4a,5,9b-hexahydro-1 H -pyrido[4,3- b Indole (CPD-039); (1-morpholino-3-(1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)propion-1-one (CPD-048); 3-(8-chloro-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indol-2-yl)-1-morpholinoprop-1-one (CPD-049); 2-(2,2-Dimethoxyethyl)-8-fluoro-2,3,4,5-tetrahydro-1 H -pyrido[4,3- b Indole (CPD-051); 4-(2-hydroxy-3-(8-methyl-1,3,4,5-tetrahydro-2-) H -pyrido[4,3- b Indole-2-yl)propoxy)benzoic acid (CPD-056); (2-Bromo-5-fluorophenyl)(2,8-dimethyl-1,2,3,4,4a,9b-hexahydro-5 H -pyrido[4,3- b Indole-5-yl)methyl ketone (CPD-065); and (1-((((1 H -imidazol-5-yl)methyl)amino)methyl)cyclopropyl)methanol (CPD-105); Or its pharmaceutically acceptable salt.

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