Ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1) inhibitors and uses thereof

Abstract

Described herein are ENPP1 inhibitors, and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for treating diseases or disorders associated with ENPP1.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of International Application No. PCT / CN2022 / 074739, filed January 28, 2022, and International Application No. PCT / CN2022 / 140318, filed December 20, 2022, which are incorporated by reference in their entireties. [Background technology]

[0002] The ectonucleotide pyrophosphatase-phosphodiesterase 1 (ENPP1) enzyme is present in a wide variety of tissues and cell types, including lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 degrades ATP and other nucleoside triphosphates, releasing AMP or other nucleoside monophosphates, as well as pyrophosphate (PPi). The enzyme can also hydrolyze other nucleoside monophosphate esters. ENPP1 has been identified as the predominant 2'-3'-cGAMP hydrolase in cultured cells, tissue extracts, and blood. Tissues and blood from ENPP1 knockout mice lack 2'-3'-cGAMP hydrolase activity. High levels of ENPP1 are associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease, an inflammatory disease resulting from crystal deposition of CPPD in joints and surrounding tissues. ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular cancers, pancreatic cancers, thyroid cancers, and breast cancers, and is associated with resistance to chemotherapy. ENPP1 upregulation and ENPP1 variants have also been implicated in insulin resistance and type 2 diabetes, and it has been reported that the enzymatic activity of ENPP1 is required for the inhibition of insulin receptor signaling.

[0003] Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA from viruses, bacteria, damaged mitochondria, or cancer cells. The cGAMP molecule then binds to the stimulator of interferon genes (STING) protein, generating a signaling response that activates innate immunity, resulting in the production of type I interferons and antiviral, immune-stimulating cytokines. The cGAS enzyme, cGAMP messenger, and STING are also involved in host defense against RNA viruses and immune regulation of tumor growth. ENPP1 has been identified as an enzyme that naturally hydrolyzes cGAMP and therefore counters the innate immune response against infectious agents, damaged cells, and cancer cells. The efficacy of nonhydrolyzable cGAMP analogs in inducing functional immune responses is higher than the native hydrolyzable cGAMP. Viral infection has been demonstrated to be enhanced by ENPP1 overexpression and is attenuated by silencing ENPP1.

[0004] Therefore, inhibitors of cGAMP hydrolysis can be used to increase the effectiveness of immune response against cancer cells and tumors, as well as infections caused by RNA viruses, DNA viruses, or bacteria.Inhibitors of ENPP1 and cGAMP or nucleoside triphosphate hydrolysis can be used to treat inflammatory diseases associated with high levels of nucleotidase, reduced nucleoside triphosphate, reduced cGAMP, or low levels of nucleoside monophosphate, or diseases associated with high levels of nucleosides or nucleoside monophosphate.For these reasons, ENPP1 is a preferred therapeutic target for the treatment of diseases such as cancer and viral infections. Summary of the Invention

[0005] Formula (I):

[0006] [ka] Disclosed herein is a compound of the formula: During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, -NH-, or -O-; R 1 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 6; R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0007] [ka] is a single or double bond, where:

[0008] [ka] is a double bond, X is N or CR X and Y is N or CR Y and

[0009] [ka] is a single bond, X is C(=O) and Y is NR Y1 or C(R Y2 )2, R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y1is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y2 are each independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently and optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 4 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 4 come together to form oxo, m is 0 to 4; R 5 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is, each independently, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom form an oxo.

[0010] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0011] [ka] It is a compound of the formula:

[0012] In some embodiments of the compound of Formula (I), the compound has the formula (Ib):

[0013] [ka] It is a compound of the formula:

[0014] Also disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colon cancer, or sarcoma. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is a leukemia, lymphoma, or myeloma. In some embodiments, the hematological malignancy is a B-cell malignancy. In some embodiments, the hematological malignancy is multiple myeloma. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastatic cancer.

[0015] Also disclosed herein is a method of treating an infectious disease in a subject in need thereof, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the infectious disease is a viral infection. In some embodiments, the viral infection is caused by a DNA virus. In some embodiments, the viral infection is caused by a herpes virus. In some embodiments, the herpes virus is selected from herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpes virus 6A (HHV-6A), human herpes virus 6B (HHV-6B), human herpes virus 7 (HHV-7), and Kaposi's sarcoma-associated herpes virus (KSHV). In some embodiments, the herpes virus is herpes simplex virus 1 (HSV-1). In some embodiments, the viral infection is caused by a retrovirus. In some embodiments, the retrovirus is human immunodeficiency virus (HIV). In some embodiments, the retrovirus is HIV-1, HIV-2, or human T-lymphotropic virus (HTLV). In some embodiments, the viral infection is caused by a hepatitis virus. In some embodiments, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV). In some embodiments, the viral infection is caused by a vaccinia virus (VACV), adenovirus, or human papilloma virus (HPV). In some embodiments, the viral infection is caused by an RNA virus. In some embodiments, the viral infection is caused by a dengue virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or Zika virus.

[0016] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] definition In the following description, certain specific details are given to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" or "comprising," are to be construed in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the subject invention.

[0018] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0019] The following terms, as used herein, have the following meanings unless otherwise indicated:

[0020] "Oxo" refers to =O.

[0021] "Carboxyl" refers to --COOH.

[0022] "Cyano" refers to -CN.

[0023] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range appears herein, such as "C1-C6 alkyl" or "C1-6 alkyl", it means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also includes occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1- 10In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless otherwise specified herein, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0024] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" appears herein, it is meant that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also includes occurrences of the term "alkenyl" where no numerical range is specified. Unless otherwise specified in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0025] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" appears in this specification, it means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also includes occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specified in this specification, alkynyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0026] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0027] "Alkoxy" means a group of the formula -OR a where R a is an alkyl radical as defined. Unless otherwise specified in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0028] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specified herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0029] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3-C4, C5-C6, C7-C8, C9-C10, C11-C12, C13-C14, C15-C16, C17-C18, C18-C19, C20-C210, C22-C30, C23-C31, C24-C25-C32, C25-C33, C26-C34, C27-C35, C28-C36, C29-C37, C38-C39, C39-C40, C39-C41, C38-C42, C39-C43, C44-C45, C45-C46, C46-C47, C48-C49, C49-C51, C49-C52, C49-C53, C49-C54, C49-C55, C49-C56, C49-C57, C49-C58, C49-C59 15 Fully saturated cycloalkyl or C3-C 15Cycloalkenyl, 3 to 10 carbon atoms (C3-C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10 membered fully saturated cycloalkyl or a 3 to 10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6 membered fully saturated cycloalkyl or a 3 to 6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6 membered fully saturated cycloalkyl or a 5 to 6 membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0030] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0031] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0032] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyl groups. In some embodiments, the alkyl is substituted with one hydroxyl group. In some embodiments, the alkyl is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0033] "Aminoalkyl" refers to an alkyl radical as defined above that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0034] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, composed of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise specified herein, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0035] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2-C4). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and the like. Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. It is noted that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3-8 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-7 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specified herein, a heterocycloalkyl may be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0036] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may contain fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl, and indolyl. nyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0037] The term "optional" or "optionally" is intended to mean that the subsequently described event or circumstance may or may not occur, and that the description includes examples of when said event or circumstance occurs and when it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible. Thus, it should be understood that any substituents described typically have a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0038] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0039] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0040] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition following initiation of a pathological event or contact with a pathogenic agent, and stabilization of disease (e.g., disease does not worsen) or remission of disease.

[0041] As used herein, an "ENPP1-associated disease or disorder" or, alternatively, an "ENPP1-mediated disease or disorder" means any disease or other deleterious condition in which ENPP1, or a mutant thereof, is known or suspected to play a role.

[0042] compound Described herein are compounds, or pharma- ceutically acceptable salts thereof, that are useful for the treatment of a disease or disorder associated with ENPP1.

[0043] Formula (A):

[0044] [ka] Disclosed herein is a compound of the formula: During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, -NH-, or -O-; R 1 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NRc R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 6; R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0045] [ka] is a single or double bond, where:

[0046] [ka] is a double bond, X is N or CR X and Y is N or CR Y and

[0047] [ka] is a single bond, X is C(=O) and Y is NR Y1 or C(R Y2 )2, R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y2 are each independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently and optionally substituted with one or more R; R7 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of one or more R 8 is replaced by R 8 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NRb C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 8 come together to form oxo, R 5 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is, each independently, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Alternatively, two R on the same atom form an oxo.

[0048] In some embodiments of the compounds of Formula (A), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of one or more R 8 is replaced by.

[0049] In some embodiments of the compounds of Formula (A), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of one or more R 8 is replaced by.

[0050] In some embodiments of the compounds of Formula (A), R 7 is C1-C6 alkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of one or more R 8 is replaced by.

[0051] In some embodiments of the compounds of Formula (A), R 7 is C1-C6 alkyl or C2-C6 alkynyl, where alkyl and alkynyl are each independently one or more R 8 is replaced by.

[0052] In some embodiments of the compounds of Formula (A), R 7 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R 8 is replaced by.

[0053] In some embodiments of the compounds of Formula (A), R 7 is aryl or heteroaryl, where aryl and heteroaryl are each independently one or more R 8 is replaced by.

[0054] In some embodiments of the compounds of Formula (A), R 7 is one or more R 8 is an aryl substituted with

[0055] Formula (I):

[0056] [ka] Disclosed herein is a compound of the formula: During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, -NH-, or -O-; R 1 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 6; R 2is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0057] [ka] is a single or double bond, where:

[0058] [ka] is a double bond, X is N or CR X and Y is N or CR Y and

[0059] [ka] is a single bond, X is C(=O) and Y is NR Y1 or C(R Y2 )2, R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y2 are each independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently and optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 4 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR bC(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 4 come together to form oxo, m is 0 to 4; R 5 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is, each independently, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Alternatively, two R on the same atom form an oxo.

[0060] Formula (I):

[0061] [ka] Disclosed herein is a compound of the formula: During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, -NH-, or -O-; R 1are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 1 come together to form oxo, n is 0 to 6; R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0062] [ka] is a single or double bond, where:

[0063] [ka] is a double bond, X is N or CR X and Y is N or CR Y and

[0064] [ka] is a single bond, X is C(=O) and Y is NR Y1 or C(R Y2 )2, R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Y2are each independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently and optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 4 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 4 come together to form oxo, m is 0 to 4; R 5 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 are hydrogen, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's atogether with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkyl(cycloalkyl), C-C alkyl(heterocycloalkyl), C-C alkyl(aryl), or C-C alkyl(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R is, each independently, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom form an oxo.

[0065] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0066] [ka] It is a compound of the formula:

[0067] In some embodiments of the compound of Formula (A), (I), or (Ia), X is N and Y is N. In some embodiments of the compound of Formula (A), (I), or (Ia), X is CR X and Y is N. In some embodiments of the compound of Formula (A), (I), or (Ia), X is C(C1-C3 alkyl) and Y is N. In some embodiments of the compound of Formula (A), (I), or (Ia), X is N and Y is CR Y In some embodiments of the compound of Formula (A), (I), or (Ia), X is CR X and Y is CR Y It is.

[0068] In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R Xis hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is methyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is CD3. In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is cyclopropyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R X is a halogen.

[0069] In some embodiments of the compounds of Formula (A), (I), or (Ia), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R Y is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R Y is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), or (Ia), R Y is hydrogen. In some embodiments of the compounds of Formula (A), (I), or (Ia), R Y is C1-C6 alkyl.

[0070] In some embodiments of the compound of Formula (I), the compound has the formula (Ib):

[0071] [ka] It is a compound of the formula:

[0072] In some embodiments of the compound of Formula (A), (I), or (Ib), Y is NRY1 In some embodiments of the compound of Formula (A), (I), or (Ib), Y is C(R Y2 )2.

[0073] In some embodiments of the compounds of Formula (A), (I), or (Ib), R Y1 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ib), R Y1 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), or (Ib), R Y1 is C1-C3 alkyl or C1-C3 haloalkyl.

[0074] In some embodiments of the compounds of Formula (A), (I), or (Ib), R Y2 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (A), (I), or (Ib), R Y2 are each independently hydrogen or C1-C6 alkyl.

[0075] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is cycloalkyl or heterocycloalkyl.

[0076] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is cycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is 3-12 membered cycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is 5- or 6-membered cycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is 3-7 membered monocyclic cycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is 5-12 membered bicyclic cycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is 7-12 membered bicyclic cycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), Ring A is a 9-12 membered bicyclic cycloalkyl.

[0077] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a heterocycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a 3-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a 5- or 6-membered heterocycloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a 3-7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a 5-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), Ring A is a 7-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), Ring A is a 9-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S.

[0078] In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is aryl or heteroaryl. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is aryl. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is phenyl. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is heteroaryl. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is a 6-membered monocyclic heteroaryl. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is pyridinyl. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), ring A is pyridazinyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is pyrimidinyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is pyrazinyl.

[0079] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a spiro bicyclic ring. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), ring A is a fused bicyclic ring.

[0080] In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib), L is a bond. In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib), L is -NH-. In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib), L is -O-.

[0081] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 1 are each independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 1 are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 1 are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib), R 1 are each independently a halogen. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 1 is F.

[0082] In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 0 to 2. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 0 or 1. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 1 or 2. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 0. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 1. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 2. In some embodiments of the compound of formula (A), (I), (Ia), or (Ib), n is 3.

[0083] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib),

[0084] [ka] teeth

[0085] [ka] It is.

[0086] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib),

[0087] [ka] teeth

[0088] [ka] In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib),

[0089] [ka] teeth

[0090] [ka] It is.

[0091] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib),

[0092] [ka] teeth

[0093] [ka] It is.

[0094] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib),

[0095] [ka] teeth

[0096] [ka] In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib),

[0097] [ka] teeth

[0098] [ka] In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib),

[0099] [ka] teeth

[0100] [ka] In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib),

[0101] [ka] teeth

[0102] [ka] It is.

[0103] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 2is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 2 is hydrogen. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 2 is C1-C6 alkyl.

[0104] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 3 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 3 is hydrogen. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 3 is C1-C6 alkyl.

[0105] In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is 5- or 6-membered cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is 5- or 6-membered heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is a fully saturated ring. In some embodiments of the compounds of formula (I), (Ia), or (Ib), ring B is a partially saturated ring.

[0106] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is aryl or heteroaryl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is aryl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is phenyl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is heteroaryl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is 5- or 6-membered heteroaryl. Ring B is 5-membered heteroaryl. Ring B is 6-membered heteroaryl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is heteroaryl containing 1-3 nitrogens and 0-1 oxygen. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), ring B is heteroaryl containing 2-4 nitrogens. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), Ring B is a heteroaryl containing 1 or 2 nitrogens.

[0107] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 4 are each independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 4 are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 4are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 4 are each independently C1-C6 alkyl.

[0108] In some embodiments of the compound of formula (I), (Ia), or (Ib), m is 0 to 2. In some embodiments of the compound of formula (I), (Ia), or (Ib), m is 0 or 1. In some embodiments of the compound of formula (I), (Ia), or (Ib), m is 0. In some embodiments of the compound of formula (I), (Ia), or (Ib), m is 1. In some embodiments of the compound of formula (I), (Ia), or (Ib), m is 2. In some embodiments of the compound of formula (I), (Ia), or (Ib), m is 3.

[0109] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0110] [ka] teeth

[0111] [ka] It is.

[0112] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0113] [ka] teeth

[0114] [ka] It is.

[0115] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0116] [ka] teeth

[0117] [ka] It is.

[0118] In some embodiments of the compounds of Formula (I), (Ia), or (Ib),

[0119] [ka] teeth

[0120] [ka] It is.

[0121] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is hydrogen, halogen, CN, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is hydrogen, -CN, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is hydrogen, -CN, -OR a or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is hydrogen, halogen, -OR aor C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 -OR a or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is C1-C6 alkoxy or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is C1-C3 alkoxy or C1-C3 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 -OR a In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is C1-C6 alkoxy. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is OCH. In some embodiments, OCH is OCD. In some embodiments of the compound of Formula (A), (I), (Ia), or (Ib), R 5 is C1-C3 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is methyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is -O-C1-C3 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 5 is -OMe.

[0122] In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 6 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 6 is hydrogen, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 6 is hydrogen, -CN, or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 6 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (A), (I), (Ia), or (Ib), R 6 is hydrogen.

[0123] In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a is each independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0124] In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b Each is hydrogen. In some embodiments of the compounds disclosed herein, R b are each independently C1-C6 alkyl.

[0125] In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkyl(heteroaryl). In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d Each is hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently C1-C6 alkyl.

[0126] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0127] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl.

[0128] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R X , R Y , R Y1 , R Y2 , R a , Rb , R c , and R d One or more of the groups contains deuterium at a ratio higher than the natural abundance of deuterium.

[0129] In some embodiments of the compounds disclosed herein, one or more 1 H is the following R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R X , R Y , R Y1 , R Y2 , R a , R b , R c , and R d At least one of the groups is substituted with one or more deuterium atoms.

[0130] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R X , R Y , R Y1 , R Y2 , R a , R b , R c , and R d The abundance of deuterium in each of is independently, by molar fraction, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0131] In some embodiments of the compounds disclosed herein, one or more of rings A or B may be 1 H is replaced by one or more deuterium atoms.

[0132] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0133] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is one of the compounds in Table 1.

[0134] [Table 1-1]

[0135] [Table 1-2]

[0136] [Table 1-3]

[0137] [Table 1-4]

[0138] [Table 1-5]

[0139] [Table 1-6]

[0140] [Table 1-7]

[0141] [Table 1-8]

[0142] [Table 1-9]

[0143] [Table 1-10]

[0144] [Table 1-11]

[0145] [Table 1-12]

[0146] In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, are selected from the group consisting of the following compounds:

[0147] [ka] It is one of them.

[0148] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinctive physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered along with the resolving agent by any practical means that does not result in racemization.

[0149] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having atomic masses or mass numbers different from the atomic masses or mass numbers normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein are respectively: 2 H(D), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl. Compounds described herein, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds that incorporate a radioactive isotope, such as C, are useful in drug and / or substrate tissue distribution assays. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability.

[0150] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar. In some embodiments, one or more of the substituents disclosed herein contain deuterium in a proportion greater than the natural abundance of deuterium. In some embodiments, one or more 1 H is substituted with one or more deuterium atoms by one or more of the substituents disclosed herein.

[0151] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0152] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0153] In some embodiments, the compounds described herein contain acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0154] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds disclosed herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, Hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0155] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compounds with a pharma- ceutically acceptable inorganic or organic acid, including but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids including but not limited to, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoic acid, 4-methyl-2-phenylpropionic ... (yl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not themselves pharma-ceutically acceptable, are utilized in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers and their pharma-ceutically acceptable acid addition salts.

[0156] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, sulfate, or ammonia, or with a pharma- ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Typical examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4 and the like.

[0157] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0158] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, the present disclosure provides a method of treating a disease by administering a compound in the form of such a solvate. In some embodiments, the present disclosure provides a method of treating a disease by administering a composition comprising a compound in the form of such a solvate. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization with pharmaceutically acceptable solvents.

[0159] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom with the switch of a single bond and adjacent double bond. When combining sequences that allow tautomerization, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are considered. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH.

[0160] Treatment Disclosed herein is a method of treating a disease regulated at least in part by ENPP1 in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0161] Disclosed herein are methods of treating cancer in a subject, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0162] Disclosed herein is a method for inhibiting ENPP1 in a subject in need of ENPP1 inhibition, comprising administering to the subject an amount of a compound or a pharmaceutically acceptable salt thereof. Disclosed herein is a method for regulating the STING pathway in a subject in need of immune STING pathway regulation by hydrolyzing cGAMP and / or generating immunosuppressive adenosine, comprising administering to the subject an amount of a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has cancer.

[0163] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is breast cancer, lung cancer, ovarian cancer, head and neck cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colon cancer, or sarcoma.

[0164] In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is a leukemia, lymphoma, or myeloma. In some embodiments, the hematological malignancy is a B-cell malignancy. In some embodiments, the hematological malignancy is multiple myeloma.

[0165] In some embodiments, the cancer is a recurrent or refractory cancer, hi some embodiments, the cancer is a metastatic cancer.

[0166] In some embodiments, the cancer is hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, or breast cancer. In some embodiments, the cancer is basal cell carcinoma, biliary tract cancer, osteosarcoma, brain tumor (e.g., glioblastoma multiforme, glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineoblastoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblast ... Pericytoma (hemangiopercytoma), metastatic brain tumor, ventricular ependymoma, astrocytoma, oligodendroglioma, oligoastrocytoma, juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, neuronal glioma, subependymal cell tumor, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, multiple glioblastoma, brainstem glioma, oligodendroglioma, ventricular ependymoma, oligoastrocytoma, cerebellar astrocytoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, cerebral gliomatosis, multifocal glioma gliomatous tumor, multicentric glioblastoma multiforme tumor, paraganglioma, neuronal glioma, breast cancer, head and neck cancer, respiratory system cancer, urinary system cancer, choriocarcinoma, colon cancer, connective tissue cancer, endometrial cancer, esophageal cancer, eye cancer, gastric cancer cancer), gastrointestinal tract cancer, genitourinary tract cancer, blood cancer (e.g., acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, solitary myeloma, localized myeloma, extramedullary myeloma, small lymphocytic lymphoma, B-cell non-Hodgkin's lymphoma, and large B-cell lymphoma), epithelial tumors, kidney cancer, laryngeal cancer, lung cancer, cancer of the lymphatic system, melanoma, myeloma, neuroblastoma, oral cancer (e.g., lip, tongue, mouth, and pharynx), ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, sarcoma, skin cancer, stomach cancer, cancer, testicular cancer, or uterine cancer.

[0167] Disclosed herein is a method of treating an infectious disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, the infectious disease is a viral infection. In some embodiments, the viral infection is caused by a DNA virus. In some embodiments, the viral infection is caused by a herpes virus. In some embodiments, the herpes virus is selected from herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpes virus 6A (HHV-6A), human herpes virus 6B (HHV-6B), human herpes virus 7 (HHV-7), and Kaposi's sarcoma-associated herpes virus (KSHV). In some embodiments, the herpes virus is herpes simplex virus 1 (HSV-1). In some embodiments, the viral infection is caused by a retrovirus. In some embodiments, the retrovirus is human immunodeficiency virus (HIV). In some embodiments, the retrovirus is HIV-1, HIV-2, or human T-lymphotropic virus (HTLV). In some embodiments, the viral infection is caused by a hepatitis virus. In some embodiments, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV). In some embodiments, the viral infection is caused by a vaccinia virus (VACV), adenovirus, or human papilloma virus (HPV). In some embodiments, the viral infection is caused by an RNA virus. In some embodiments, the viral infection is caused by a dengue virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus, or Zika virus.

[0168] dosage In certain embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0169] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In such applications, the exact amount will vary depending on the patient's health, weight, and the like. When used in a patient, the amount effective for such use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status, and response to the drugs, as well as the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharma- ceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0170] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound may be administered chronically, i.e., for an extended period of time, including the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0171] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily stopped for a period of time (i.e., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, such as, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday is, by way of example only, 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0172] Once improvement of the patient's condition has occurred, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, can be reduced as a function of the symptoms to a level that sustains improvement of the disease, disorder, or condition. However, in certain embodiments, the patient will require intermittent or daily treatment for an extended period of time upon recurrence of symptoms.

[0173] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but may nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0174] However, doses typically utilized for adult treatment range from 0.01 mg to 5000 mg per day. In one aspect, doses utilized for adult treatment range from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is suitably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0175] In one embodiment, a suitable daily dosage of the compound described herein, or a pharma- ceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the amount of active ingredient in the daily dosage or dosage form will be less than or greater than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the medical practitioner.

[0176] The toxicity and therapeutic efficacy of such treatment regimens are 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within the range of ED 100 with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0177] In any of the foregoing aspects, further embodiments are provided in which an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is administered (a) systemically to a mammal, and / or (b) orally to a mammal, and / or (c) intravenously to a mammal, and / or (d) by injection to a mammal, and / or (e) locally to a mammal, and / or (f) non-systemically or locally to a mammal.

[0178] In any of the foregoing aspects, further embodiments are provided that comprise a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times to the mammal over the course of a day.

[0179] In any of the foregoing aspects, further embodiments are provided that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently as in a single administration, (ii) the multiple administrations are spaced apart by 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, or (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0180] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, transdermal, vaginal, auricular, nasal, and topical.In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, and intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0181] In certain embodiments, compounds as described herein are administered locally rather than systemically, often in a depot or sustained release formulation, for example by injection of the compound directly into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In yet other embodiments, drugs are delivered in targeted drug delivery systems, for example in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively absorbed by the organ. In yet other embodiments, compounds as described herein are provided in the form of immediate release formulations, extended release formulations, or intermediate release formulations. In yet other embodiments, compounds as described herein are administered locally.

[0182] Pharmaceutical Compositions / Formulations The compounds described herein are administered to subjects in need of administration, either alone or in combination with pharma- ceutically acceptable carriers, excipients or diluents, in pharmaceutical compositions according to standard pharmaceutical practice.In one embodiment, the compounds of the present disclosure can be administered to animals.The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0183] In another aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into a preparation that can be used pharmaceutically.The suitable formulation depends on the route of administration selected. Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0184] In some embodiments, the pharma- ceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0185] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal.The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and immediate mixing and controlled release formulations.

[0186] Pharmaceutical compositions containing a compound described herein, or a pharma- ceutically acceptable salt thereof, may be manufactured in a conventional manner such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0187] The pharmaceutical composition for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, to obtain tablets or dragee cores, if desired.Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone), or calcium phosphate.If necessary, disintegrants such as crosslinked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, for example, sodium alginate, are added.In some embodiments, dyes or pigments are added to the coating of tablets or dragees to identify or characterize different combinations of doses of active compounds.

[0188] Orally administered pharmaceutical compositions include push-type capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-type capsules contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds are dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0189] Pharmaceutical compositions for parenteral use are formulated as infusions or injections.In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the compounds described herein or their pharma-ceutically acceptable salts.In some embodiments, pharmaceutical compositions include liquid carriers.In some embodiments, liquid carriers are solvents or liquid dispersion media, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof.In some embodiments, pharmaceutical compositions further include preservatives to prevent the growth of microorganisms.

[0190] combination Disclosed herein are methods of treating diseases or disorders associated with ENPP1 using the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, in combination with an additional therapeutic agent.

[0191] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

[0192] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0193] In some embodiments, the additional therapeutic agent is an ALK inhibitor, e.g., crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib, or lorlatinib; an androgen receptor inhibitor, e.g., enzalutamide, apalutamide, abiraterone acetate, orteronel, galeterone, ceviteronel, bicalutamide, or flutamide; an anti-tumor agent, e.g., oxaliplatin, carboplatin, or cisplatin; an aromatase inhibitor, exemestane, letrozole, anastrozole; Fulvestrant, or tamoxifen, BCL-2 inhibitors, such as venetoclax, BCR-ABL inhibitors, such as imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, dansertib, saracatinib, or PF03814735, BRAF inhibitors, such as vemurafenib or dabrafenib, CD20 antibodies, such as rituximab, tositumomab, or ofatumumab, CDK4 / 6 inhibitors, such as alvocidib, palbociclib, ribociclib, trilaciclib, or abemaciclib, CTLA-4 inhibitors such as tremelimumab or ipilimumab, DNA synthesis inhibitors such as capecitabine, gemcitabine, nelarabine, or hydroxycarbamide, epidermal growth factor receptor (EGFR) inhibitors such as gefitinib, osimertinib, cetuximab, or panitumumab, ERK inhibitors such as ulixertinib, MK8353, or LY3214996, KRAS inhibitors such as AMG-510, MRTX849, or ARS-3248, FGFR inhibitors such as infigratinib, dovitinib, , erdafitinib, TAS-120, pemigatinib, BLU-554, or AZD4547, FLT3 inhibitors such as sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, or crenolanib, heat shock protein (HSP) inhibitors such as tanespimycin, hedgehog antagonists such as vismodegib, HER2 receptor inhibitors such as trastuzumab, pertuzumab, neratinib, lapatinib, or lapatinib, histone deacetylase inhibitors (HDIs) such as vorinostat,Immunomodulators such as afutuzumab, lenalidomide, thalidomide, or pomalidomide, CD40 inhibitors such as dacetuzumab, MEK inhibitors such as trametinib, cobimetinib, binimetinib, or selumetinib, MET inhibitors such as crizotinib or cabozantinib, mTOR inhibitors such as temsirolimus, ridaforolimus, everolimus or sirolimus, PD1 inhibitors such as nivolumab or pembrolizumab, PDL1 inhibitors such as MSB0010718C, YW243.55.S70, MPDL32 80A, MEDI-4736, MSB-0010718C, or MDX-1105, PI3K inhibitors such as pictilisib, dactolisib, alpelisib, bupalisib, taselisib, idelalisib, duvelisib, or umbralisib, PIK3CA inhibitors, pro-apoptotic receptor agonists (PARA) such as dulanermin, proteasome inhibitors such as bortezomib, SHP2 inhibitors, or tyrosine kinase inhibitors such as erlotinib, linifanib, sunitinib, or pazopanib. EXAMPLES

[0194] Example 1: Synthesis of N-(4-((6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)sulfamide

[0195] [ka]

[0196] Step 1: General procedure for the preparation of 3-bromo-2-methoxypyridin-4-amine To a solution of compound 1_1 (5 g, 40.3 mmol) in DCM (100 mL) was added NBS (7.17 g, 40.3 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. After removing the solvent under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 1_2 (7 g, 85.9% yield) as a yellow solid. LCMS: [M+H] + =203.0. 1 H NMR: (400MHz, DMSO-d6) δ7.60 (d, J = 5.6 Hz, 1H), 6.37 (d, J = 5.6 Hz, 1H), 6.20 (s, 2H), 3.81 (s, 3H).

[0197] Step 2: General procedure for the preparation of 3-bromo-5-iodo-2-methoxypyridin-4-amine (compound 1_3) To a solution of compound 1_2 (7 g, 34.7 mmol) in MeCN / AcOH (70 mL / 7 mL) was added NIS (8.60 g, 38.2 mmol) at 0° C. The mixture was stirred at room temperature for 16 h. After the solvent was removed under reduced pressure, the resulting residue was diluted with water (100 mL). The aqueous phase was extracted with DCM (100 mL×2). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the corresponding compound 1_3 (10.3 g, 90% yield) as a yellow solid. The crude product was used directly in the next step. LCMS: [M+H] + =328.8.

[0198] Step 3: General procedure for the preparation of (E)-3-bromo-5-(2-ethoxyvinyl)-2-methoxypyridin-4-amine (compound 1_5) A mixture of compound 1_3 (10 g, 30.5 mmol), compound 1_4 (6.65 g, 33.6 mmol), K3PO4 (19.40 g, 91.5 mmol), SPhos (1.3 g, 3.1 mmol), and Pd(OAc)2 (697.5 mg, 3.1 mmol) in MeCN / H2O (80 mL / 20 mL) was stirred at 110 °C for 10 h under N2 atmosphere. After removing the solvent under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 1_5 (3.5 g, 42% yield) as a yellow solid. LCMS: [M+H] + =273.0.

[0199] Step 4: General procedure for the preparation of 7-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine (compound 1_6) To a solution of compound 1_5 (3.5 g, 12.9 mmol) in EtOH (20 mL) was added concentrated hydrochloric acid (20 mL). The mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to give the corresponding compound 1_6 (2 g, 69.0% yield) as a brown solid. The crude product was used directly in the next step. LCMS: [M+H] + =227.0.

[0200] Step 5: General procedure for the preparation of 6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridine (compound 1_8) A mixture of compound 1_6 (2 g, 8.85 mmol), compound 1_7 (2.75 g, 13.2 mmol), Cs2CO3 (8.66 g, 26.55 mmol), and Pd(PPh3)4 (1.03 g, 0.89 mmol) in DMF (20 mL) and H2O (5 mL) was stirred at 90° C. under N2 atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 1_8 (500 mg, 25.0% yield) as a purple solid. LCMS: [M+H] + =229.1. 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.39(s,1H),7.80(d,J=2.4Hz,1H),7.38-7.30(m,1H),6.90(d,J=2.4Hz,1H),6.55-6.49(m,1H),4.00(s,6H).

[0201] Step 6: General procedure for the preparation of 3-bromo-6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridine (compound 1_9) To a solution of compound 1_8 (500 mg, 2.19 mmol) in DCM (10 mL) was added NBS (312 mg, 1.75 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 s. After removing the solvent under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 1_9 (180 mg, 26.9% yield) as a yellow solid. LCMS: [M+H] + =307.0.

[0202] Step 7: General procedure for the preparation of 6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridine (compound 1_11) A mixture of compound 1_9 (180 mg, 0.59 mmol), compound 1_10 (0.5 mL), Cs2CO3 (577 mg, 1.77 mmol), XPhos (87 mg, 0.18 mmol), and Pd2(dba)3 (55 mg, 0.06 mmol) in dioxane (10 mL) was stirred at 110° C. for 16 h under N2 atmosphere. After removing the solvent under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 1_11 (120 mg) as a yellow solid. LCMS: [M+H] + =243.1.

[0203] Step 8: General procedure for the preparation of tert-butyl (4-((6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)carbamate (compound 1_13) To a solution of compound 1_11 (120 mg, 0.49 mmol) in DMF (5 mL) was added NaH (59 mg, 1.47 mmol, 60% in oil) at 0° C. The reaction mixture was stirred at this temperature for 0.5 h under N2 atmosphere. Compound 1_12 (211 mg, 0.74 mmol) was then added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 1_13 (80 mg) as a yellow solid. LCMS: [M+H] + =448.3.

[0204] Step 9: General procedure for the preparation of 4-((6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)aniline (compound 1_14) A solution of compound 1_13 (80 mg, 0.18 mmol) in DCM (5 mL) and TFA (1 mL) was stirred at room temperature for 2 h. After removing the solvent under reduced pressure, the resulting residue was purified by preparative HPLC to give the corresponding compound 1_14 (40 mg, 64.5% yield) as a white solid. LCMS: [M+H] + =348.2.

[0205] Step 10: General procedure for the preparation of N-(4-((6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)sulfamide To a solution of compound 1_14 (40 mg, 0.12 mmol) in DCM (5 mL) was added compound 1_15 (28 mg, 0.24 mmol) and TEA (36 mg, 0.36 mmol). The reaction was stirred at room temperature for 2 h. After removing the solvent under reduced pressure, the resulting residue was purified by preparative HPLC to give Example 1 (1.5 mg, 2.9% yield). LCMS: [M+H] +=427. 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.37(s,1H),7.69(d,J=2.0Hz,1H),7.02-6.96(m,3H),6.93(d,J=8.4 Hz,2H),6.65(d,J=8.4Hz,2H),6.20(d,J=2.0Hz,1H),4.83(s,2H),3.86(s,3H),3.78(s,3H),2.25(s,3H).

[0206] Example 2: Synthesis of N-(4-((6-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)sulfamide

[0207] [ka]

[0208] The title compound was synthesized as described in Example 1. LCMS: [M+H] + =397.1. 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.71(s,1H),7.77(d,J=2.0Hz,1H),7.31(d,J=3.2Hz,1H),6.9 6(d,J=8.4Hz,2H),6.67-6.61(m,3H),6.21(d,J=2.0Hz,1H),4.83(s,2H),3.86(s,3H),2.28(s,3H).

[0209] Example 3: Synthesis of N-(4-((6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)phenyl)sulfamide

[0210] [ka]

[0211] The title compound was synthesized as described in Example 1. LCMS: [M+H] + =413.1.1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.69(d,J=2.0Hz,1H),7.28(d,J=3.2Hz,1H),6.93(d,J=8.4Hz ,2H),6.65-6.55(m,3H),6.18(d,J=2.0Hz,1H),6.05(s,1H),4.94(s,2H),3.87(s,3H),3.77(s,3H).

[0212] Example 4: Synthesis of 3,5-difluoro-4-((6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0213] [ka]

[0214] To a solution of compound 1_11 (90 mg, 0.37 mmol) in DMF (5 mL) was added NaH (44 mg, 1.11 mmol, 60% in oil) at 0° C. The mixture was stirred under N2 atmosphere at 0° C. for 0.5 h. Compound 4_1 (116 mg, 0.41 mmol) was then added. The reaction mixture was stirred at room temperature for 2 h. After diluting the reaction mixture with water (30 mL), the aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC to give Example 4 (17 mg, 10.3%). LCMS: [M+H] + =448.1. 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.61(d,J=2.4Hz,1H),7.58(s,2H),7.31(d,J=7.2Hz,2 H),6.90(s,1H),6.11(d,J=2.4Hz,1H),5.13(s,2H),3.81(s,3H),3.77(s,3H),2.25(s,3H).

[0215] Example 5: Synthesis of 4-((6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0216] [ka]

[0217] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =398.1. 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),7.62-7.56(m,3H),7.36(d,J=3.2Hz,1H),7.24(s,2H),6.72(d ,J=8.4Hz,2H),6.64(d,J=3.2Hz,1H),6.04(d,J=2.0Hz,1H),5.16(s,2H),3.80(s,3H),3.76(s,3H).

[0218] Example 6: Synthesis of 4-((6-methoxy-3-methyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0219] [ka]

[0220] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =412.1. 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.62-7.54(m,3H),7.23(s,2H),7.07(s,1H),6.76(d ,J=8.4Hz,2H),6.05(d,J=2.0Hz,1H),5.05(s,2H),3.79(s,3H),3.77(s,3H),2.29(s,3H).

[0221] Example 7: Synthesis of 3,5-difluoro-4-((6-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0222] [ka]

[0223] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =434.2. 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.60(d,J=2.0Hz,1H),7.57(s,2H),7.29(d,J=7.2Hz,2H),7.21( d,J=3.2Hz,1H),6.58(d,J=3.2Hz,1H),6.08(d,J=2.0Hz,1H),5.26(s,2H),3.81(s,3H),3.77(s,3H).

[0224] Example 8: Synthesis of 4-((6-methoxy-7-(3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0225] [ka]

[0226] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =398.1. 1 H NMR(400MHz,CD3OD)δ8.53(s,1H),7.71(d,J=6.8Hz,2H),7.26(s,1H),7.22(s,1H),6. 83(d,J=7.6Hz,2H),6.73(s,1H),6.12(s,1H),4.83(s,2H),3.88(s,3H),2.23(s,3H).

[0227] Example 9: Synthesis of 4-((6-methoxy-7-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0228] [ka]

[0229] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =394.1. 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.56(d,J=8.4Hz,2H),7.34-7.27(m,2H),7.29-7.19(m,4 H),7.09-7.04(m,2H),6.67(d,J=3.6Hz,1H),6.56(d,J=8.0Hz,2H),4.88(s,2H),3.74(s,3H).

[0230] Example 10: Synthesis of 4-((6-methoxy-3-methyl-7-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0231] [ka]

[0232] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =408.1. 1 H NMR(400MHz,CD3OD)δ8.56(s,1H),7.64(d,J=8.8Hz,2H),7.40-7.30(m,1H),7.30-7.23( m,2H),7.16(s,1H),7.10-7.04(m,2H),6.560(d,J=8.0Hz,2H),4.94(s,2H),3.86(s,3H).

[0233] Example 11: Synthesis of 4-((6-methoxy-7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0234] [ka]

[0235] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =452.1. 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.16(s,1H),7.69(s,1H),7.60(d,J=8.4Hz,2H),7.44(d,J= 3.2Hz,1H),7.26(s,2H),6.69(d,J=3.2Hz,1H),6.62(d,J=8.4Hz,2H),5.16(s,2H),3.77(s,3H).

[0236] Example 12: Synthesis of 4-((6-methoxy-7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0237] [ka]

[0238] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =426.1.

[0239] 1 H NMR:(400MHz,DMSO-d6)δ8.45(s,1H),7.57(d,J=8.0Hz,2H),7.27(s,2H),7.0 9-6.97(m,5H),6.60(d,J=8.0Hz,2H),4.84(s,2H),3.74(s,3H),2.31(s,3H).

[0240] Example 13: Synthesis of 4-((6-methoxy-3-methyl-7-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0241] [ka]

[0242] The title compound was synthesized as described in Example 4. LCMS: [M+H] + =409.2. 1 H NMR(400MHz,DMSO-d6)δ8.56(d,J=4.0Hz,1H),8.49(s,1H),7.57-7.47(m,3H),7.32-7.20(m,3H), 7.10(s,1H),7.03(d,J=8.0Hz,1H),6.55(d,J=8.4Hz,2H),4.89(s,2H),3.76(s,3H),2.32(s,3H).

[0243] Example 14: Synthesis of 4-[(3,6-dimethyl-7-phenylpyrrolo[3,2-c]pyridin-1-yl)methyl]-3,5-difluorobenzene-1-sulfonamide

[0244] [ka]

[0245] Step 1: General procedure for the preparation of 7-bromo-3,6-dimethyl-2-(trimethylsilyl)-1H-pyrrolo[3,2-c]pyridine (compound 14_3) To a solution of compound 14_1 (4.8 g, 15.4 mmol) in DMF (50 mL) was added LiCl (652.26 mg, 15.4 mmol), Na2CO3 (1.6 g, 15.4 mmol), Pd(dppf)Cl2 (1.12 g, 15.4 mmol), and compound 14_2 (5.2 g, 46.2 mmol). The reaction mixture was stirred overnight at 100 °C under N2 atmosphere. After the solvent was concentrated under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 14_3 (2.7 g, 59.0% yield) as a yellow solid. LCMS: [M+H] + =299.0.

[0246] Step 2: General procedure for the preparation of 7-bromo-3,6-dimethyl-1H-pyrrolo[3,2-c]pyridine (compound 14_4) To a solution of compound 14_3 (2.7 g, 9.1 mmol) in THF (30 mL) was added TBAF (7.1 g, 27.4 mmol). The reaction mixture was stirred at room temperature for 16 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 14_4 (1.2 g, 58.7% yield) as a white solid. LCMS: [M+H] + =226.9.

[0247] Step 3: General procedure for the preparation of 4-(((3-bromo-2-methoxy-5-nitropyridin-4-yl)amino)methyl)benzenesulfonamide (compound 14_6) To a solution of compound 14_4 (750.0 mg, 3.3 mmol) in DMF (8 mL) was added NaH (240.0 mg, 10.0 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 30 min. Compound 14_5 (953.3 mg, 3.3 mmol) was then added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated NaCl solution (3×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 14_6 (330 mg, 23.0% yield) as a yellow solid. LCMS: [M+H] + =429.9.

[0248] Step 4: General procedure for the preparation of 4-[(3,6-dimethyl-7-phenylpyrrolo[3,2-c]pyridin-1-yl)methyl]-3,5-difluorobenzene-1-sulfonamide To a solution of compound 14_6 (220.0 mg, 0.5 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added K2CO3 (212.0 mg, 1.5 mmol), XPhos-Pd-G2 (40.2 mg, 0.05 mmol), and phenylboronic acid (124.7 mg, 1.0 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by preparative HPLC to give Example 14 (22.7 mg, 10.4% yield). LCMS: [M+H] + =428.1. 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.61(s,2H),7.43-7.38(m,3H),7.35(d,J =7.2Hz,2H),7.23(s,2H),6.88(s,1H),4.78(s,2H),2.27(s,3H),2.19(s,3H).

[0249] Example 15: Synthesis of 4-((6-methyl-7-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0250] [ka]

[0251] The title compound was synthesized as described in Example 14. LCMS: [M+H] + =378.1. 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.58(d,J=8.4Hz,2H),7.37(d,J=3.2Hz,2H),7.32-7.25(m ,4H),7.07-7.02(m,2H),6.73(d,J=3.2Hz,1H),6.56(d,J=8.0Hz,2H),4.87(s,2H),2.16(s,3H).

[0252] Example 16: Synthesis of 4-((3,6-dimethyl-7-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0253] [ka]

[0254] The title compound was synthesized as described in Example 14. LCMS: [M+H] + =392.1. 1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.58(d,J=8.4Hz,2H),7.36(t,J=7.2Hz,1H),7.28( s,4H),7.09-7.03(m,3H),6.60(d,J=8.4Hz,2H),4.77(s,2H),2.33(s,3H),2.16(s,3H).

[0255] Example 17: Synthesis of 4-((3,6-dimethyl-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0256] [ka]

[0257] The title compound was synthesized as described in Example 14. LCMS: [M+H] + =432.2. 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.72(d,J=2.0Hz,1H),7.59(s,2H),7.35(d,J=7 .0Hz,2H),6.94(s,1H),6.18(d,J=2.1Hz,1H),5.02(s,2H),3.81(s,3H),2.27(s,3H).

[0258] Example 18: Synthesis of 4-((3,6-dimethyl-7-(1-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0259] [ka]

[0260] The title compound was synthesized as described in Example 14. LCMS: [M+H] + =486.1. 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.56(s,1H),7.54(s,2H),7.36(d,J=6.8Hz,2H),7.00(s,1H),6.69(s,1H),5.01(s,2H),2.29(s,6H).

[0261] Example 19: Synthesis of 4-[(6-methoxy-3-methyl-2-oxo-7-phenylimidazo[5,4-c]pyridin-1-yl)methyl]benzene-1-sulfonamide

[0262] [ka]

[0263] Step 1: General procedure for the preparation of 4-{[(5-amino-2-methoxy-3-phenylpyridin-4-yl)amino]methyl}benzene-1-sulfonamide (Compound 19_2) To a solution of compound 22_8 (160.0 mg, 0.42 mmol) in THF (3 mL), TEA (126.3 mg, 1.25 mmol) and compound 19_1 (145.0 mg, 0.83 mmol) were added. The reaction mixture was stirred at 0° C. for 1 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 19_2 (120 mg, 70.3% yield) as a yellow solid. LCMS: [M+H] + =411.0.

[0264] Step 2: General procedure for the preparation of 4-[(6-methoxy-3-methyl-2-oxo-7-phenylimidazo[5,4-c]pyridin-1-yl)methyl]benzene-1-sulfonamide To a solution of compound 19_2 (80.0 mg, 0.20 mmol) in DMF (2 mL) was added K2CO3 (80.8 mg, 0.59 mmol) and methyl iodide (30.43 mg, 0.214 mmol). The reaction mixture was stirred at room temperature for 6 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by preparative HPLC to give Example 19 (15.74 mg, 19.0% yield). LCMS: [M+H] + =425.1. 1 H NMR:(400MHz,DMSO-d6)δ8.02(s,1H),7.54(d,J=8.4Hz,2H),7.33-7.25(m,3H),7.21(t,J=7. 6Hz,2H), 7.01(d,J=7.2Hz,2H),6.68(d,J=8.4Hz,2H),4.63(s,2H),3.69(s,3H),3.43(s,3H).

[0265] Example 20: Synthesis of 4-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0266] [ka]

[0267] The title compound was synthesized as described in Example 19. LCMS: [M+H] + =409.2. 1 H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.56(d,J=8.4Hz,2H),7.25(d,J=7.6Hz,5H),7 .01(d,J=7.2Hz,2H),6.70(d,J=8.4Hz,2H),4.58(s,2H),3.47(s,3H),2.09(s,3H).

[0268] Example 21: Synthesis of 4-((6-methoxy-7-phenyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)benzenesulfonamide

[0269] [ka]

[0270] Step 1: General procedure for the preparation of 3-bromo-4-chloro-2-methoxypyridine (compound 21_2) To a solution of compound 21_1 (5.0 g, 34.83 mmol) in DMF (20 mL) was added N-bromosuccinimide (6.2 g, 34.83 mmol). The reaction mixture was stirred at 90° C. for 16 h. After the reaction was quenched with water (30 mL), the resulting aqueous solution was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with saturated NaCl (2×30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 21_2 (2.4 g, 31.0% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ8.27(s,1H), 6.88(s,1H), 3.91(s,3H).

[0271] Step 2: General procedure for the preparation of 5-bromo-4-chloro-6-methoxynicotinaldehyde (compound 21_3) To a solution of compound 21_2 (1.0 g, 4.5 mmol) in anhydrous THF (20 mL) at -78 °C under N2 atmosphere, lithium diisopropylamide in n-hexane (2 M, 3.4 mL, 6.8 mmol) was slowly added, and the mixture was stirred at -78 °C for 1 h. Anhydrous DMF (1 mL) was added, and stirring was continued for 30 min. The mixture was gradually warmed to room temperature and quenched with saturated aqueous NH4Cl (30 mL). The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 1) and brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 21_3 (0.32 g, 28.4% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ10.39(s,1H), 8.46(s,1H), 4.06(s,3H).

[0272] Step 3: General procedure for the preparation of 7-bromo-6-methoxy-1H-pyrazolo[4,3-c]pyridine (compound 21_4) To a solution of compound 21_3 (350 mg, 1.40 mmol) in EtOH (5 mL) was added hydrazine monohydrate (350 mg, 7.0 mmol, 98%). The resulting mixture was stirred in a sealed tube at 70° C. overnight. Water was added to dilute the mixture, and then it was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL×1), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 21_4 (130 mg, 40.8%) as a white solid. LCMS: [M+H] + =227.9.

[0273] Step 4: General procedure for the preparation of 4-((7-bromo-6-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)benzenesulfonamide (compound 21_4) To a solution of compound 21_4 (130 mg, 0.57 mmol) in DMF (5 mL), NaH (35 mg, 0.86 mmol, 60% in oil) was added and the mixture was stirred at 0° C. for 0.5 h under N2 atmosphere. Compound 1_12 (171 mg, 0.68 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (20 ml×2). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 21_4 (60 mg, 26.5%) as a white solid. LCMS: [M+H] + =396.9.

[0274] Step 5: General procedure for the preparation of 4-((6-methoxy-7-phenyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 21_5 (60.0 mg, 0.15 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added K2CO3 (21.8 mg, 0.30 mmol), XPhos-Pd-G2 (40.2 mg, 0.05 mmol), and phenylboronic acid (36.6 mg, 0.30 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 6 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by preparative HPLC to give Example 21 (8.66 mg, 14.5% yield). LCMS: [M+H] + =395.2. 1 H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.71(s,1H),7.57(d,J=8.4Hz,2H),7.48-7 .36(m,3H),7.34-7.18(m,4H),6.66(d,J=8.4Hz,2H),5.31(s,2H),4.07(s,3H).

[0275] Example 22: Synthesis of 4-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0276] [ka]

[0277] Step 1: General procedure for the preparation of 3-bromo-4-chloro-5-nitropyridin-2-ol (compound 22_2) THF (50 mL) was cooled to -78°C and anhydrous NH3 (20 mL) was condensed into THF. Potassium t-butoxide (3.1 g, 27.5 mmol) was added and the mixture was allowed to warm to -35°C. Compound 22_1 (2.6 g, 11 mmol) in THF (20 mL) was cooled to 0°C and a solution of t-BuOOH (5 M in decane, 2.2 mL, 11 mmol) was added over 5 min. This solution was then added dropwise over 0.5 h to the KO t-Bu solution and stirred at -35°C for 1 h, then carefully quenched with 10 mL of saturated NH4Cl solution. The mixture was allowed to warm to room temperature and stirred overnight. The organics were then concentrated and the residue was acidified with NH4Cl solution and filtered. The solid was washed with cold H2O and dried to give the title compound 22_2 (2.5 g, 92%) as a dark brown solid. LCMS: [MH]-=250.9.

[0278] Step 2: General procedure for the preparation of 3-bromo-4-chloro-2-methoxy-5-nitropyridine (compound 22_4) To a solution of compound 22_2 (872 mg, 3.45 mmol) in dichloromethane (10 mL) was added compound 22_3 (1.02 g, 6.89 mmol). The mixture was stirred at 55° C. under N2 atmosphere for 16 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 22_4 (400 mg, 43.5% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δ8.97(s,1H),4.08(s,3H).

[0279] Step 3: General procedure for the preparation of 4-(((3-bromo-2-methoxy-5-nitropyridin-4-yl)amino)methyl)benzenesulfonamide (compound 22_6) To a solution of compound 22_4 (400 mg, 1.49 mmol) in acetonitrile (5 mL) was added compound 22_5 (334 mg, 1.49 mmol) and DIPEA (773 mg, 5.99 mmol). The mixture was stirred at 60° C. for 2 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 22_6 (288 mg, 46% yield) as a yellow solid. LCMS: [M+H] + =416.8,5.

[0280] Step 4: General procedure for the preparation of 4-(((2-methoxy-5-nitro-3-phenylpyridin-4-yl)amino)methyl)benzenesulfonamide (compound 22_7) To a solution of compound 22_6 (288 g, 0.69 mmol) in dioxane-H2O (5 mL) was added phenylboronic acid (168 mg, 1.38 mmol), XPhosPd-G2 (54 mg, 0.068 mmol), and K2CO3 (286 mg, 2.07 mmol). The mixture was stirred at 100 °C under N2 atmosphere for 16 h. After the solvent was concentrated under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 22_7 (228 g, 79.6% yield) as a green solid. LCMS: [M+H] + =415.0,5.

[0281] Step 5: General procedure for the preparation of 4-(((5-amino-2-methoxy-3-phenylpyridin-4-yl)amino)methyl)benzenesulfonamide (compound 22_8) To a solution of compound 22_7 (228 mg, 0.55 mmol) in ethanol (5 mL) was added Raney Ni (50 mg) and hydrazine monohydrate (138 mg, 2.76 mmol, 98%). The mixture was stirred at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a pale yellow solid. The resulting solid was purified by flash silica gel chromatography to give the corresponding compound 22_8 (100 mg, 47.3% yield). LCMS: [M+H] + =385.1.

[0282] Step 6: General procedure for the preparation of 4-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 22_8 (100 mg, 0.26 mmol) in ethanol (3 mL) was added triethyl orthoacetate (422 mg, 2.6 mmol) and Py-HCl (30 mg, 0.26 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to give Example 22 (73 mg, 68.6% yield). LCMS: [M+H] + =409.1. 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.60(d,J=8.4Hz,2H),7.35-7.27(m,3H),7.22(t,J=7.6 Hz,2H),7.07(d,J=6.8Hz,2H),6.66(d,J=8.4Hz,2H),4.93(s,2H),3.76(s,3H),2.37(s,3H).

[0283] Example 23: Synthesis of 4-((6-methoxy-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0284] [ka]

[0285] The title compound was synthesized as described in Example 22. LCMS: [M+H] + =395.1. 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.37(s,1H),7.53(d,J=8.2Hz,2H),7.35-7. 25(m,5H),7.06(d,J=7.3Hz,2H),6.53(d,J=8.2Hz,2H),5.07(s,2H),3.77(s,3H).

[0286] Example 24: Synthesis of 3,5-difluoro-4-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0287] [ka]

[0288] Step 1: General procedure for the preparation of 4-(((3-bromo-2-methoxy-5-nitropyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 24_3) To a solution of compound 22_4 (128 mg, 0.48 mmol) in acetonitrile (3 mL) was added compound 24_1 (107 mg, 0.48 mmol) and DIPEA (248 mg, 1.93 mmol). The mixture was stirred at 60° C. for 2 h. The solvent was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography to give the corresponding compound 24_2 (98 mg, 45.3% yield) as a yellow solid. LCMS: [M+H] + =452.8.

[0289] Step 2: General procedure for the preparation of 3,5-difluoro-4-(((2-methoxy-5-nitro-3-phenylpyridin-4-yl)amino)methyl)benzenesulfonamide (compound 24_3) To a solution of compound 24_2 (98 mg, 0.22 mmol) in dioxane-H2O (3 mL) was added phenylboronic acid (53 mg, 0.44 mmol), XPhos-Pd-G2 (17 mg, 0.02 mmol), and K2CO3 (90 mg, 0.065 mmol). The mixture was stirred under N2 atmosphere at a temperature under 100 °C for 16 h. The solvent was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography to give the corresponding compound 24_3 (89 mg, 91.3% yield) as a yellow solid. LCMS: [M+H] + =450.9.

[0290] Step 3: General procedure for the preparation of 4-(((5-amino-2-methoxy-3-phenylpyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 24_4) To a solution of compound 24_3 (89 mg, 0.19 mmol) in ethanol (2 mL) was added Raney Ni (50 mg) and hydrazine monohydrate (49 mg, 0.98 mmol). The mixture was stirred at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a pale yellow solid, which was purified by flash silica gel chromatography to give the corresponding compound 24_4 (28 mg, 33.7% yield) as a yellow solid. LCMS: [M+H] + =420.9.

[0291] Step 4: General procedure for the preparation of 3,5-difluoro-4-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 24_4 (28 mg, 0.06 mmol) in acetonitrile (2 mL) was added triethyl orthoacetate (108 mg, 0.66 mmol) and Py-HCl (1 mg, 0.006 mmol). The reaction was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the corresponding example 24 (20 mg, 66.6% yield). LCMS: [M+H] + =416.1.1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.61(s,2H),7.35-7.29(m,1H),7.28- 7.17(m,4H),7.02(d,J=7.2Hz,2H),5.12(s,2H),3.74(s,3H),2.48(s,3H).

[0292] Example 25: Synthesis of 4-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0293] [ka]

[0294] The title compound was synthesized as described in Example 24. LCMS: [M+H] + =427.1. 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),7.52-7.42(m,3H),7.37(d,J=9.6Hz,1H),7.30(t,J=7.6Hz,1H),7. 17(t,J=7.6Hz,2H),6.94(t,J=7.2Hz,2H),6.42(t,J=7.6Hz,1H),4.97(s,2H),3.75(s,3H),2.44(s,3H).

[0295] Example 26: Synthesis of 4-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0296] [ka]

[0297] Step 1: General procedure for the preparation of 3-bromo-2-methylpyridin-4-amine (compound 26_2) To a solution of compound 26_1 (7.6 g, 70.4 mmol) in acetonitrile (80 mL) was added NBS (37 g, 207.8 mmol) at -50° C. The mixture was stirred at -50° C. for 3 h. The solvent was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography to give the corresponding compound 26_2 (7.4 g, 56% yield) as a white solid. 1 H NMR: (400MHz, DMSO-d6) δ7.82 (d, J = 5.6 Hz, 1H), 6.51 (d, J = 5.6 Hz, 1H), 6.15 (s, 2H), 2.42 (s, 3H).

[0298] Step 2: General procedure for the preparation of 3-bromo-2-methylpyridin-4-ol (compound 26_3) To a solution of compound 26_2 (7.4 g, 39.8 mmol) in H2O (60 mL) and H2SO4 (30 mL) was added NaNO2 (5.5 g, 79.6 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. After heating at 100 °C for 6 h, the solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography to give the corresponding compound 26_3 (3.8 g, 51% yield) as a white solid.

[0299] Step 3: General procedure for the preparation of 3-bromo-2-methyl-5-nitropyridin-4-ol (compound 26_4) To a solution of compound 26_3 (3.8 g, 20.3 mmol) in H2SO4 (20 mL) was added KNO3 (4.02 g, 40.6 mmol). The mixture was stirred at 80°C for 16 h. After the reaction mixture was cooled to 0°C, ammonium hydroxide was carefully added to adjust the pH to about 5-6. The title compound precipitated and was collected by filtration. The resulting solid was then dried in vacuum at 50°C to give compound 26_4 (2.65 g, 48.3% yield) as a pale yellow solid. LCMS: [M+H] + =232.9.

[0300] Step 4: General procedure for the preparation of 3-bromo-4-chloro-2-methyl-5-nitropyridine (compound 26_5) To a solution of compound 26_4 (2.65 g, 11.4 mmol) in POCl3 (20 mL) was added N,N-dimethylaniline (1.38 g, 11.4 mmol) at 0° C. The reaction mixture was stirred at 100° C. for 1 h. The solvent was removed under vacuum to give the crude product, which was purified by flash silica gel chromatography to give compound 26_5 (1.46 g, 51.1% yield) as a yellow solid. LCMS: [M+H] + =251.0.

[0301] Step 5: General procedure for the preparation of 4-(((3-bromo-2-methyl-5-nitropyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 26_6) To a solution of compound 26_5 (1.46 g, 5.84 mmol) in acetonitrile (12 mL) was added compound 24_2 (1.30 g, 5.84 mmol) and DIPEA (2.63 g, 11.68 mmol). The reaction mixture was stirred at 60° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography to give the corresponding compound 26_6 (624 mg, 24.7% yield) as a white solid. LCMS: [M+H] + =437.0.

[0302] Step 6: General procedure for the preparation of 3,5-difluoro-4-(((2-methyl-5-nitro-3-phenyl)pyridin-4-yl)amino)methyl)benzenesulfonamide (compound 26_7) To a solution of compound 26_6 (624 mg, 1.43 mmol) in dioxane-H2O (10 mL / 1 mL) was added phenylboronic acid (349 mg, 2.86 mmol), XPhos-Pd-G2 (60 mg, 0.14 mmol), Pd2(dba)3 (131 mg, 0.14 mmol), and K2CO3 (624 mg, 4.29 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography to give the corresponding compound 26_9 (372 mg, 0.16 mmol, 42.7% yield) as a white solid. LCMS: [M+H] + =435.3.

[0303] Step 7: General procedure for the preparation of 4-(((5-amino-2-methyl-3-phenylpyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 26_8) To a solution of compound 26_7 (372 mg, 0.85 mmol) in ethanol (5 mL) was added Raney Ni (100 mg, 1.6 mmol) and hydrazine monohydrate (214 mg, 4.25 mmol). The reaction mixture was stirred at room temperature for 10 min. The mixture was filtered and the filtrate was concentrated in vacuo to give a pale yellow solid, which was purified by flash silica gel chromatography to give the corresponding compound 26_8 (173 mg, 50% yield) as a white solid. LCMS: [M+H] + =404.9.

[0304] Step 8: General procedure for the preparation of 4-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 26_8 (173 mg, 0.43 mmol) in ethanol (3 mL) was added compound 24_7 (693 mg, 4.3 mmol) and Py-HCl (49 mg, 0.43 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the corresponding example 26 (40 mg, 0.12 mmol, 21.8% yield). LCMS: [M+H] + =429.1. 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.62(s,2H),7.40-7.30(m,1H),7.33-7.21(m,4H),7.07-7.02(m,2H),5.09(s,2H),2.49(s,3H),2.16(s,3H).

[0305] Example 27: Synthesis of 3,5-difluoro-4-((6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0306] [ka]

[0307] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =415.1. 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.30(s,1H),7.63(s,2H),7.38(t,J=7.4Hz,1H),7.3 2(t,J=7.3Hz,2H),7.25(d,J=7.4Hz,2H),7.11(d,J=7.0Hz,2H),5.17(s,2H),2.20(s,3H).

[0308] Example 28: Synthesis of 3,5-difluoro-4-((6-methyl-7-(o-tolyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0309] [ka]

[0310] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =429.1. 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.31(s,1H),7.65(s,2H),7.36-7.22(m,3H),7. 22-7.11(m,2H),7.03(d,J=6.8Hz,1H),5.16-5.06(m,2H),2.12(s,3H),1.69(s,3H).

[0311] Example 29: Synthesis of 4-((6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0312] [ka]

[0313] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =379.1. 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.42(s,1H),7.56(d,J=8.4Hz,2H),7.38(t,J=7.6Hz, 1H),7.33-7.23(m,4H),7.12-6.98(m,2H),6.55(d,J=8.4Hz,2H),5.04(s,2H),2.21(s,3H).

[0314] Example 30: Synthesis of 4-((4-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0315] [ka]

[0316] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =379.1. 1 H NMR(400MHz,CD3OD)δ8.49(s,1H),7.95(s,1H),7.58(d,J=8.4Hz,2H),7.42(t,J=7.4Hz,1H) ,7.34(t,J=7.4Hz,2H),7.20-7.07(m,2H),6.52(d,J=8.5Hz,2H),5.36(s,2H),2.89(s,3H).

[0317] Example 31: Synthesis of 4-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0318] [ka]

[0319] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =393.1. 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.62(d,J=8.4Hz,2H),7.38-7.25(m,5H),7. 08(d,J=7.2Hz,2H),6.66(d,J=8.4Hz,2H),4.90(s,2H),2.38(s,3H),2.19(s,3H).

[0320] Example 32: Synthesis of 4-((2,4-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0321] [ka]

[0322] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =393.1. 1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.58(d,J=8.3Hz,2H),7.38(t,J=7.4Hz,1H),7.29(t,J=7 .4Hz,4H),7.17(d,J=7.1Hz,2H),6.64(d,J=8.2Hz,2H),5.16(s,2H),2.75(s,3H),2.48(s,3H).

[0323] Example 33: Synthesis of 4-((6-(difluoromethoxy)-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0324] [ka]

[0325] The title compound was synthesized as described in Example 22. LCMS: [M+H] + =445.1. 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.81-7.44(t,J=72.0Hz,1H),7.60(d,J=8.3Hz,2H),7.36(d,J=7.5Hz,1H ),7.32(s,2H),7.27(t,J=7.6Hz,2H),7.12(d,J=7.2Hz,2H),6.67(d,J=8.3Hz,2H),5.00(s,2H),2.43(s,3H).

[0326] Example 34: Synthesis of 3,5-difluoro-4-((6-methyl-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0327] [ka]

[0328] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =483.1. 1H NMR (400MHz, DMSO-d6) δ9.12(s,1H),7.65(s,2H),7.40(t,J=7.5Hz,1H),7.32-7.26(m,4H),7.10(d,J=7.3Hz,2H),5.29(s,2H),2.23(s,3H).

[0329] Example 35: Synthesis of 4-(1-(6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)benzenesulfonamide

[0330] [ka]

[0331] The title compound was synthesized as described in Example 22. LCMS: [M+H] + =423.4. 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),7.70(d,J=8.0Hz,2H),7.50-7.29(m,7H),7.10( d,J=8.0Hz,2H),5.16-5.04(m,1H),3.77(s,3H),1.97(s,3H),1.56(d,J=6.8Hz,3H).

[0332] Example 36: Synthesis of 2-fluoro-4-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0333] [ka]

[0334] The title compound was synthesized as described in Example 24. LCMS: [M+H] + =427.2.

[0335] 1H NMR:(400MHz,CD3OD)δ8.47(s,1H),7.62(t,J=8.0Hz,1H),7.31(t,J=7.2Hz,1H),7.21(t,J= 7.6Hz,2H),6.99(d,J=6.8Hz,2H),6.37-6.30(m,2H),5.03(s,2H),3.80(s,3H),2.49(s,3H).

[0336] Example 37: Synthesis of phenyl 4-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)sulfamate

[0337] [ka]

[0338] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =409.0. 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.96(s,2H),7.40-7.25(m,3H),7.13- 7.05(m,4H),6.54(d,J=8.7Hz,2H),4.84(s,2H),2.40(s,3H),2.20(s,3H).

[0339] Example 38: Synthesis of 4-((2-(difluoromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0340] [ka]

[0341] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =465.1. 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.64(s,2H),7.48(t,J=51.6Hz,1H),7.37(t, J=7.6Hz,1H),7.31-7.20(m,4H),7.09(d,J=7.6Hz,2H),5.27(s,2H),2.21(s,3H).

[0342] Example 39: Synthesis of 4-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0343] [ka]

[0344] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =455.1. 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.63(s,2H),7.40-7.24(m,5H),7.09(d, J=7.6Hz,2H),5.22(s,2H),2.22-7.24(m,1H),2.16(s,3H),1.04-0.91(m,4H).

[0345] Example 40: Synthesis of 4-((2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0346] [ka]

[0347] The title compound was synthesized as described in Example 22. LCMS: [M+H] + =379.1. 1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.57(d,J=8.4Hz,2H),7.40(t,J=7.4Hz,1H),7.32(t,J=7. 5Hz,2H), 7.21(d,J=6.9Hz,2H),7.12(bs,2H),6.64(d,J=8.3Hz,2H),5.17(s,2H),2.49(d,3H).

[0348] Example 41: Synthesis of 4-((6-cyano-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0349] [ka]

[0350] The title compound was synthesized as described in Example 22. LCMS: [M+H] + =404.1. 1 H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.56(d,J=8.4Hz,2H),7.44(t,J=7.5Hz,1H),7.3 6-7.30(m,4H),7.24(d,J=7.0Hz,2H),6.68(d,J=8.4Hz,2H),5.23(s,2H),2.60(s,3H).

[0351] Example 42: Synthesis of 3,5-difluoro-4-((6-methyl-2-(methyl-d3)-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0352] [ka]

[0353] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =432.1. 1H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.63(s,2H),7.38(t,J=7.4Hz,1H),7.34-7.19(m,4H),7.04(d,J=7.2Hz,2H),5.09(s,2H),2.15(s,3H).

[0354] Example 43: Synthesis of 3,5-difluoro-4-((2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0355] [ka]

[0356] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =415.1. 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.99(s,1H),7.61(s,2H),7.40(t,J=7. 4Hz, 1H), 7.34 (t, J=7.2Hz, 2H), 7.22-7.12 (m, 4H), 5.36 (s, 2H), 2.59 (s, 3H).

[0357] Example 44: Synthesis of 3,5-difluoro-4-((7-(2-fluorophenyl)-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0358] [ka]

[0359] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =447.2. 1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.64(s,2H),7.49-7.42(m,1H),7.26-7. 16(m,4H),7.10(t,J=9.1Hz,1H),5.23-5.12(m,2H),2.55(s,3H),2.15(s,3H).

[0360] Example 45: Synthesis of 3,5-difluoro-4-((7-(3-fluorophenyl)-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0361] [ka]

[0362] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =447.2. 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.61(s,2H),7.32-7.18(m,4H),7.07-6 .98(m,1H),6.82-6.77(m,1H),5.23-5.06(m,2H),2.52(s,3H),2.17(s,3H).

[0363] Example 46: Synthesis of 3,5-difluoro-4-((7-(4-fluorophenyl)-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0364] [ka]

[0365] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =447.2. 1H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.63(s,2H), 7.27(d,J=8.0Hz,2H),7.16-7.02(m,4H),5.13(s,2H),2.51(s,3H),2.14(s,3H).

[0366] Example 47: Synthesis of 3,5-difluoro-4-((2-(fluoromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0367] [ka]

[0368] Step 1: General procedure for the preparation of 4-((2-(chloromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide (compound 47_1) To a solution of compound 26_8 (200 mg, 0.495 mmol) in EtOH (1 mL) was added 2-chloro-1,1,1-trimethoxyethane (1 mL) and p-toluenesulfonic acid monohydrate (47.03 mg, 0.247 mmol). The reaction mixture was irradiated with microwave radiation at 120° C. for 1 h. The reaction was quenched at room temperature by dropwise addition of H2O. The aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give the corresponding compound 47_1 (129 mg, 56.35%) as a white solid. LCMS: [M+H] + =463.1.

[0369] Step 2: General procedure for the preparation of 3,5-difluoro-4-((2-(fluoromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 47_1 (55 mg, 0.119 mmol) in DMSO (2 mL) was added benzyltriethylammonium chloride (2.71 mg, 0.012 mmol) and KF (20.71 mg, 0.356 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 47 (2.1 mg, 3.96%). LCMS: [M+H] + =447.1. 1 H NMR(400MHz,CD3OD)δ8.88(s,1H),7.42(t,J=7.2Hz,1H),7.33(t,J=7.7Hz,2H),7.26(d, J=7.6Hz,2H),7.11(d,J=7.3Hz,2H),5.69(d,J=47.2Hz,2H),5.30(s,2H),2.28,(s,3H).

[0370] Example 48: Synthesis of 4-((6-ethyl-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0371] [ka]

[0372] The title compound was synthesized as described in Example 26. LCMS: [M+H] + =443.2. 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.65(s,2H),7.41-7.33(m,1H),7.30-7.22(m,4H),7. 05(d,J=7.2Hz,2H),5.07(s,2H),2.51(s,3H),2.40(q,J=7.6Hz,2H),1.02(t,J=7.6Hz,3H).

[0373] Example 49: Synthesis of 4-((6-ethyl-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0374] [ka]

[0375] To a solution of compound 47_1 (60 mg, 0.13 mmol) in dimethylamine / THF (3 mL, 2 M, 6.0 mmol) was added DIPEA (0.043 mL, 0.26 mmol). The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 49 (38 mg, 64.1%). LCMS: [M+H] + =472.1. 1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.35(t,J=7.3Hz,1H),7.28(t,J=7.3Hz,2H),7. 15-7.05(m,4H),6.25(brs,2H),5.18(s,2H),3.62(s,2H),2.18(s,3H),2.11(s,3H).

[0376] Example 50: Synthesis of 3,5-difluoro-4-((6-methyl-7-phenyl-2-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0377] [ka]

[0378] To a solution of compound 26_8 (100 mg, 0.247 mmol) in EtOH (5 mL) was added 2,2,2-trifluoroacetaldehyde (121 mg, 1.235 mmol). The reaction mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 50 (0.87 mg, 0.71%). LCMS: [M+H] + =497.2.

[0379] Example 51: Synthesis of 4-((2-(cyclopropylmethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0380] [ka]

[0381] To a solution of compound 26_8 (100 mg, 0.247 mmol) in EtOH / AcOH (5 mL / 1 mL) was added cyclopropanecarbaldehyde (86 mg, 1.235 mmol). The reaction mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 51 (40 mg, 34.53%). LCMS: [M+H] + =469.2. 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.62(s,2H),7.36(t,J=7.4Hz,1H),7.31-7.18(m,4H),7.03(d,J=7.0Hz, 2H),5.11(s,2H),2.78(d,J=6.8Hz,2H),2.16(s,3H),1.25-1.08(m,1H),0.57-0.36(m,2H),0.21-0.16(m,2H).

[0382] Example 52: Synthesis of 4-((7-cyclopropyl-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0383] [ka]

[0384] Step 1: General procedure for the preparation of 4-(((3-cyclopropyl-2-methyl-5-nitropyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 52_1) To a solution of compound 26_6 (500 mg, 1.14 mmol) in dioxane / H2O (10 mL / 1 mL) was added cyclopropylboronic acid (295 mg, 3.43 mmol), XPhos (57 mg, 0.12 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and K2CO3 (474 ​​mg, 3.43 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure, and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 52_1 (100 mg, 22.0% yield) as a white solid. LCMS: [M+H] + =399.1.

[0385] Step 2: General procedure for the preparation of 4-(((5-amino-3-cyclopropyl-2-methylpyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 52_2) To a solution of compound 52_1 (100 mg, 0.25 mmol) in methanol (5 mL) was added Pd / C (20 mg, 10% wt). The reaction was stirred at room temperature under H2 atmosphere for 16 h. The mixture was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 52_2 (75 mg, 81.1% yield) as a pale yellow solid. LCMS: [M+H] + =369.1.

[0386] Step 3: General procedure for the preparation of 4-((7-cyclopropyl-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 52_2 (75 mg, 0.20 mmol) in ethanol (3 mL) was added 1,1,1-triethoxyethane (330 mg, 2.04 mmol) and Py-HCl (12 mg, 0.10 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding example 52 (20 mg, 25.0% yield). LCMS: [M+H] + =393.1. 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),7.62(s,2H),7.50(d,J=7.5Hz,2H),6.08(s,2H) ,2.60(s,3H),2.42(s,3H),1.95-1.86(m,1H),1.18-1.12(m,2H),0.71-0.64(m,2H).

[0387] Example 53: Synthesis of 6-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0388] [ka]

[0389] Step 1: General procedure for the preparation of 6-(((3-bromo-2-methyl-5-nitropyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (compound 53_2) To a solution of compound 26_5 (500 mg, 1.99 mmol) in acetonitrile (12 mL) was added compound 53_1 (447 mg, 2.39 mmol) and DIPEA (770 mg, 5.97 mmol). The reaction mixture was stirred at 60° C. for 2 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 53_2 (530 mg, 66.3% yield) as a yellow solid. LCMS: [M+H] + =402.0.

[0390] Step 2: General procedure for the preparation of 6-(((2-methyl-5-nitro-3-phenylpyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (compound 53_3) To a solution of compound 53_2 (530 mg, 1.32 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (241 mg, 1.98 mmol), XPhos (67 mg, 0.14 mmol), Pd2(dba)3 (65 mg, 0.07 mmol), and K2CO3 (546 mg, 3.96 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 53_3 (430 mg, 81.7% yield) as a yellow solid. LCMS: [M+H] + =400.1.

[0391] Step 3: General procedure for the preparation of 6-(((5-amino-2-methyl-3-phenylpyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (compound 53_4) To a solution of compound 53_3 (100 mg, 0.25 mmol) in methanol (5 mL) was added Pd / C (20 mg, 10% wt). The reaction solution was stirred at room temperature under H2 atmosphere for 16 h. The solution was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 53_4 (60 mg, 64.9% yield) as a pale yellow solid. LCMS: [M+H] + =370.1.

[0392] Step 4: General procedure for the preparation of 6-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 53_4 (60 mg, 0.16 mmol) in ethanol (3 mL) was added cyclopropanecarbaldehyde (56 mg, 0.80 mmol) and AcOH (0.05 mL). The reaction mixture was stirred at 70° C. for 12 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding example 53 (21 mg, 32.9% yield). LCMS: [M+H] + =420.2. 1 H NMR 1 H NMR(400MHz,DMSOd6)δ8.73(s,1H),8.68(d,J=2.0Hz,1H),8.02-7.94(m,1H),7.59(s,2H),7.34(t,J=7.4Hz,1H),7.23(t,J=7.6Hz,2 H),6.98(d,J=7.2Hz,2H),6.70(d,J=8.3Hz,1H),5.15(s,2H),2.16(s,3H),2.07-1.98(m,1H),1.05-0.97(m,2H),0.96-0.89(m,2H).

[0393] Example 54: Synthesis of 5-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-2-sulfonamide

[0394] [ka]

[0395] Step 1: General procedure for the preparation of 2-methyl-5-nitro-3-phenylpyridin-4-ol (compound 54_1) To a solution of compound 26_4 (500 mg, 2.15 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (523 mg, 4.29 mmol), XPhos (105 mg, 0.22 mmol), Pd2(dba)3 (101 mg, 0.11 mmol), and K2CO3 (890 mg, 6.45 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure, and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 54_1 (154 mg, 31.2% yield) as a white solid. LCMS: [M+H] + =231.1.

[0396] Step 2: General procedure for the preparation of 4-chloro-2-methyl-5-nitro-3-phenylpyridine (compound 54_2) To a solution of compound 54_1 (154 mg, 0.67 mmol) in POCl3 (5 mL) was added N,N-dimethylaniline (81 mg, 0.67 mmol) at 0° C. The reaction mixture was stirred at 100° C. for 1 h. The solvent was removed under vacuum to give the crude product, which was purified by flash silica gel chromatography to give compound 54_2 (60 mg, 36.1% yield) as a white solid. LCMS: [M+H] + =249.1.

[0397] Step 3: General procedure for the preparation of 5-(((2-methyl-5-nitro-3-phenylpyridin-4-yl)amino)methyl)pyridine-2-sulfonamide (compound 54_4) To a solution of compound 54_2 (60 mg, 0.24 mmol) in acetonitrile (5 mL) was added compound 54_3 (54 mg, 0.29 mmol) and DIPEA (155 mg, 1.20 mmol). The reaction mixture was stirred at 60° C. for 2 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 54_4 (40 mg, 41.5% yield) as a yellow solid. LCMS: [M+H] + =400.1.

[0398] Step 4: General procedure for the preparation of 5-(((5-amino-2-methyl-3-phenylpyridin-4-yl)amino)methyl)pyridine-2-sulfonamide (compound 54_5) To a solution of compound 54_4 (40 mg, 0.10 mmol) in methanol (5 mL) was added Pd / C (20 mg, 10% wt). The reaction mixture was stirred at room temperature under H2 atmosphere for 16 h. The reaction was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 54_5 (20 mg, 54.1% yield) as a pale yellow solid. LCMS: [M+H] + =370.1.

[0399] Step 4: General procedure for the preparation of 5-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-2-sulfonamide To a solution of compound 54_5 (20 mg, 0.054 mmol) in ethanol (3 mL) was added cyclopropanecarbaldehyde (19 mg, 0.27 mmol) and AcOH (0.5 mL). The reaction mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding example 54 (6 mg, 26.4% yield). LCMS: [M+H] + =420.2. 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.87(s,1H),7.72(d,J=8.1Hz,1H),7.43(s,2H),7.37(t,J=7.1Hz,1H),7.27(t, J=7.3Hz,2H),7.11-7.05(m,3H),5.14(s,2H),2.18(s,3H),2.11-1.04(m,1H),1.10-1.03(m,2H),0.98-0.92(m,2H).

[0400] Example 55: Synthesis of 4-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylbenzenesulfonamide

[0401] [ka]

[0402] Step 1: General procedure for the preparation of 4-(((3-bromo-2-methyl-5-nitropyridin-4-yl)amino)methyl)-2-methylbenzenesulfonamide (compound 55_2) To a solution of compound 26_5 (400 mg, 1.59 mmol) in acetonitrile (10 mL) was added compound 55_1 (382 mg, 1.92 mmol) and DIPEA (615 mg, 4.77 mmol). The reaction mixture was stirred at 60° C. for 2 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 55_2 (480 mg, 72.7% yield) as a yellow solid. LCMS: [M+H] + =415.0.

[0403] Step 2: General procedure for the preparation of 2-methyl-4-(((2-methyl-5-nitro-3-phenylpyridin-4-yl)amino)methyl)benzenesulfonamide (compound 55_3) To a solution of compound 55_2 (480 mg, 1.16 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (211 mg, 1.73 mmol), XPhos (55 mg, 0.12 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and K2CO3 (480 mg, 3.48 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 55_3 (380 mg, 79.7% yield) as a yellow solid. LCMS: [M+H] + =413.1.

[0404] Step 3: General procedure for the preparation of 4-(((5-amino-2-methyl-3-phenylpyridin-4-yl)amino)methyl)-2-methylbenzenesulfonamide (compound 55_4) To a solution of compound 55_3 (100 mg, 0.24 mmol) in methanol (5 mL) was added Pd / C (20 mg, 10% wt). The reaction solution was stirred at room temperature under H2 atmosphere for 16 h. The reaction solution was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 55_4 (80 mg, 86.3% yield) as a pale yellow solid. LCMS: [M+H] + =383.1.

[0405] Step 4: General procedure for the preparation of 4-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-2-methylbenzenesulfonamide To a solution of compound 55_4 (80 mg, 0.21 mmol) in ethanol (5 mL) was added cyclopropanecarbaldehyde (73 mg, 1.05 mmol) and AcOH (1.0 mL). The reaction mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding example 55 (32 mg, 35.4% yield). LCMS: [M+H] + =433.2. 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.63(d,J=8.1Hz,1H),7.43-7.22(m,5H),7.07(d,J=7.1Hz,2H),6.47(s,1H),6. 42(d,J=8.2Hz,1H),5.02(s,2H),2.44(s,3H),2.17(s,3H),2.04-1.96(m,1H),1.08-1.00(m,2H),0.98-0.92(m,2H).

[0406] Example 56: Synthesis of 3,5-difluoro-4-((6-methoxy-3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0407] [ka]

[0408] The title compound was synthesized as described in Example 19. LCMS: [M+H] + =461.2. 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.59(s,2H),7.36-7.18(m,5H),7.07(d,J=6.9Hz,2H),4.74(s,2H),3.70(s,3H),3.39(s,3H).

[0409] Example 57: Synthesis of 3,5-difluoro-4-((6-methoxy-2-oxo-7-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide

[0410] [ka]

[0411] Step 1: General procedure for the preparation of 3,5-difluoro-4-((6-methoxy-7-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide (compound 57_2) To a solution of compound 57_1 (350 mg, 1.56 mmol) in DMF (5 mL) was added NaH (44 mg, 1.11 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 0.5 h under N2 atmosphere. Compound 4_1 (536 mg, 1.87 mmol) was then added. The reaction mixture was stirred at room temperature for 2 h. After diluting the reaction mixture with water (20 mL), the aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 57_2 (260 mg, 38.8% yield) as a pale yellow solid. LCMS: [M+H] + =430.1.

[0412] Step 2: General procedure for the preparation of 4-((3,3-dibromo-6-methoxy-2-oxo-7-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide (compound 57_3) To a solution of compound 57_2 (260 mg, 0.61 mmol) in i-BuOH (10 mL) was added pyridinium tribromide (586 mg, 1.83 mmol) in portions at 0° C. The reaction mixture was stirred at room temperature for 6 h and then quenched with H2O (100 mL). The mixture was stirred for 10 min and extracted with ethyl acetate (20 mL×2). The combined organic layers were separated, washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 57_3 (120 mg, 32.9% yield) as a pale yellow solid. LCMS: [M+H] + =602.1.

[0413] Step 3: General procedure for the preparation of 3,5-difluoro-4-((6-methoxy-2-oxo-7-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 57_3 (120 mg, 0.20 mmol) in THF (10 mL) was added Zn power (130 mg, 2.0 mmol) and ammonium chloride (212 mg, 2.0 mmol). The mixture was stirred at 60° C. for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by preparative HPLC to give the corresponding example 57 (46 mg, 51.9% yield). LCMS: [M+H] + =446.2. 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.53(s,2H),7.36-7.16(m,5H),7.03(d,J=7.7Hz,2H),4.54(s,2H),3.69(s,2H),3.69(s,3H).

[0414] Example 58: Synthesis of 4-((7-(cyclopent-1-en-1-yl)-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0415] [ka]

[0416] Step 1: General procedure for the preparation of 4-(((3-(cyclopent-1-en-1-yl)-2-methyl-5-nitropyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 58_1) To a solution of compound 26_6 (500 mg, 1.14 mmol) in dioxane / H2O (10 mL / 1 mL) was added cyclopent-1-en-1-ylboronic acid (384 mg, 3.43 mmol), XPhos (57 mg, 0.12 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and K2CO3 (474 ​​mg, 3.43 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 58_1 (130 mg, 26.8% yield) as a yellow solid. LCMS: [M+H] + =425.1.

[0417] Step 2: General procedure for the preparation of 4-(((5-amino-3-(cyclopent-1-en-1-yl)-2-methylpyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 58_2) To a solution of compound 58_1 (130 mg, 0.31 mmol) in methanol (5 mL) was added Pd / C (20 mg, 10% wt). The reaction was stirred at room temperature under H2 atmosphere for 16 h. The reaction solution was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 58_2 (80 mg, 66.2% yield) as a pale yellow solid. LCMS: [M+H] + =395.2.

[0418] Step 3: General procedure for the preparation of 4-((7-(cyclopent-1-en-1-yl)-2,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 58_2 (80 mg, 0.20 mmol) in ethanol (3 mL) was added 1,1,1-triethoxyethane (330 mg, 2.04 mmol) and Py-HCl (12 mg, 0.10 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the corresponding example 58 (15 mg, 17.6% yield). LCMS: [M+H] + =419.2. 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.64(s,2H),7.48(d,J=7.8Hz,2H),5.75 -5.41(m,3H),2.60-2.59(m,2H),2.48(s,3H),2.37(s,3H),2.18-1.80(m,4H).

[0419] Example 59: Synthesis of 4-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0420] [ka]

[0421] Step 1: General procedure for the preparation of 3,5-difluoro-4-((6-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide (compound 59_1) A mixture of compound 26_8 (200 mg, 0.49 mmol) and urea (588 mg, 9.8 mmol) in a three-neck round-bottom flask was heated to 150° C. and stirred at this temperature for 3 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for 1 h. The precipitate was filtered and the filter cake was dried to give crude product compound 59_1 (70 mg, 32.9% yield) as a yellow solid. The crude product was used in the next step without further purification. LCMS: [M+H] + =431.1.

[0422] Step 2: General procedure for the preparation of 4-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 59_1 (70 mg, 0.16 mmol) in DMF (5 mL) was added NaH (13 mg, 0.32 mmol, 60% in oil) under ice bath. The mixture was stirred at this temperature for 30 min. Methyl iodide (50 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The obtained residue was purified by preparative HPLC to give the corresponding Example 59 (18 mg, 24.9% yield). LCMS: [M+H] + =445.2. 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.61(s,2H),7.40-7.23(m,5H),7.09(d,J=7.2Hz,2H),4.67(s,2H),3.42(s,3H),2.10(s,3H).

[0423] Example 60: Synthesis of 3,5-difluoro-4-((6-methyl-7-phenyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0424] [ka]

[0425] To a solution of compound 47_1 (60 mg, 0.13 mmol) in THF (3 ml) was added pyrrolidine (46 mg, 0.65 mmol). The reaction was stirred at 60° C. for 1 h. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 60 (30 mg, 46.5%). LCMS: [M+H] + =498.3.1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.59(s,2H),7.37-7.20(m,5H),7.11(d,J=7.7H) z,2H),5.19(s,2H),3.83(s,2H),2.40-2.34(m,4H),2.19(s,3H),1.51-1.45(m,4H).

[0426] Example 61: Synthesis of 4-((7-(cyclopent-1-en-1-yl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0427] [ka]

[0428] Step 1: General procedure for the preparation of 4-((7-(cyclopent-1-en-1-yl)-6-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide (compound 61_2) A mixture of compound 61_1 (75.0 mg, 0.183 mmol) and urea (109.8 mg, 1.827 mmol) in a three-neck round-bottom flask was stirred at 160° C. for 1 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for 1 h. The precipitate was filtered and the filter cake was dried to give crude product compound 61_2 (40.0 mg, 50.2% yield) as a yellow solid. The crude product was used in the next step without further purification. LCMS: [M+H] + =437.1.

[0429] Step 2: General procedure for the preparation of 4-((7-(cyclopent-1-en-1-yl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 61_2 (40.0 mg, 0.092 mmol) in DMF (5 mL) was added NaH (8 mg, 0.18 mmol, 60% in oil) under ice bath. The reaction mixture was stirred at this temperature for 30 min. Methyl iodide (39 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The obtained residue was purified by preparative HPLC to give the corresponding Example 61 (2 mg, 4.8% yield). LCMS: [M+H] + =451.2. 1 H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.63(s,2H),7.45(d,J=7.2Hz,2H),5.64(s, 1H), 5.22 (s, 2H), 3.78 (s, 3H), 2.51 (s, 3H), 2.50-2.34 (m, 4H), 1.86-1.72 (m, 2H).

[0430] Example 62: Synthesis of 4-((7-(cyclopent-1-en-1-yl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0431] [ka]

[0432] Step 1: General procedure for the preparation of 4-((7-(cyclopent-1-en-1-yl)-6-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide (compound 62_1) A mixture of compound 58_2 (80 mg, 0.20 mmol) and urea (2.4 g, 40 mmol) in a three-neck round-bottom flask was stirred at 160° C. for 1 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for 1 h. The precipitate was filtered and the filter cake was dried to give crude product compound 62_1 (30 mg, 35.2% yield) as a yellow solid. The crude product was used in the next step without further purification. LCMS: [M+H] + =421.1.

[0433] Step 2: General procedure for the preparation of 4-((7-(cyclopent-1-en-1-yl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 62_1 (30 mg, 0.071 mmol) in DMF (5 mL) was added NaH (6 mg, 0.14 mmol, 60% in oil) under ice bath. The reaction mixture was stirred at this temperature for 30 min. Then methyl iodide (20 mg, 0.14 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The obtained residue was purified by preparative HPLC to give the corresponding Example 62 (8 mg, 25.8% yield). LCMS: [M+H] + =435.2. 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.61(s,2H),7.45(d,J=5.6Hz,2H),5.55(s,1H),5.27-5. 07(m,2H),3.36(s,3H),2.70-2.64(m,2H),2.38-2.26(m,1H),2.32(s,3H),2.21-1.71(m,3H).

[0434] Example 63: Synthesis of 3,5-difluoro-4-((2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0435] [ka]

[0436] Step 1: General procedure for the preparation of 4-(((2,3-dimethyl-5-nitropyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 63_1) To a solution of compound 26_6 (500 mg, 1.14 mmol) in dioxane / H2O (10 mL / 1 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (432 mg, 3.43 mmol), XPhos (57 mg, 0.12 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and K2CO3 (474 ​​mg, 3.43 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 63_1 (180 mg, 42.3% yield) as a yellow solid. LCMS: [M+H] + =373.1.

[0437] Step 2: General procedure for the preparation of 4-(((5-amino-2,3-dimethylpyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 63_2) To a solution of compound 63_1 (180 mg, 0.48 mmol) in methanol (5 mL) was added Pd / C (30 mg, 10% wt). The reaction was stirred at room temperature under H2 atmosphere for 16 h. The reaction solution was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 63_2 (90 mg, 54.4% yield) as a pale yellow solid. LCMS: [M+H] + =343.1.

[0438] Step 3: General procedure for the preparation of 3,5-difluoro-4-((2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 63_2 (90 mg, 0.26 mmol) in ethanol (3 mL) was added 1,1,1-triethoxyethane (426 mg, 2.63 mmol) and Py-HCl (12 mg, 0.10 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding example 63 (13 mg, 13.5% yield). LCMS: [M+H] + =367.2. 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.62(s,2H),7.52(d,J=7.2Hz,2H),5.80(s,2H),2.51(s,3H),2.47(s,3H),2.39(s,3H).

[0439] Example 64: Synthesis of 4-((2,6-dimethyl-7-(prop-1-yn-1-yl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide

[0440] [ka]

[0441] Step 1: General procedure for the preparation of 3,5-difluoro-4-(((2-methyl-5-nitro-3-(prop-1-yn-1-yl)pyridin-4-yl)amino)methyl)benzenesulfonamide (Compound 64_1) To a solution of compound 26_6 (500 mg, 1.14 mmol) in DMF (10 mL) was added prop-1-yne (5.7 mL, 1 M in DMF, 5.70 mmol), CuI (108 mg, 0.57 mmol), Pd(PPh3)2Cl2 (106 mg, 0.23 mmol), TBAI (85 mg, 0.23 mmol), and TEA (345 mg, 3.43 mmol). The reaction mixture was stirred at 110 °C under N2 atmosphere for 16 h. The reaction mixture was then diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 ml x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 64_1 (40 mg, 8.8% yield) as a yellow solid. LCMS: [M+H] + =397.1.

[0442] Step 2: General procedure for the preparation of 4-(((5-amino-2-methyl-3-(prop-1-yn-1-yl)pyridin-4-yl)amino)methyl)-3,5-difluorobenzenesulfonamide (compound 64_2) To a solution of compound 64_1 (40 mg, 0.10 mmol) in ethanol (5 mL) was added Zn power (33 mg, 0.50 mmol) and NH4Cl (53 mg, 1.0 mmol). The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was filtered and the filter cake was washed with MeOH (15 mL×3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 64_2 (25 mg, 67.6% yield) as a pale yellow solid. LCMS: [M+H] + =367.1.

[0443] Step 3: General procedure for the preparation of 4-((2,6-dimethyl-7-(prop-1-yn-1-yl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-3,5-difluorobenzenesulfonamide To a solution of compound 64_2 (25 mg, 0.068 mmol) in ethanol (3 mL) was added 1,1,1-triethoxyethane (111 mg, 0.68 mmol) and Py-HCl (6 mg, 0.05 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding example 64 (10 mg, 37.5% yield). LCMS: [M+H] + =391.2. 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),7.67(s,2H),7.55(d,J=7.8Hz,2H),6.03(s,2H),2.70(s,3H),2.60(s,3H),2.12(s,3H).

[0444] Example 65: Synthesis of 6-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0445] [ka]

[0446] To a solution of compound 53_4 (33 mg, 0.089 mmol) in EtOH (1 mL) was added 1,1,1-triethoxyethane (145 mg, 0.89 mmol) and pyridinium chloride (4.45 mg, 0.039 mmol). The reaction mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 65 (12 mg, 34.1%). LCMS: [M+H] + =394.2. 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.66(d,J=1.8Hz,1H),7.97(dd,J=8.2,2.3Hz,1H),7.58(s,2H),7.35(t,J=7.4 Hz,1H),7.24(t,J=7.6Hz,2H),6.96(d,J=7.0Hz,2H),6.65(d,J=8.3Hz,1H),5.01(s,2H),2.43(s,3H),2.16(s,3H).

[0447] Example 66: Synthesis of 5-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-2-sulfonamide

[0448] [ka]

[0449] To a solution of compound 54_5 (40 mg, 0.11 mmol) in EtOH (3 mL), triethyl orthoacetate (52.7 mg, 0.325 mmol) and Py-HCl (1.3 mg, 0.011 mmol) were added. The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the corresponding Example 66 (10.0 mg, 23.5% yield). LCMS: [M+H] + =394.2. 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.80(d,J=1.6Hz,2H),7.69(d,J=7.2Hz,1H),7.39-7.33(m ,1H),7.30-7.23(m,2H),7.18(s,2H),7.08-6.99(m,3H),4.99(s,2H),2.44(s,3H),2.19(s,3H).

[0450] Example 67: Synthesis of 6-((6-methyl-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0451] [ka]

[0452] A mixture of compound 53_4 (100 mg, 0.27 mmol) in trifluoroacetic acid (5 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the corresponding Example 67 (5.0 mg, 4.1%). LCMS: [M+H] + =448.1. 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.61(s,1H),7.96(d,J=8.4Hz,1H),7.58(s,2H),7.34(t,J=7.7H z,1H),7.22(t,J=7.3Hz,2H),6.98(d,J=6.8Hz,2H),6.85(d,J=8.2Hz,1H),5.22(s,2H),2.22(s,3H).

[0453] Example 68: Synthesis of 6-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide

[0454] [ka]

[0455] Step 1: General procedure for the preparation of 5-(benzylthio)-3-fluoropicolinonitrile (compound 68_2) To a solution of compound 68_1 (10 g, 49.8 mmol) in toluene (100 mL) was added phenylmethanethiol (6.2 g, 49.8 mmol), Xantphos (1.73 g, 2.99 mmol), Pd2(dba)3 (1.40 g, 1.50 mmol), and TEA (25.2 g, 249 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 68_2 (10.1 g, 83.1% yield) as a yellow solid. LCMS: [M+H] + =245.0.

[0456] Step 2: General procedure for the preparation of tert-butyl ((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)carbamate (compound 68_3) To a solution of compound 68_2 (10 g, 41.3 mmol) in methanol (80 mL) was added Raney Ni (1 g, 16 mmol), (Boc)2O (18 g, 82.6 mmol), and TEA (12.5 g, 123.9 mmol). The reaction was stirred under H2 (4 Mpa) at room temperature for 16 h. The reaction mixture was filtered through Celite and the filter cake was washed with MeOH (50 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 68_3 (6.2 g, 43.5% yield) as a white solid. LCMS: [M+H] + =349.1.

[0457] Step 3: General procedure for the preparation of ((5-(benzylthio)-3-fluoropyridin-2-yl)methanamine (compound 68_4) To a solution of compound 68_3 (6.2 g, 17.8 mmol) in DCM (20 mL) was added HCl / dioxane (4 M, 10 mL). The reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give the corresponding compound 68_4 (4.1 g, 92.8% yield) as a white solid. The crude product was used in the next step without further purification. LCMS: [M+H] + =249.1.

[0458] Step 4: General procedure for the preparation of N-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-3-bromo-2-methyl-5-nitropyridin-4-amine (compound 68_5) To a solution of compound 26_5 (200 mg, 0.75 mmol) in acetonitrile (10 mL) was added compound 68_4 (186 mg, 0.75 mmol) and DIPEA (290 mg, 0.22 mmol). The reaction mixture was stirred at 60° C. for 4 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 68_5 (260 mg, 72.5% yield) as a yellow solid. LCMS: [M+H] + =463.0.

[0459] Step 5: General procedure for the preparation of N-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-methyl-5-nitro-3-phenylpyridin-4-amine (compound 68_6) To a solution of compound 68_5 (200 mg, 0.43 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (79 mg, 0.65 mmol), XPhos-Pd-G2 (33 mg, 0.043 mmol), and K2CO3 (178 mg, 1.29 mmol). The reaction mixture was stirred under N2 atmosphere at a temperature under 100 °C for 16 h. The solvent was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography to give the corresponding compound 68_6 (160 mg, 80.5% yield) as a yellow solid. LCMS: [M+H] + =461.1.

[0460] Process 6:N 4 General procedure for the preparation of -((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methyl-5-phenylpyridine-3,4-diamine (compound 68_7) To a solution of compound 68_6 (160 mg, 0.35 mmol) in MeOH (5 mL) was added DCM (5 mL) and Pd / C (30 mg, 10% wt). The reaction was stirred at room temperature under H2 atmosphere for 16 h. The reaction was filtered and the filter cake was washed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 68_7 (150 mg, 89.6% yield) as a pale yellow solid. LCMS: [M+H] + =431.1.

[0461] Step 7: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 68_8) To a solution of compound 68_7 (150 mg, 0.35 mmol) in EtOH (5 mL) was added triethyl orthoacetate (565 mg, 3.48 mmol) and Py-HCl (4 mg, 0.035 mmol). The reaction mixture was stirred at 100° C. for 1 h. The solvent was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give the corresponding compound 68_8 (140 mg, 88.4% yield) as a yellow solid. LCMS: [M+H] + =455.2.

[0462] Step 8: General procedure for the preparation of 6-((2,6-dimethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide To a solution of compound 68_8 (140 mg, 0.31 mmol) in acetonitrile (10 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / MeCN (153 mg / 2 mL, 0.78 mmol) was added dropwise. The reaction mixture was stirred at a temperature under 0° C. for 30 min. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and ammonium hydroxide (0.5 mL) was added. The reaction was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 68 (30 mg, 23.4% yield). LCMS: [M+H] + =412.1. 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.50(s,1H),7.81(dd,J=9.1Hz,1H),7.71(s,2H),7.35(t,J =7.5Hz,1H),7.22(t,J=7.6Hz,2H),6.86(d,J=7.1Hz,2H),5.13(s,2H),2.46(s,3H),2.14(s,3H).

[0463] Example 69: Synthesis of 5-fluoro-6-((6-methyl-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0464] [ka]

[0465] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methyl-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (compound 69_1) A solution of compound 68_7 (150 mg, 0.35 mmol) in trifluoroacetic acid (5 mL). The reaction mixture was stirred at 100° C. for 3 h. The solvent was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 69_1 (120 mg, 67.7% yield) as a yellow solid. LCMS: [M+H] + =509.1.

[0466] Step 2: General procedure for the preparation of 5-fluoro-6-((6-methyl-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 69_1 (120 mg, 0.24 mmol) in acetonitrile (10 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C. was added a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (118 mg / 2 mL, 0.60 mmol) dropwise. The reaction mixture was stirred at 0° C. for 30 min. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and ammonium hydroxide (0.5 mL) was added at 0° C. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to give the corresponding Example 69 (20 mg, 18.2% yield). LCMS: [M+H] + =466.2. 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.49(s,1H),7.88-7.80(m,1H),7.70(s,2H),7 .38(t,J=7.4Hz,1H),7.24(t,J=7.7Hz,2H),6.93(s,2H),5.34(s,2H),2.20(s,3H).

[0467] Example 70: Synthesis of 6-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide

[0468] [ka]

[0469] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 70_1) To a solution of compound 68_7 (150 mg, 0.35 mmol) in ethanol (3 mL) was added cyclopropanecarbaldehyde (123 mg, 1.75 mmol) and AcOH (0.1 mL). The reaction mixture was stirred at 70° C. for 12 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 70_1 (80 mg, 47.8% yield) as a white solid. LCMS: [M+H] + =481.2.

[0470] Step 2: General procedure for the preparation of 6-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide To a solution of compound 70_1 (80 mg, 0.17 mmol) in acetonitrile (10 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0°C, a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (84 mg / 2 mL, 0.43 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (20 mL x 2). The organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL). The mixture was cooled to 0°C and ammonium hydroxide (0.5 mL) was added. The reaction solution was stirred at 0°C for 3 min. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the corresponding Example 70 (12 mg, 16.5% yield). LCMS: [M+H] + =438.2. 1H NMR:(400MHz,DMSO-d6)δ8.70(s,1H),8.51(s,1H),7.86-7.77(m,1H),7.60(s,2H),7.34(t,J=7.5Hz,1H),7 .22(t,J=7.6Hz,2H),6.89(d,J=7.2Hz,2H),5.29(s,2H),2.15-2.07(m,1H),2.13(s,3H),1.07-0.90(m,4H).

[0471] Example 71: Synthesis of 6-((2-cyclopropyl-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0472] [ka]

[0473] A solution of compound 53_4 (80 mg, 0.22 mmol) in difluoroacetic acid (5 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding compound 71 (10 mg, 11.0% yield). LCMS: [M+H] + =430.1. 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.61(d,J=1.8Hz,1H),7.95(dd,J=8.3,2.3Hz,1H),7.58(s,2H),7.41(t,J=51.6Hz,1 H),7.33(t,J=7.6Hz,1H),7.21(t,J=7.7Hz,2H),6.96(d,J=7.0Hz,2H),6.72(d,J=8.1Hz,1H),5.21(s,2H),2.21,(s,3H).

[0474] Example 72: Synthesis of 6-((2-(difluoromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide

[0475] [ka]

[0476] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-(difluoromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 72_1) A solution of compound 68_7 (150 mg, 0.35 mmol) in difluoroacetic acid (5 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography to give the corresponding compound 72_1 (60 mg, 35.1% yield) as a white solid. LCMS: [M+H] + =491.1.

[0477] Step 2: General procedure for the preparation of 6-((2-(difluoromethyl)-6-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide To a solution of compound 72_1 (60 mg, 0.12 mmol) in acetonitrile (10 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (59 mg / 2 mL, 0.30 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (20 mL×2). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the corresponding Example 72 (8 mg, 14.6% yield). LCMS: [M+H] + =448.1. 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.48(s,1H),7.82(d,J=8.8Hz,1H),7.71(s,2H),7.39(t,J=51.6 Hz,1H),7.36(t,J=7.4Hz,1H),7.23(t,J=7.6Hz,2H),6.92(d,J=7.0Hz,2H),5.31(s,2H),2.19(s,3H).

[0478] Example 73: Synthesis of 5-fluoro-6-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0479] [ka]

[0480] Step 1: General procedure for the preparation of N-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-3-bromo-2-methoxy-5-nitropyridin-4-amine (compound 73_1) To a solution of compound 22_4 (500 mg, 1.87 mmol) in acetonitrile (10 mL) was added compound 68_4 (464 mg, 1.87 mmol) and DIPEA (724 mg, 5.61 mmol). The reaction mixture was stirred at 60° C. for 4 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 73_1 (620 mg, 69.2% yield) as a yellow solid. LCMS: [M+H] + =479.0.

[0481] Step 2: General procedure for the preparation of N-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-methoxy-5-nitro-3-phenylpyridin-4-amine (compound 73_2) To a solution of compound 73_1 (620 mg, 1.29 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (237 mg, 1.94 mmol), XPhos-Pd-G2 (103 mg, 0.13 mmol), and K2CO3 (534 mg, 3.87 mmol). The reaction mixture was stirred under N2 atmosphere at a temperature under 100 °C for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 73_2 (540 mg, 87.6% yield) as a yellow solid. LCMS: [M+H] + =477.1.

[0482] Process 3:N 4 General procedure for the preparation of -((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methoxy-5-phenylpyridine-3,4-diamine (compound 73_3) To a solution of compound 73_2 (540 mg, 1.13 mmol) in MeOH (6 mL) / DCM (6 mL) was added Pd / C (100 mg, 10% wt). The reaction mixture was stirred at room temperature under H2 atmosphere for 16 h. The reaction solution was filtered and the filter cake was washed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 73_3 (450 mg, 88.9% yield) as a pale yellow solid. LCMS: [M+H] + =447.1.

[0483] Step 4: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 73_4) To a solution of compound 73_3 (450 mg, 1.01 mmol) in EtOH (10 mL) was added triethyl orthoacetate (1.63 g, 10.1 mmol) and Py-HCl (12 mg, 0.10 mmol). The reaction mixture was stirred at 100° C. for 1 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 73_4 (420 mg, 88.6% yield) as a yellow solid. LCMS: [M+H] + =471.2.

[0484] Step 5: General procedure for the preparation of 5-fluoro-6-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 73_4 (420 mg, 0.89 mmol) in acetonitrile (10 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (438 mg / 3 mL, 0.30 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C. Ammonium hydroxide (3 mL) was added dropwise and the reaction solution was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 73 (180 mg, 47.2% yield). LCMS: [M+H] + =428.3. 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.47(s,1H),7.77(d,J=9.2Hz,1H),7.70(s,2H),7.29(t,J= 7.2Hz,1H),7.17(t,J=7.6Hz,2H),6.85(d,J=7.6Hz,2H),5.15(s,2H),3.73(s,3H),2.44(s,3H).

[0485] Example 74: Synthesis of 6-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0486] [ka]

[0487] Step 1: General procedure for the preparation of 4-(((3-bromo-2-methoxy-5-nitropyridin-4-yl)amino)methyl)benzenesulfonamide (compound 74_1) To a solution of compound 22_4 (500 mg, 1.87 mmol) in acetonitrile (10 mL) was added compound 53_1 (350 mg, 1.87 mmol) and DIPEA (724 mg, 5.61 mmol). The reaction mixture was stirred at 60° C. for 2 h. After removing the solvent under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 74_1 (620 mg, 79.3% yield) as a yellow solid. LCMS: [M+H] + =418.0.

[0488] Step 4: General procedure for the preparation of 6-(((2-methoxy-5-nitro-3-phenylpyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (compound 74_2) To a solution of compound 74_1 (620 mg, 1.48 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (271 mg, 2.22 mmol), XPhos-Pd-G2 (118 mg, 0.15 mmol), and K2CO3 (613 mg, 4.44 mmol). The mixture was stirred at 100 °C under N2 atmosphere for 16 h. After removing the solvent under reduced pressure, the resulting residue was purified by flash silica gel chromatography to give the corresponding compound 74_2 (520 mg, 84.4% yield) as a yellow solid. LCMS: [M+H] + =416.1.

[0489] Step 5: General procedure for the preparation of 6-(((5-amino-2-methoxy-3-phenylpyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (compound 74_3) To a solution of compound 74_2 (520 mg, 1.25 mmol) in MeOH (6 mL) / DCM (6 mL) was added Pd / C (100 mg, 10% wt). The reaction mixture was stirred at room temperature under H2 atmosphere for 16 h. The reaction solution was filtered and the filter cake was washed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 74_3 (440 mg, 91.3% yield) as a pale yellow solid. LCMS: [M+H] + =386.1.

[0490] Step 3: General procedure for the preparation of 6-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 74_3 (100 mg, 0.26 mmol) in EtOH (5 mL), 1,1,1-triethoxyethane (421 mg, 2.59 mmol) and pyridinium chloride (3 mg, 0.026 mmol) were added. The reaction mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding example 74 (15 mg, 14.1%). LCMS: [M+H] + =410.2. 1 H NMR(400MHz,DMSO-d6)δ8.65(d,J=1.8Hz,1H),8.49(s,1H),7.94(dd,J=8.3,2.3Hz,1H),7.56(s,2H),7.29(t,J=7.4 Hz,1H),7.19(t,J=7.5Hz,2H),6.96(d,J=6.9Hz,2H),6.63(d,J=8.4Hz,1H),5.03(s,2H),3.74(s,3H),2.41(s,3H).

[0491] Example 75: Synthesis of 6-((2-(difluoromethyl)-6-methoxy-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0492] [ka]

[0493] A solution of compound 74_3 (80 mg, 0.21 mmol) in trifluoroacetic acid (5 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 75 (12 mg, 13.0%). LCMS: [M+H]=446.2. 1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.59(d,J=2.4Hz,1H),7.99-7.88(m,1H),7.56(s,2H),7.38(t,J=51.6Hz,1H), 7.28(t,J=7.6Hz,1H),7.17(t,J=7.6Hz,2H),6.95(d,J=7.2Hz,2H),6.68(d,J=8.3Hz,1H),5.22(s,2H),3.79(s,3H).

[0494] Example 76: Synthesis of 6-((2-(difluoromethyl)-6-methoxy-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide

[0495] [ka]

[0496] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-(difluoromethyl)-6-methoxy-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 76_1) A solution of compound 73_3 (100 mg, 0.22 mmol) in 2,2-difluoroacetic acid (3 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 76_1 (73 mg, 64.3%) as a pale yellow solid. LCMS: [M+H] + =507.0.

[0497] Step 2: General procedure for the preparation of 6-((2-(difluoromethyl)-6-methoxy-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide To a solution of compound 76_1 (73 mg, 0.14 mmol) in acetonitrile (5 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (69 mg / 1 mL, 0.30 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added dropwise and the reaction solution was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 76 (10 mg, 15.0% yield). LCMS: [M+H] + =416.1. 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.46(s,1H),7.77(dd,J=9.1,1.7Hz,1H),7.72(s,2H),7.37(t,J=51 .6Hz,1H),7.29(t,J=7.6Hz,1H),7.18(t,J=7.5Hz,2H),6.91(d,J=6.8Hz,2H),5.33(s,2H),3.78(s,3H).

[0498] Example 77: Synthesis of 6-((6-methoxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0499] [ka]

[0500] A solution of compound 74_3 (80 mg, 0.21 mmol) in trifluoroacetic acid (5 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 77 (13 mg, 15.3%). LCMS: [M+H] + =464.2. 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.60(d,J=1.9Hz,1H),7.93(dd,J=8.2,2.2Hz,1H),7.56(s,2H),7.29(t ,J=7.5Hz,1H),7.17(t,J=7.5Hz,2H),6.97(d,J=6.3Hz,2H),6.80(d,J=8.4Hz,1H),5.24(s,2H),3.80(s,3H).

[0501] Example 78: Synthesis of 5-fluoro-6-((6-methoxy-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0502] [ka]

[0503] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methoxy-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (compound 78_1) A solution of compound 73_3 (100 mg, 0.22 mmol) in trifluoroacetic acid (3 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 78_1 (80 mg, 68.1%) as a pale yellow solid. LCMS: [M+H] + =525.1.

[0504] Step 2: General procedure for the preparation of 5-fluoro-6-((6-methoxy-7-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 78_1 (80 mg, 0.15 mmol) in acetonitrile (5 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (74 mg / 1 mL, 0.38 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (10 mL×3). The organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 78 (18 mg, 24.5% yield). LCMS: [M+H] + =482.2. 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.47(s,1H),7.80-7.63(m,3H),7.32-7.28(m,1H),7.24-7.14(m,2H),6.91(s,2H),5.35(s,2H),3.79(s,3H).

[0505] Example 79: Synthesis of 6-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide

[0506] [ka]

[0507] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methyl-7-phenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (compound 79_1) A mixture of compound 68_7 (200 mg, 0.46 mmol) in urea (552 mg, 9.2 mmol) was stirred at 150° C. for 3 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for an additional 1 h. The precipitate was filtered and the filter cake was dried to give crude compound 79_1 (100 mg, 47.2% yield) as a yellow solid. LCMS: [M+H] + =457.1.

[0508] Step 2: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-3,6-dimethyl-7-phenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (compound 79_2) To a solution of compound 79_1 (100 mg, 0.22 mmol) in DMF (5 mL) was added NaH (18 mg, 0.44 mmol, 60% in oil) under ice bath. The mixture was stirred at this temperature for 30 min and methyl iodide (62 mg, 0.44 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 79_2 (60 mg, 58.2% yield) as a white solid. LCMS: [M+H] + =471.2.

[0509] Step 3: General procedure for the preparation of 6-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide To a solution of compound 79_2 (60 mg, 0.13 mmol) in acetonitrile (5 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (64 mg / 1 mL, 0.33 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (10 mL×3). The organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added and the reaction solution was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to give the corresponding Example 79 (8 mg, 14.7% yield). LCMS: [M+H] + =428.2. 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.35(s,1H),7.79-7.64(m,3H),7.30(t,J=7.4Hz,1 H),7.18(t,J=7.6Hz,2H),6.86(d,J=7.5Hz,2H),4.80(s,2H),3.48(s,3H),2.06(s,3H).

[0510] Example 80: Synthesis of 5-fluoro-6-((6-methoxy-3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0511] [ka]

[0512] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methoxy-7-phenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (compound 80_1) A mixture of compound 73_3 (200 mg, 0.45 mmol) in urea (552 mg, 9.2 mmol) was stirred at 150° C. for 3 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for 1 h. The precipitate was filtered and the filter cake was dried to give crude compound 80_1 (90 mg, 42.5% yield) as a yellow solid. LCMS: [M+H] + =473.1.

[0513] Step 2: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-methoxy-3-methyl-7-phenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (compound 80_2) To a solution of compound 80_1 (90 mg, 0.19 mmol) in DMF (5 mL) was added NaH (15 mg, 0.38 mmol, 60% in oil) under ice bath. The mixture was stirred at this temperature for 30 min and methyl iodide (62 mg, 0.44 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 80_2 (55 mg, 59.4% yield) as a white solid. LCMS: [M+H] + =487.2.

[0514] Step 3: General procedure for the preparation of 5-fluoro-6-((6-methoxy-3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 80_2 (55 mg, 0.11 mmol) in acetonitrile (5 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (43 mg / 1 mL, 0.22 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the mixture was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added and the reaction solution was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 80 (9 mg, 18.0% yield). LCMS: [M+H] + =444.2. 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.01(s,1H),7.78-7.68(m,3H),7.24(t,J=7.4Hz,1 H),7.13(t,J=7.6Hz,2H),6.84(d,J=7.1Hz,2H),4.86(s,2H),3.68(s,3H),3.44(s,3H).

[0515] Example 81: Synthesis of 6-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0516] [ka]

[0517] Step 1: General procedure for the preparation of 6-((6-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide (compound 81_1) A mixture of compound 53_4 (200 mg, 0.54 mmol) in urea (648 mg, 10.8 mmol) was stirred at 150° C. for 3 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for 1 h. The precipitate was filtered and the filter cake was dried to give crude compound 80_1 (80 mg, 37.4% yield) as a yellow solid. LCMS: [M+H] + =396.1.

[0518] Step 2: General procedure for the preparation of 6-((3,6-dimethyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 81_1 (80 mg, 0.20 mmol) in DMF (5 mL) was added NaH (16 mg, 0.40 mmol, 60% in oil) under ice bath. The mixture was stirred at this temperature for 30 min and methyl iodide (62 mg, 0.44 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The obtained residue was purified by preparative HPLC to give the corresponding Example 81 (9 mg, 10.9% yield). LCMS: [M+H] + =410.2. 1 H NMR(400MHz,DMSO-d6)δ8.63(d,J=2.1Hz,1H),8.36(s,1H),7.92(dd,J=8.3,2.3Hz,1H),7.54(s,2H),7.28(t,J=7.5 Hz,1H),7.17(t,J=7.5Hz,2H),6.91(d,J=7.0Hz,2H),6.85(d,J=8.2Hz,1H),4.67(s,2H),3.47(s,3H),2.08(s,3H).

[0519] Example 82: Synthesis of 6-((6-methoxy-3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0520] [ka]

[0521] Step 1: General procedure for the preparation of 6-((6-methoxy-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide (compound 82_1) A mixture of compound 74_3 (200 mg, 0.52 mmol) in urea (624 mg, 10.4 mmol) was stirred at 150° C. for 3 h. The reaction mixture was then diluted with water (10 mL) and stirred at room temperature for 1 h. The precipitate was filtered and the filter cake was dried to give crude compound 82_1 (110 mg, 51.4% yield) as a yellow solid. LCMS: [M+H] + =4121.

[0522] Step 2: General procedure for the preparation of 6-((6-methoxy-3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 82_1 (110 mg, 0.27 mmol) in DMF (5 mL) was added NaH (22 mg, 0.54 mmol, 60% in oil) under ice bath. The mixture was stirred at this temperature for 30 min and methyl iodide (77 mg, 0.54 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The obtained residue was purified by preparative HPLC to give the corresponding Example 82 (23 mg, 20.2% yield). LCMS: [M+H] + =426.2. 1H NMR(400MHz,DMSO-d6)δ8.61(d,J=1.9Hz,1H),8.02(s,1H),7.89(dd,J=8.2,2.2Hz,1H),7.56(s,2H),7.24(t,J=7.4 Hz,1H),7.13(t,J=7.5Hz,2H),6.89(d,J=7.1Hz,2H),6.80(d,J=8.3Hz,1H),4.73(s,2H),3.69(s,3H),3.51(s,3H).

[0523] Example 83: Synthesis of 5-fluoro-6-((6-hydroxy-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0524] [ka]

[0525] To a solution of Example 73 (150 mg, 0.35 mmol) in DMF (5 mL) was added pyridine hydrochloride (257 mg, 3.50 mmol). The reaction mixture was stirred at 100° C. for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding Example 83 (75 mg, 51.7% yield). LCMS: [M+H] + =414.2. 1 H NMR(400MHz,DMSO-d6)δ11.49(brs,1H),8.54(s,1H),7.85(s,1H),7.76(dd,J=9.1,1.6Hz,1H),7.72( s,2H),7.23(t,J=7.4Hz,1H),7.13(t,J=7.6Hz,2H),6.80(d,J=7.1Hz,2H),5.04(s,2H),2.35(s,3H).

[0526] Example 84: Synthesis of 4-((6-(methoxy-d3)-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide

[0527] [ka]

[0528] Step 1: General procedure for the preparation of 3-bromo-2-chloropyridin-4-amine (compound 84_2) To a solution of compound 84_1 (20 g, 156 mmol) in acetonitrile (120 mL) was added NBS (29 g, 163 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (80 mL). The aqueous phase was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 84_2 (21 g, 65.1% yield) as a white solid. LCMS: [M+H] + =207.0.

[0529] Step 2: General procedure for the preparation of 3-bromo-2-chloro-5-nitropyridin-4-amine (compound 84_3) A solution of compound 84_2 (21 g, 101 mmol) in H2SO4 (100 mL) was stirred under N2 for 5 min. Then KNO3 (20.4 g, 202 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water (300 mL) and stirred for 2 h. The mixture was filtered. The filter cake was washed with water (50 mL x 3) and dried to give compound 84_3 (18 g, 70.4% yield) as a white solid. LCMS: [M+H] + =252.0.

[0530] Step 3: General procedure for the preparation of 3-bromo-2-(methoxy-d3)-5-nitropyridin-4-amine (compound 84_4) To a solution of compound 84_3 (18 g, 71 mol) in methanol-D4 (80 mL) was added KNO3 (29.4 g, 213 mmol). The reaction mixture was stirred at 60 °C under N2 atmosphere for 4 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 84_4 (10.5 g, 59.4% yield) as a white solid. LCMS: [M+H] + =251.1.

[0531] Step 4: General procedure for the preparation of 3-bromo-4-chloro-2-(methoxy-d3)-5-nitropyridine (compound 84_5) To a solution of compound 84_4 (5 g, 20 mmol) in MeCN (50 mL) was added isoamyl nitrite (7 g, 60 mmol) and CuCl (6 g, 600 mol). The reaction mixture was stirred at 60° C. under N2 atmosphere for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 84_5 (3 g, 59.4% yield) as a white solid. LCMS: [M+H] + =270.0.

[0532] Step 5: General procedure for the preparation of 6-(((3-bromo-2-(methoxy-d3)-5-nitropyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (compound 84_6) To a solution of compound 84_5 (2 g, 7.4 mmol) in acetonitrile (20 mL), compound 22_5 (1.38 g, 7.4 mmol) and DIPEA (2.9 g, 22.2 mmol) were added. The reaction mixture was stirred at 60° C. for 4 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 84_6 (2.6 g, 83.5% yield) as a yellow solid. LCMS: [M+H] + =421.0.

[0533] Step 6: General procedure for the preparation of 4-(((2-(methoxy-d3)-5-nitro-3-phenylpyridin-4-yl)amino)methyl)benzenesulfonamide (compound 84_7) To a solution of compound 84_6 (200 mg, 0.47 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (86 mg, 0.71 mmol), XPhos-Pd-G2 (37 mg, 0.047 mmol), and K2CO3 (195 mg, 1.41 mmol). The mixture was stirred under N2 atmosphere at a temperature under 100 °C for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 84_7 (160 mg, 80.7% yield) as a yellow solid. LCMS: [M+H] + =418.1.

[0534] Step 7: General procedure for the preparation of 4-(((5-amino-2-(methoxy-d3)-3-phenylpyridin-4-yl)amino)methyl)benzenesulfonamide (compound 84_8) To a solution of compound 84_7 (160 mg, 0.38 mmol) in MeOH (3 mL) / DCM (3 mL) was added Pd / C (30 mg, 10% wt). The reaction solution was stirred at room temperature under H2 atmosphere for 16 h. The reaction mixture was filtered and the filter cake was washed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 84_8 (110 mg, 74.1% yield) as a pale yellow solid. LCMS: [M+H] + =388.1.

[0535] Step 8: General procedure for the preparation of 4-((6-(methoxy-d3)-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzenesulfonamide To a solution of compound 84_8 (110 mg, 0.28 mmol) in EtOH (5 mL) was added triethyl orthoacetate (461 mg, 2.8 mmol) and Py-HCl (3 mg, 0.028 mmol). The reaction was stirred at 100° C. for 1 h. The solvent was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the corresponding example 84 (23 mg, 19.7% yield). LCMS: [M+H] + =412.2. 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.60(d,J=8.4Hz,2H),7.34-7.27(m,3H),7.22(t ,J=7.5Hz,2H),7.07(d,J=7.0Hz,2H),6.66(d,J=8.3Hz,2H),4.93(s,2H),2.37(s,3H).

[0536] Example 85: Synthesis of 5-fluoro-6-((6-(methoxy-d3)-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide

[0537] [ka]

[0538] Step 1: General procedure for the preparation of N-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-3-bromo-2-(methoxy-d3)-5-nitropyridin-4-amine (compound 85_1) To a solution of compound 83_5 (1 g, 3.7 mmol) in acetonitrile (10 mL) was added compound 68_4 (918 mg, 3.7 mmol) and DIPEA (1.5 g, 11.1 mmol). The reaction mixture was stirred at 60° C. for 4 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 85_1 (1.3 g, 72.9% yield) as a yellow solid. LCMS: [M+H] + =482.0.

[0539] Step 2: General procedure for the preparation of N-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-(methoxy-d3)-5-nitro-3-phenylpyridin-4-amine (compound 85_2) To a solution of compound 85_1 (500 mg, 1.04 mmol) in dioxane / H2O (10 mL / 1 mL) was added phenylboronic acid (190 mg, 1.55 mmol), XPhos-Pd-G2 (86 mg, 0.11 mmol), and K2CO3 (431 mg, 3.12 mmol). The mixture was stirred under N2 atmosphere at a temperature under 100 °C for 16 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 85_2 (420 mg, 84.5% yield) as a yellow solid. LCMS: [M+H] + =480.1.

[0540] Step 3: General procedure for the preparation of N4-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-(methoxy-d3)-5-phenylpyridine-3,4-diamine (compound 85_3) To a solution of compound 85_2 (420 mg, 0.88 mmol) in MeOH (8 mL) / DCM (8 mL) was added Pd / C (100 mg, 10% wt). The reaction was stirred at room temperature under H2 atmosphere for 16 h. The reaction solution was filtered and the filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 85_3 (320 mg, 81.3% yield) as a pale yellow solid. LCMS: [M+H] + =450.1.

[0541] Step 4: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-6-(methoxy-d3)-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 85_4) To a solution of compound 85_3 (160 mg, 0.36 mmol) in EtOH (5 mL) was added triethyl orthoacetate (577 mg, 3.56 mmol) and Py-HCl (4 mg, 0.036 mmol). The reaction was stirred at 100° C. for 1 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 85_4 (130 mg, 77.1% yield) as a yellow solid. LCMS: [M+H] + =474.1.

[0542] Step 5: General procedure for the preparation of 5-fluoro-6-((6-(methoxy-d3)-2-methyl-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyridine-3-sulfonamide To a solution of compound 85_4 (130 mg, 0.27 mmol) in acetonitrile (5 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin / acetonitrile (133 mg / 2 mL, 0.68 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the mixture was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to give the corresponding Example 85 (40 mg, 33.9% yield). LCMS: [M+H] + =431.3. 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.47(s,1H),7.77(dd,J=9.2,2.0Hz,1H),7.71(s,2H),7 .29(t,J=7.6Hz,1H),7.17(t,J=7.6Hz,2H),6.85(d,J=7.6Hz,2H),5.16(s,2H),2.44(s,3H).

[0543] Example 86: Synthesis of 6-((2-(difluoromethyl)-6-(methoxy-d3)-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide

[0544] [ka]

[0545] Step 1: General procedure for the preparation of 1-((5-(benzylthio)-3-fluoropyridin-2-yl)methyl)-2-(difluoromethyl)-6-(methoxy-d3)-7-phenyl-1H-imidazo[4,5-c]pyridine (compound 86_1) A solution of compound 85_3 (160 mg, 0.36 mmol) in trifluoroacetic acid (5 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give the corresponding compound 86_1 (80 mg, 44.1% yield) as a yellow solid. LCMS: [M+H] + =510.2.

[0546] Step 2: General procedure for the preparation of 6-((2-(difluoromethyl)-6-(methoxy-d3)-7-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl)-5-fluoropyridine-3-sulfonamide To a solution of compound 86_1 (80 mg, 0.16 mmol) in acetonitrile (5 mL) / AcOH (0.3 mL) / H2O (0.2 mL) at 0° C., a solution of 1,3-dichloro-5,5-dimethylhydantoin (79 mg / 2 mL, 0.40 mmol) in acetonitrile was added dropwise. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL) and the mixture was cooled to 0° C. Ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at 0° C. for 3 min. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to give the corresponding Example 86 (17 mg, 23.2% yield). LCMS: [M+H] + =467.3. 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.46(s,1H),7.77(dd,J=9.2,1.6Hz,1H),7.37(t,J=51.6Hz,1 H),7.29(t,J=7.6Hz,1H),7.18(t,J=7.6Hz,2H),7.00(brs,2H),6.91(d,J=7.2Hz,2H),5.33(s,2H).

[0547] Example A: Enzyme Assay ATP-Glo ​​Assay: 1. Compounds were manually diluted in DMSO to give 11-point 3-fold dilutions. 0.02 μL of compound was then transferred by ECHO to a 384 assay plate. 2. 2 μL of a particular concentration of ENPP1 was added to a 384 assay plate. Centrifuge at 1000 RPM for 1 minute. 3. 2 μL of a specific concentration of ATP was added to the assay plate. Centrifuge at 1000 RPM for 1 minute. 4. Incubate at 25°C for 60 minutes. 5. 4 μL of AMP-Glo ​​Reagent was added to the assay plate. 6. Centrifuge at 1000 RPM for 1 minute and incubate at 25°C for 1 hour. 7. 8 μL of Kinase Detection Reagent was added to the assay plate. 8. Centrifuge at 1000 RPM for 1 minute and incubate at 25°C for 1 hour. The final assay reaction mixture contained a buffer of 50 mM Tris pH 8.8, 250 mM NaCl, and 0.1% BSA. 9. US LUM was read as RLU by Envision. 10. The raw data was analyzed using the equation (V. Data Analysis).

[0548] cGAMP-Glo ​​Assay: 1. Compounds were manually diluted in DMSO to give 11-point 3-fold dilutions. 0.02 μL of compound was then transferred by ECHO to a 384 assay plate. 2. 2 μL of the specified concentration of ENPP1 was added to the 384 assay plate and centrifuged at 1000 RPM for 1 minute. 3. 2 μL of a specific concentration of 2'3'-cGAMP was added to the assay plate and centrifuged at 1000 RPM for 1 minute. 4. Incubate at 25°C for 60 minutes. 5. 4 μL of AMP-Glo ​​Reagent was added to the assay plate. 6. Centrifuge at 1000 RPM for 1 minute and incubate at 25°C for 1 hour. 7. 8 μL of Kinase Detection Reagent was added to the assay plate. 8. Centrifuge at 1000 RPM for 1 minute and incubate at 25°C for 1 hour. The final assay reaction mixture contained a buffer of 50 mM Tris pH 8.8, 250 mM NaCl, and 0.1% BSA. 9. US LUM was read as RLU by Envision. 10. The raw data was analyzed using the equation (V. Data Analysis).

[0549] The data are shown in Table 2.

[0550]

Table 2-1

[0551]

Table 2-2

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond, —NH—, or —O—; R １ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom １ come together to form an oxo, n is 0 to 6; R ２ is hydrogen, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, R ３ is hydrogen, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, 【Chemistry 2】 is a single or double bond, where: 【Transformation 3】 is a double bond, X is N or CR Ｘ and Y is N or CR Ｙ and 【Chemistry 4】 is a single bond, X is C(=O) and Y is NR Ｙ１ or C(R Ｙ２ ) ２ and R Ｘ represents hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Ｙ represents hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Ｙ１ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R Ｙ２ are each independently hydrogen, halogen, —CN, —OH, or —OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are each independently and optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ４ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom ４ come together to form an oxo, m is 0 to 4; R ５ is hydrogen, halogen, -CN, -NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ６ is hydrogen, halogen, -CN, -NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ａ are each independently C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R ａ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, two R ｂ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkyl (cycloalkyl), C １ -C ６ Alkyl (heterocycloalkyl), C １ -C ６ Alkyl (aryl), or C １ -C ６ alkyl(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently a halogen, —CN, —OH, or —OCH ３ , —S(═O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NHCH ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , —C(═O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; Alternatively, two R on the same atom form an oxo. The compound, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound has formula (Ia): 【Transformation 5】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X is CR X , Y is N, and R X is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X is CR X , Y is CR Y , R X is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, and R Y is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl.

5. The compound of claim 1, wherein the compound has formula (Ib): 【Transformation 6】 2. The compound of claim 1, which is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Y is NR Y1 and R Y1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridinyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, and n is 0 or 1.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or C 1 -C 6 alkyl and R 3 is hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is aryl or heteroaryl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, and m is 0 or 1.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is —OR a or C 1 -C 6 alkyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or C 1 -C 6 alkyl. 【Request Item 15】 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 2. The compound of claim 1, which is a compound selected from the group consisting of:

16. The compound 【Transformation 8】 2. The compound of claim 1, wherein:

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

19. Use of the pharmaceutical composition of claim 17 in the manufacture of a medicament for treating cancer.

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