STING antagonists and uses thereof

Abstract

The present disclosure relates to a compound of formula (I) for use in treating, for example, a condition, disease, or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). TIFF2023550182000107.tif79110, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. The disclosure also features compositions containing the compound of Formula (I), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and methods of using and making the compound of Formula (I), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from International Patent Application No. PCT / CN2020 / 130793, filed November 23, 2020. The entire contents of the above application are incorporated herein by reference. [Background technology]

[0002] STING, also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / ERIS, is a protein encoded by the TMEM173 gene in humans. STING has been shown to play a role in innate immunity. STING induces the production of type I interferons when cells are infected with intracellular pathogens, such as viruses, mycobacteria, and intracellular parasites. STING-mediated type I interferons protect infected and nearby cells from local infection in an autocrine and paracrine manner.

[0003] Cytosolic DNA recognition is centrally mediated by the STING pathway. In this context, STING, a transmembrane protein restricted to the endoplasmic reticulum (ER), acts as a second messenger receptor for 2',3' cyclic GMP-AMP (hereafter referred to as cGAMP), which is produced by cGAS after dsDNA binding. In addition, STING can also function as a primary pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs proceeds via the carboxy-terminal region of STING, which targets the cytosol and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocalization to the Golgi, a process essential for promoting the interaction of STING with TBK1. This protein complex then signals through the transcription factor IRF-3 to induce type I interferons (IFNs) and other co-regulated antiviral factors. Additionally, STING has been shown to trigger NF-κB and MAP kinase activation. After initiating signaling, STING is rapidly degraded, which is thought to be a critical step in terminating the inflammatory response. Summary of the Invention [Problem to be solved by the invention]

[0004] Excessive activation of STING is associated with a subset of isolated autoinflammatory conditions, so-called type I interferonopathies. Examples of these diseases include the clinical syndrome called STING-associated vasculopathy of infancy (SAVI), which is caused by gain-of-function mutations in TMEM173 (the gene for STING). Furthermore, STING has been implicated in the pathogenesis of Aicardi-Goutières syndrome (AGS) and genetic forms of lupus. In contrast to SAVI, dysregulation of nucleic acid metabolism underlies the sequential innate immune activation in AGS. Apart from these genetic disorders, emerging evidence points to a more general pathogenic role for STING in various inflammation-associated disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Thus, small-molecule-based pharmacological interventions in the STING signaling pathway hold significant potential for the treatment of a wide range of diseases. [Means for solving the problem]

[0005] The present disclosure provides antagonists of STING, e.g., inhibitors of structural formula (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2), pharmaceutically acceptable salts, stereoisomers, tautomers, and compositions thereof. It has been unexpectedly discovered that the compounds disclosed herein, which require a specific combination of a specific bicyclic core structure and substituents at specific positions, effectively inhibit STING activity.

[0006] [ka]

[0007] The present disclosure further provides methods of using the compounds disclosed herein (e.g., compounds of structural formula (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), and pharmaceutically acceptable salts and compositions thereof, to inhibit the activity of STING. The present disclosure further provides methods for using the compounds disclosed herein (e.g., compounds of structural formula (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), and pharmaceutically acceptable salts, stereoisomers, tautomers, or compositions thereof, to treat conditions, diseases, or disorders in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., autoimmune disease or cancer) in a subject (e.g., a human).

[0008] An "antagonist" of STING includes compounds that directly bind to or modify STING at the protein level such that STING activity is reduced, e.g., by inhibiting, blocking, or dampening agonist-mediated responses, altered distribution, or other. STING antagonists include chemical compounds that prevent or inhibit STING signaling.

[0009] In one aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formula (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0010] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any one of the formulas described herein (e.g., Structural Formulas (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, as defined in any one of the embodiments described herein, in admixture with at least one pharmaceutically acceptable carrier.

[0011] In another aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., Structural Formulas (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, as defined in any one of the embodiments described herein, for use as a pharmaceutical.

[0012] In another aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, as defined in any one of the embodiments described herein, for use in treating a condition, disease, or disorder characterized by amelioration by antagonizing STING, e.g., a condition, disease, or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., an autoimmune disease or cancer) in a subject (e.g., a human).

[0013] In another aspect, the disclosure provides a method of treating a condition, disease, or disorder characterized by amelioration by antagonizing STING, e.g., a condition, disease, or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) is responsible for the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., an autoimmune disease or cancer) in the subject (e.g., human), in a subject in need of such prevention and / or treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of the formulas described herein (e.g., Structural Formulas (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, as defined in any one of the embodiments described herein.

[0014] In another aspect, the disclosure provides use of a compound of any one of the formulas described herein (e.g., Structural Formulas (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, as defined in any one of the embodiments described herein, for the manufacture of a medicament for treating a condition, disease, or disorder characterized by amelioration by antagonizing STING, e.g., a condition, disease, or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., an autoimmune disease or cancer) in a subject (e.g., a human).

[0015] In another aspect, the disclosure provides a compound of any one of the formulas described herein (e.g., structural formulas (I), (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, as defined in any one of the embodiments described herein, for use in the treatment of a condition, disease, or disorder for which an antagonist of STING is indicated.

[0016] In another aspect, the disclosure provides methods for inhibiting STING activity in a cell or in a patient. In some embodiments, the method comprises contacting a cell or administering to a patient a compound of structural formula (I) (e.g., (IA), (IB-1), (IB-2), (IC-1), or (IC-2)), a pharmaceutically acceptable salt, stereoisomer, tautomer, or composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0017] 1.Compound In a first embodiment, the present disclosure provides a compound represented by structural formula (I):

[0018] [ka]

[0019] and a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: (i) when A2 is C, A1 is CH or N, B2 is NR1, and B1 is N or CH;

[0020] [ka]

[0021] is attached to the carbon atom next to B1, or B1 is C,

[0022] [ka]

[0023] is bound to B1, (ii) when A2 is N, A1 is CH and B2 is N; B1 is CH,

[0024] [ka]

[0025] is attached to the carbon atom next to B1, or B1 is C,

[0026] [ka]

[0027] is bound to R1 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, -(CH2) (0または1) -C 3~7 Cycloalkyl, -(CH2) (0または1) -C 4~7 Cycloalkenyl, or -(CH2) (0または1) -3 to 7-membered heterocyclyl, and the cycloalkyl, cycloalkenyl, or heterocyclyl represented by R1 is not halogen, -OH, oxo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, and NR 11 R 12 and optionally substituted with one or more substituents independently selected from the group consisting of: R3 is H, halogen, CN, OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -C(O)R 11, -C(O)OR 11 , -C(O)NR 11 R 12 , -NR 11 C(O)C 1~6 Alkyl, NR 11 R 12 , -P(=O)R 11 R 12 , -S(O)2R 11 , -S(O)NR 11 R 12 , -O (0または1) -C 3~7 Cycloalkyl, -O (0または1) -C 4~7 Cycloalkenyl, -O (0または1) -3 to 7-membered heterocyclyl, -O (0または1) -6 to 10-membered aryl, -O (0または1) -5-8 membered heteroaryl, -(CH2) (0または1) -C 3~7 Cycloalkyl, -(CH2) (0または1) -C 4~7 Cycloalkenyl, -(CH2) (0または1) -3 to 7-membered heterocyclyl, or -(CH2) (0または1) -aryl, and the alkyl, alkenyl, alkynyl, aryl, or heteroaryl represented by R3 or in the group represented by R3 is not halogen, -OH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -NR 11 R 12 , and -N(R 11 )C(O)OR 12 and wherein the cycloalkyl, cycloalkenyl, or heterocyclyl represented by R3 or within the group represented by R3 is selected from the group consisting of halogen, —OH, oxo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -C(O)OC 1~6 Alkyl, and NR 11 R 12and optionally substituted with one or more substituents independently selected from the group consisting of: R4, R5, and R6 are independently H, halogen, CN, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , -NR 11 C(O)C 1~6 Alkyl, NR 11 R 12 , -P(=O)R 11 R 12 , -S(O)2R 11 , -S(O)NR 11 R 12 , -O (0または1) -C 3~7 Cycloalkyl, -O (0または1) -C 4~7 Cycloalkenyl, -O (0または1) -3 to 7-membered heterocyclyl, -O (0または1) -6 to 10-membered aryl, -O (0または1) -5-8 membered heteroaryl, -(CH2) (0または1) -C 3~7 Cycloalkyl, -(CH2) (0または1) -C 4~7 Cycloalkenyl, -(CH2) (0または1) -3 to 7-membered heterocyclyl, or -(CH2) (0または1) -aryl, and the alkyl, alkenyl, alkynyl, alkoxy, aryl, or heteroaryl represented by R4, R5, or R6, or in the group represented by R4, R5, or R6, is not halogen, -OH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -NR 11 R 12 , and -N(R 11 )C(O)OR 12and wherein the cycloalkyl, cycloalkenyl, or heterocyclyl represented by R4, R5, or R6 or in the group represented by R4, R5, or R6 is selected from the group consisting of halogen, —OH, oxo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -C(O)OC 1~6 Alkyl, and NR 11 R 12 and optionally substituted with one or more substituents independently selected from the group consisting of: At least one of R3, R4, R5, and R6 is not hydrogen; R7 and R8 are independently H, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 haloalkoxy, R 11 and R 12 Each instance of H, C 1~6 Alkyl, C 1~6 Haloalkyl, or -C(O)OC 1~6 alkyl].

[0028] In a second embodiment, the present disclosure provides a compound represented by structural formula (IA):

[0029] [ka]

[0030] wherein the definitions of the variables are provided in Structural Formula (I), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0031] In a third embodiment, the present disclosure provides a compound represented by structural formula (IB-1): (IB-2):

[0032] [ka]

[0033] wherein the definitions of the variables are provided in Structural Formula (I), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0034] In a fourth embodiment, the present disclosure provides a compound represented by structural formula (IC-1) or (IC-2):

[0035] [ka]

[0036] wherein the definitions of the variables are provided in Structural Formula (I), a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0037] In a fifth embodiment, the present disclosure provides a compound according to the first, second, or third embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is selected from the group consisting of H, C, 1~4 Alkyl, -(CH2) (0または1) -C 3~4 cycloalkyl or 3- to 6-membered heterocyclyl, and the cycloalkyl or heterocyclyl represented by R1 is substituted with halogen, —OH, and C 1~4 and optionally substituted with one or more substituents independently selected from the group consisting of alkyl.

[0038] In a sixth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, or fifth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R7 and R8 is independently H or halogen.

[0039] In a seventh embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, or sixth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R and R is independently selected from H, halogen, C 1~6 Alkyl, or C 1~6 It is haloalkyl.

[0040] In an eighth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is independently selected from H, halogen, CN, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , -NR 11 C(O)C 1~6 Alkyl, NR 11 R 12 , -S(O)2R 11 , -S(O)NR 11 R 12 , C 3~7 Cycloalkyl, -(CH2) (0または1) -3 to 7-membered heterocyclyl, -O (0または1) -3 to 7-membered heterocyclyl, phenyl, -O (0または1) - 5-6 membered heteroaryl, and the alkyl, alkoxy, phenyl, or heteroaryl represented by R4 or in the group represented by R4 is not halogen, -OH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -NR 11 R 12 , and -N(R 11 )C(O)OR 12and wherein the cycloalkyl or heterocyclyl represented by R4 is selected from the group consisting of halogen, —OH, oxo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -C(O)OC 1~6 Alkyl, and NR 11 R 12 and optionally substituted with one or more substituents independently selected from the group consisting of:

[0041] In a ninth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is independently selected from H, halogen, CN, OH, C 1~6 Alkyl, C 1~6 Alkoxy, -C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , -NR 11 C(O)C 1~6 Alkyl, NR 11 R 12 , -P(=O)R 11 R 12 , -S(O)2R 11 , -S(O)NR 11 R 12 , C 3~7 Cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, -O (0または1) - 5-6 membered heteroaryl, and the alkyl, alkoxy, phenyl, or heteroaryl represented by R6 or in the group represented by R6 is not halogen, -OH, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -NR 11 R 12 , and -N(R 11 )C(O)OR 12and wherein the cycloalkyl or heterocyclyl represented by R6 is selected from the group consisting of halogen, —OH, oxo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -C(O)OC 1~6 Alkyl, and NR 11 R 12 and optionally substituted with one or more substituents independently selected from the group consisting of:

[0042] In a tenth embodiment, the present disclosure provides a compound according to the first, second, third, fifth, sixth, seventh, eighth, or ninth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is selected from the group consisting of H, C, 1~4 Alkyl, -(CH2) (0または1) -C 3~4 In one particular embodiment, R is H or C 1~4 It is alkyl (eg, methyl).

[0043] In an eleventh embodiment, the present disclosure provides a compound, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, according to the first, second, third, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, wherein each instance of A is CH.

[0044] In a twelfth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R7 and R8 is independently H or F.

[0045] In a thirteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R3 and R5 is independently H, F, Cl, or CF3.

[0046] In a fourteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is independently selected from H, halogen, CN, C 1~4 Alkyl (OH or -NR 11 R 12 (optionally replaced by ), C 1~4 Haloalkyl, C 1~4 Alkoxy (C 1~4 optionally substituted with alkoxy), C 1~4 Haloalkoxy, C 2~4 Alkynyl, -C(O)OR 11 , -C(O)NR 11 R 12 , -S(O)2R 11 , -(CH2) (0または1) -5-6 membered heterocyclyl, -O (0または1) -5- to 6-membered heterocyclyl, -O-5- to 6-membered heteroaryl, and the heteroaryl in the group represented by R4 is halogen, -OH, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 and optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, and the heterocyclyl represented by R4 is selected from the group consisting of halogen, —OH, oxo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, -C(O)OC 1~4 Alkyl, and NR 11 R 12and optionally substituted with one or more substituents independently selected from the group consisting of:

[0047] In a fifteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is independently selected from H, halogen, CN, C 1~4 Alkyl (-NR 11 R 12 (optionally replaced by ), C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, -C(O)OR 11 , -C(O)NR 11 R 12 , -P(=O)R 11 R 12 , -S(O)2R 11 , 5-6 membered heterocyclyl, and the heterocyclyl represented by R6 is halogen, -OH, oxo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, -C(O)OC 1~4 Alkyl, and NR 11 R 12 and optionally substituted with one or more substituents independently selected from the group consisting of:

[0048] In a sixteenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is independently selected from H, halogen, CN, C 1~4 Alkyl (-NR 11 R 12 (optionally replaced by ), C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C2~4 Alkynyl, -C(O)NR 11 R 12 or 5-6 membered oxygen-containing heterocyclyl. In one particular embodiment, R4 is -NR 11 R 12 C optionally substituted with 1~4 alkyl, and R 11 is H or C 1~2 alkyl, and R 12 is H, C 1~4 Alkyl, or C 1~4 It is haloalkyl.

[0049] In a seventeenth embodiment, the present disclosure provides a compound according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each instance of R is independently selected from H, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, or -C(O)OC 1~4 In one particular embodiment, R6 is H, F, or CN.

[0050] In one embodiment, the compound, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof is selected from the compounds disclosed in the Examples and Table 1. 2.Definition The term "halogen" as used herein refers to fluoride, chloride, bromide, or iodide.

[0051] The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy" or "haloalkyl", refers to a group of the formula -C n H (2n+1)"(C1-C4) alkyl" refers to a saturated aliphatic, straight-chain or branched monovalent hydrocarbon group of the formula (I). Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., (C1-C4) alkyl. As used herein, a "(C1-C4) alkyl" group refers to a group having 1 to 4 carbon atoms in a straight-chain or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.

[0052] The term “alkylene” as used herein is a group of the formula —C n H 2n - means a straight or branched chain divalent hydrocarbon radical of the formula: -. Non-limiting examples include ethylene and propylene.

[0053] The term "alkenyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced with double bonds. The term "alkynyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced with triple bonds.

[0054] The term "alkoxy" refers to an alkyl group attached through an oxygen connecting atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0055] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, optionally substituted with one or more halogen atoms. The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy optionally substituted with one or more hydroxy groups.

[0056] The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon group having 3 to 12 ring carbons, preferably 3 to 7 ring carbons. Any substitutable ring atom may be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0057] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group having 3 to 12 ring carbons, preferably 4 to 7 ring carbons, which cycloalkenyl groups may optionally be substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl groups can have any degree of saturation, provided that none of the rings in the ring system are aromatic, and cycloalkenyl groups are not entirely saturated. Cycloalkenyls can contain multiple fused and / or bridged and / or spirocyclic rings.

[0058] The term "heterocyclyl" or "heterocycle" refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, quaternized nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (a "3- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "3- to 7-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, if valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") systems, where polycyclic ring systems include fused, bridged, or spirocyclic ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can contain heteroatoms in one or more rings within the polycyclic ring system. Substituents can be present on one or more rings within the polycyclic ring system.

[0059] In general, a cycloalkyl or heterocyclyl can be unsubstituted or, where valences allow, substituted with one or more substituents, which can be independently selected from several groups, such as oxo, -CN, halogen, alkyl, and alkoxyl, and optionally, alkyl substituents can be further substituted.

[0060] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares adjacent pairs of carbon atoms with other rings in the system) group having a fully conjugated pi-electron system. Representative examples of aryl are phenyl and naphthyl.

[0061] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur. Preferably, a heteroaryl is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 41 -C 42 -C 43 -C 54 -C 55 -C 56 -C 57 -C 58 -C 59 -C 60 -C 61 -C 62 -C 63 -C 74 -C 75 -C 76 -C 77 -C 78 -C 79 -C 80 -C 81 -C 82 -C 83 -C 84 -C 85 -C 86 -C 87 -C 88 -C 90 -C 91 -C 92 -C 93 -C 94 -C 95 -C 96 -C 97 -C 98 -C 99 -C 100 -C 101 -C 112 -C 113 -C 114 -C 115 -C 120 -C 125 -C 135 -C 145 -C 156 -C 166 -C 177 -C 188 -C 199 -C 199 -C 199 -C 5~10 Based on aryl. Heteroaryl groups may be bonded through a ring carbon atom or, if valence allows, through a ring nitrogen atom. Generally, heteroaryls may be unsubstituted or, if valence allows, substituted with one or more substituents, the substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH, NH alkyl, N(alkyl)), and optionally, alkyl may be further substituted. pharmaceutically acceptable salts The term " pharmaceutically acceptable salt " refers to a pharmaceutical salt, that is, a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without causing excessive toxicity, irritation, and allergic reactions, and that is consistent with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci., 1977, vol. 66, pp. 1-19.

[0062] Pharmaceutically acceptable salts of the compounds of any one of the formulae described above include acid addition and base salts. Pharmaceutically acceptable salts of the compounds disclosed herein are included in the teachings of the present invention. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s) using acidic groups, such as carboxylic acids. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium and potassium salts), and alkaline earth metal salts (e.g., magnesium and calcium salts).

[0063] Pharmaceutically acceptable salts of compounds of any one of the formulae set forth above can be prepared by one or more of three methods: (i) by reacting a compound of any one of the formulae set forth above with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of any one of the formulae described above, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) converting one salt of a compound of any one of the formulae set forth above into another salt by reaction with an appropriate acid or base or by means of a suitable ion exchange column, It can be prepared.

[0064] All three reactions are typically carried out in solution. The resulting salts can be precipitated and collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to almost non-ionized.

[0065] Compounds of any one of the formulae described above, and pharmaceutically acceptable salts thereof, can exist in unsolvated and solvated forms. Solvates and Hydrates The term "solvate" is used herein to describe a molecular complex comprising a compound of any one of the above formulae, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

[0066] The term "hydrate" is utilized when the solvent is water. The currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal ion coordinated hydrates. See Polymorphism in Pharmaceutical Solids by KR Morris (HGBrittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules are located in lattice channels where they are next to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0067] If the solvent or water is tightly bound, the complex can have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, as in the case of channel solvates and hygroscopic compounds, the water / solvent content may depend on humidity and drying conditions. In such cases, non-stoichiometry is the norm. Stereoisomers and other variations Compounds of any one of the formulae described above can exhibit one or more types of isomerism (e.g., optical, geometric, or tautomeric isomerism). Such variations are implicit in compounds of any one of the formulae described above, as so defined with reference to their structural features, and are therefore within the scope of the present disclosure.

[0068] Compounds have one or more chiral centers that can exist in various stereoisomeric forms; that is, each chiral center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

[0069] If a compound is designated by its chemical name indicating a single enantiomer (e.g., when the configuration is indicated by the chemical name "R" or "S") or its structure (e.g., when the configuration is indicated by a "wedge" bond), unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also called "enantiomerically pure"). Optical purity is the weight of the named or designated enantiomer in a mixture divided by the total weight of the mixture of both enantiomers.

[0070] Where the stereochemistry of a disclosed compound is named or represented by a structure, and the named or represented structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or a mixture of any of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or represented stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity, in this case, is determined by dividing the total weight of the stereoisomer encompassed by the name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0071] When two stereoisomers are represented by their chemical names or structures and the chemical names or structures are joined by "and," a mixture of the two stereoisomers is intended. When two stereoisomers are represented by their chemical names or structures and the names or structures are joined by "or," either one or the other of the two stereoisomers is intended, but not both.

[0072] When a disclosed compound having a chiral center is represented by a structure without indicating the configuration at that chiral center, the structure is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is represented by its chemical name without indicating the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0073] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or depicted without indicating the stereochemistry of that center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure and enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or depicted without indicating the stereochemistry of that center, the name or structure is understood to encompass all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0074] The term "geometric isomer" refers to a compound that contains at least one double bond, wherein this double bond(s) can exist in cis (also called syn or entgegen (E)) or trans (also called anti or zusammen (Z)) form, as well as mixtures thereof.

[0075] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of, for example, proton tautomerism in compounds of any one of the formulas described above containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. In addition, a single compound can exhibit more than one type of isomerism.

[0076] When a geometric isomer is represented by a name or structure, it is understood that the named or represented isomer is present to a greater extent than another isomer, i.e., the geometric isomeric purity of the named or represented geometric isomer is greater than 50% by weight, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or represented geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0077] When a disclosed compound is named or depicted by structure without stereochemistry indicated, it is understood that the name or structure encompasses one or more of the possible stereoisomers, or geometric isomers, or mixtures of the stereoisomers or geometric isomers encompassed.

[0078] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or racemate resolution (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, if a compound of any one of the formulas described above contains an acidic or basic moiety, a base or acid, for example, 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. Chiral compounds of any one of the formulas described above (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, usually heptane or hexane, containing 0-50% by volume, usually 2% to 20% by volume, of isopropanol, and 0-5% by volume of an alkylamine, usually 0.1% by volume of diethylamine. Concentration of the eluate produces the enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, e.g., Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), Vol. 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein). Columns are available from Chiral Technologies, Inc., West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

[0079] It must be emphasized that although the compounds of any one of the formulas set forth above are depicted herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the present disclosure. 3. Administration and Dosing Generally, the compound of the present disclosure is administered in an amount that is effective for treating the conditions described herein.The compound of the present disclosure can be administered as compound itself or alternatively as pharmaceutically acceptable salt.For the purpose of administration and dosage, compound itself or its pharmaceutically acceptable salt will simply be referred to as the compound of the present disclosure.

[0080] The compounds of the present disclosure are administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The compounds of the present disclosure can be administered orally, rectally, vaginally, parenterally, or topically.

[0081] The compounds of the present disclosure can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or may utilize buccal or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0082] In another embodiment, the compounds of the present disclosure can also be administered directly into the bloodstream, muscle, or internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous.Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors, and infusion techniques.

[0083] In another embodiment, the compounds of the present disclosure may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present disclosure may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may also be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be administered directly to the eye or ear.

[0084] Dosage regimens for compounds and / or compositions of the present disclosure containing the compounds are based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, dosage regimens can vary widely. In one embodiment, for treatment of the indicated conditions discussed herein, the total daily dose of a compound of the present disclosure is typically about 0.001 to about 100 mg / kg (i.e., mg of compound of the present disclosure per kg of body weight). In another embodiment, the total daily dose of a compound of the present disclosure is about 0.01 to about 30 mg / kg, in another embodiment, about 0.03 to about 10 mg / kg, and in yet another embodiment, about 0.1 to about 3 mg / kg. It is not uncommon for the administration of a compound of the present disclosure to be repeated multiple times daily (usually up to four times). If desired, the total daily dose can be increased, typically using multiple doses per day.

[0085] For oral administration, the compositions can be provided in the form of tablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, and 500 milligrams of active ingredient for symptomatic adjustment of patient dosage. Medicaments typically contain from about 0.01 mg to about 500 mg of active ingredient, or, in another embodiment, from about 1 mg to about 100 mg. During intravenous constant rate infusion, doses range from about 0.01 to about 10 mg / kg / minute.

[0086] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, e.g., primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development. 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes pharmaceutical compositions. Such pharmaceutical compositions include the disclosed compounds together with a pharmaceutically acceptable carrier. Other pharmacologically active substances may also be present.

[0087] As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc., and combinations thereof, and may include isotonic agents, such as sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, in compositions. Pharmaceutically acceptable substances, such as wetting agents or minor amounts of auxiliary substances, such as wetting agents or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.

[0088] The compositions of the present disclosure may be in a variety of forms, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0089] Typical compositions are in the form of injectable or infusible solutions, e.g., compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0090] Oral administration of solid dosage forms may be, for example, presented in separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure.In another embodiment, oral administration may be in the form of powder or granules.In another embodiment, oral administration form is sublingual, for example, lozenges.In such solid dosage forms, any one compound of the formula described above is usually combined with one or more adjuvants.Such capsules or tablets may contain controlled-release formulations.In the case of capsules, tablets, and pills, dosage forms may also contain buffering agents or may be prepared with enteric coatings.

[0091] In another embodiment, oral administration can be in liquid dosage form.Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents (for example, water) commonly used in the art.Such compositions can also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, flavoring agents (for example, sweeteners) and / or aromatic agents.

[0092] In another embodiment, the present disclosure comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0093] In another embodiment, the present disclosure comprises a topical dosage form. "Topical administration" includes, for example, transdermal administration, e.g., via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations can include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered via a transdermal device, administration is achieved using a patch, either of the reservoir and porous membrane type or various solid matrices. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated. See, e.g., Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0094] Suitable formulations for topical administration to the eye include, for example, eye drops in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or aural administration may be in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other suitable formulations for ocular and aural administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and microparticle or vesicular systems, such as niosomes or liposomes. Polymers, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers, such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, can be incorporated with preservatives, such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0095] For intranasal administration or inhalation administration, the compounds of the present disclosure are conveniently delivered from a pressurized container or nebulizer by using suitable propellants, in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or in the form presented in an aerosol spray.The formulation suitable for intranasal administration is usually administered in the form of dry powder from a dry powder inhaler (either alone or as a mixture, for example, dry-mixed with lactose, or as particles of mixed components, for example, mixed with phospholipids, for example, phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably, an atomizer that uses electrohydrodynamics to generate a fine mist), or from a nebulizer with or without suitable propellants, for example, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.For intranasal use, the powder can contain a bioadhesive agent, for example, chitosan or cyclodextrin.

[0096] In another embodiment, the present disclosure includes a rectal dosage form. Such a rectal dosage form may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternative forms can be used as needed.

[0097] Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the present disclosure can be prepared by any of the well-known techniques of pharmacy, including effective formulation and administration procedures.

[0098] The above-mentioned considerations about effective formulation and administration procedure are well known in the art and are described in standard textbooks.Drug formulation is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999. 5.Treatment method Various cytosolic pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) can be recognized by intracellular pattern recognition receptors (PRRs), such as cyclic GMP-AMP synthase (cGAS), which recognizes cytosolic nucleic acids, including dsDNA. Recognition of dsDNA by cGAS activates the enzyme, resulting in the production of cyclic GMP-AMP (cGAMP). cGAMP is then recognized by STING, which generates type 1 IFNs and leads to NF-κB-mediated production of proinflammatory cytokines and molecules.

[0099] Thus, cGAS-STING-mediated recognition of cytosolic dsDNA plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. In particular, the cGAS-STING signaling pathway has evolved to recognize cytosolic DNA, which can be either intracellular DNA viruses that infect the host, or host DNA (including mtDNA or nuclear DNA leaked into the cytosol) and bacterial CDNs that act as DAMPs.

[0100] On the other hand, overactivation of this system can lead to autoinflammation and the development of autoimmune diseases. For example, increased cGAS-STING signaling promotes acute pancreatitis, whereas its blockade by knocking out cGAS or STING reduces the incidence of pancreatitis (Zhao et al., STING signaling promotes inflammation in experimental acute pancreatitis. Gastroenterology 154:1822-1835, e2, 2018). Overactivation of cGAS-STING signaling also plays a crucial role in the pathogenesis of autoimmune diseases, including SLE. Chronic activation of the pathway leads to autoinflammatory or autoimmune disorders (Yang et al., Proc Natl Acad Sci USA 114:E4612-E4620, 2017; Chen et al., Natl Sci Rev. 5:308-310, 2018; Dou et al., Nature 550:402-406, 2017; Gluck et al., Nat Cell Biol. 19:1061-1070, 2017). Furthermore, the cGAS-STING pathway also mediates lysosomal cell death and K+ accumulation. + By inducing excretion, it also activates the NLRP3 inflammasome and the release of pro-inflammatory cytokines (IL-1β and IL-18). Therefore, specifically targeting cGAS-STING signaling is of great value for targeting autoimmune diseases, including IBD, because of the involvement of lysosomal cell death and the NLRP3 inflammasome in the pathogenesis. For example, STING deletion inhibits the activation of cGAS. - / -It completely abrogates enteritis in mice, resulting in less intestinal inflammation.

[0101] Thus, cGAS-STING signaling plays a critical role in the pathogenesis of inflammatory and autoimmune diseases, and thus one aspect of the present invention provides a method for treating a disease or condition associated with aberrant STING activity / activation / expression, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof to a subject in need of treatment.

[0102] In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., an inflammatory or autoimmune disorder). In certain embodiments, the condition, disease, or disorder is associated with or characterized by activation of the type I interferon pathway, or a type I interferonopathy.

[0103] Type I interferons are primarily involved in the immune response to viral infections and include interferon alpha (IFN-α), interferon beta (IFN-β), IFN-kappa, IFN-epsilon, and IFN-omega.

[0104] In some embodiments, the condition, disease, or disorder is a STING-related condition, such as type I interferonopathy (e.g., infantile-onset STING-associated vasculopathy (SAVI)), Aicardi-Goutières syndrome (AGS), chilblain lupus erythematosus (CHLE), genetic forms of lupus, and disorders involving inflammation, such as systemic lupus erythematosus and rheumatoid arthritis. In certain embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., cytosolic DNA-induced autoinflammatory disease). Non-limiting examples of autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), juvenile idiopathic arthritis (JIA), psoriasis, and psoriatic arthritis, which are chronic inflammatory conditions with multifactorial susceptibility. In certain embodiments, the condition is inflammatory bowel disease (IBD). In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with an employed cell therapy, colitis associated with one or more alloimmune diseases (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is an alloimmune disease (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

[0105] For example, TREX1 is a 314-aa protein encoded by a single exon on human chromosome 3p21. It is an exonuclease that degrades cytosolic DNA to prevent the generation of pathogenic immune responses. Loss of TREX1 causes AGS, SLE, familial pernio lupus (a cutaneous subtype of SLE), and retinal vasculopathy with cerebral leukodystrophy (RVCL) in humans. TREX1 mutations represent the single most common cause of monogenic SLE identified to date. Trex1 - / - The antimalarial drug hydroxychloroquine or the more potent compound X6 administered to mice prevents the development of experimental autoimmune myocarditis by inhibiting cGAMP production and ISG activation in spleen and heart tissue, as well as in peripheral blood monocytes isolated from SLE patients in vitro. This data demonstrates that inhibiting the cGAMP-STING pathway can treat autoinflammatory or autoimmune diseases, such as SLE (see An et al., Inhibition of cyclic GMP-AMP synthase using a novel antimalarial drug derivative in Trex1-deficient mice. Arthritis Rheumatol. 2018;70:1807-1819), as well as several simple type I interferonopathies, including AGS, STING-associated vasculopathy of infancy (SAVI), and DNase II activity deficiency.

[0106] Indeed, Eli Lilly and Company recently initiated a phase II / III clinical trial evaluating the efficacy and safety of baricitinib (LY3009104) in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome / chronic atypical neutrophilic dermatosis with lipodystrophy and fever (NNS / CANDLE), SAVI, and AGS. See ClinicalTrials.gov Identifier: NCT04517253. Baricitinib is a reversible Janus kinase (JAK) 1 inhibitor. The JAK / STAT pathway is a major signaling pathway for cytokines and growth factor receptors, including IFNα / β receptor (IFNAR) and IFNγ receptor (IFNGR). Small molecule inhibitors of JAK, such as baricitinib, reduce type I and type II IFN-induced STAT-1 phosphorylation (pSTAT1) in vitro in patients with CANDLE and SAVI. This suggests their utility in reducing IFN signaling and disease manifestations in patients with CANDLE and SAVI. See also ClinicalTrials.gov Identifier NCT01724580 (Eli Lilly), which is a compassionate use protocol for the treatment of autoinflammatory syndromes with baricitinib.

[0107] Thus, direct STING inhibitors, such as the compounds described herein, can similarly reduce type 1 IFN signaling and be used to treat diseases such as CANDLE, SAVI, and AGS.

[0108] Another example of using STING inhibitors to treat autoinflammatory or autoimmune diseases is a natural plant cyclopeptide called astin C (derived from Aster tataricus), which competitively binds to the same pocket on STING where CDN (cGAMP) docks. Astin C inhibits Trex1. - / - Trex1 in bone marrow-derived MΦs in vitro and with autoimmune diseases - / -Inhibits cGAS-STING signaling and the associated proinflammatory immune response in mice in vivo. See Li et al., The cyclopeptide astin C specifically inhibits the innate immune CDN sensor STING. Cell Rep. 25:3405-3421, e7, 2018.

[0109] In some embodiments, modulation of the immune system by STING provides treatment for diseases, including those caused by foreign agents. Exemplary infectious diseases caused by foreign agents that can be treated and / or prevented by the methods of the present disclosure include bacterial infections (e.g., gram-positive or gram-negative bacteria), fungal infections, parasitic infections, and viral infections. In one embodiment of the present disclosure, the infectious disease is a bacterial infection (e.g., an infection caused by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infectious disease is a fungal infection (e.g., an infection caused by a mold, yeast, or higher fungus). In yet another embodiment, the infection is a parasitic infection (e.g., an infection caused by a unicellular or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz).

[0110] In yet another embodiment, the infectious disease is a viral infection (e.g., infections caused by viruses associated with AIDS, avian influenza, chickenpox, cold sores, the common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS (including SARS-CoV-2, the pathogen that causes COVID-19), and lower or upper respiratory tract infections (e.g., respiratory syncytial virus)).

[0111] A current clinical trial (ClinicalTrials.gov Identifier: NCT04361786) is underway to study peripheral cutaneous thrombotic vasculopathy and COVID-19 infection. The interferon pathway is normally involved in antiviral defense. COVID-19 may therefore cause excessive activation of this pathway, resulting in skin involvement similar to type I interferonopathies. Indeed, a spectrum of skin lesions can occur during COVID-19 viral infection. These include nonspecific urticaria, aphthous lesions, and acrosymptoms, particularly those reminiscent of chilblains. Pathological findings have demonstrated platelet-lymphocytic vasculitis. Chilblains are sometimes associated with Raynaud's phenomenon or acrocyanosis. Skin features may exhibit pathophysiological similarities with inflammatory and respiratory vasculopathy, indicating the full severity of the disease or even involvement of other organs. In fact, genetic conditions such as familial lupus chilblains are linked to mutations in the TREX1 gene, and SAVI (Stigma-associated vasculopathy of infancy) has a similar clinical presentation. In particular, SAVI is associated with both peripheral skin and lung damage and autoantibodies, which have recently been identified as type I interferonopathies. In addition, hyperactivity of the type I interferon pathway leads to modulation of the adaptive immune response. The production of autoantibodies, particularly antiphospholipid antibodies, has thrombogenic properties. Thus, the compounds of the present invention can treat various viral infections, particularly those that cause an IFN response, such as COVID-19.

[0112] In some embodiments, the condition, disease, or disorder is hepatitis B (see, e.g., WO2015 / 061294). In some embodiments, the condition, disease or disorder is selected from cardiovascular disease (including, for example, myocardial infarction).

[0113] In some embodiments, the condition, disease or disorder is age-related macular degeneration. In some embodiments, the condition, disease, or disorder is mucositis, also known as stomatitis, which can result from chemotherapy or radiation therapy, either alone or in combination, as well as damage caused by exposure to radiation outside the context of radiation therapy.

[0114] In some embodiments, the condition, disease, or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., panuveitis).

[0115] In some embodiments, the condition, disease or disorder is selected from the group consisting of cancer, a neurological disorder, an autoimmune disease, hepatitis B, uveitis, cardiovascular disease, age-related macular degeneration, and mucositis.

[0116] In some embodiments, the condition, disease, or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung cancer including adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular carcinoma, gastric cancer or gastric cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, sex cord-stromal tumor, male germinoma, liver cancer, non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplastic disorders, myeloproliferative disorders, chronic myeloid leukemia, and hematological malignancies, including acute hematological malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer, liver cancer, anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, Schwannoma, oligodendroglioma, neuroblastoma, neuroectodermal tissue tumors, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, Wilms' tumor, as well as abnormal vascular proliferation associated with nevus syndrome, edema (e.g., associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.

[0117] In some embodiments, the condition, disease, or disorder is a neurological disorder, including disorders involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (portions located in both the central and peripheral nervous systems). Non-limiting examples of cancer include acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; cognitive impairment; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformations; Asperger's syndrome; ataxia-telangiectasia; attention deficit hyperactivity disorder; autism; autonomic nervous system disorders. Neurological dysfunction; back pain; Batten disease; Behçet's disease; Bell's palsy; benign essential blepharospasm; benign focal muscular atrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal cord tumor; Brown-Séquard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; head disorders; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease ;Chemotherapy-induced neuropathy and neuropathic pain;Chiari malformation;Chorea;Chronic inflammatory demyelinating polyneuropathy;Chronic pain;Chronic regional pain syndrome;Coffin-Lowry syndrome;Coma including persistent disturbance of consciousness;Congenital facial nerve palsy;Corticobasal degeneration;Cranial arteritis;Craniosynostosis;Creutzfeldt-Jakob disease;Cumulative trauma disorder;Cushing's syndrome;Cytomegalic inclusion body disease;Cytomegalovirus infection;Dancing eyes-dancing feet syndrome;Dandy-Walker syndrome;Dawson's disease;Demolition Sie's syndrome; Dejerin-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephalocele; trigeminal region angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; syncope; familial spastic palsy; febrile seizures; Fisher's syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher's disease; Gerstmann's syndrome;Giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barré syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head trauma; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary polyneuropathies; otic varicella; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological signs of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine chain disorders; hydranencephaly; hydrocephalus; hyperadrenocorticism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; breast Refsum's disease; infantile spasms; inflammatory myopathy; intracerebral cysts; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy's disease; Kinsbone syndrome; Klippel-Feil syndrome; Krabbe's disease; Kugelberg-Welander disease; kuru; Lafora's disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; cerebral leukodystrophy; dementia with Lewy bodies; lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuromuscular disorders) -Lon's disease or amyotrophic lateral sclerosis); lumbar discopathy; neurological sequelae of Lyme disease; Machado-Joseph disease; megacephaly; megalencephaly; Melkerson-Rosenthal syndrome; Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller-Fisher syndrome; transient stroke; mitochondrial myopathy; Moebius syndrome; juvenile unilateral upper limb muscular atrophy; motor neuron disease; Moyamoya disease; mucopolysaccharide metabolism disorders; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with dizziness; muscular dystrophy Loffey's syndrome; myasthenia gravis; myelinolytic diffuse sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; congenital myotonia; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological signs of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorder; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; subclinical spinal cord insufficiency; Ohtahara syndrome; olivopontocerebellar degeneration; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease;Congenital paramyotonia; Paraneoplastic disorders; Seizures; Parry-Romberg syndrome; Pelizaeus-Merzbacher disease; Periodic paralysis; Peripheral neuropathy; Painful neuropathy and neuropathic pain; Persistent vegetative state; Pervasive developmental disorder; Photophobic sneeze reflex; Phytanic acid storage disease; Pick's disease; Compressed nerve; Pituitary tumor; Polymyositis; Porencephaly; Post-polio syndrome; Post-herpetic neuralgia; Post-infectious encephalomyelitis; Lightheadedness; Prader-Willi syndrome; Primary lateral sclerosis; Prion Ren's disease; progressive facial hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay Hunt syndrome (types I and II); Rasmussen encephalitis; reflex sympathetic dystrophy syndrome; Refsum's disease; repetitive movement disorder; repetitive stress disorder; restless legs syndrome; retroviral-associated myelopathy; Rett's syndrome; Reye's syndrome; St. Vitus chorea; Sandhoff's disease; Schilder's disease; schizencephaly; septo-optic dystrophy Developmental disorders; Shaken baby syndrome; Herpes zoster; Shy-Drager syndrome; Sjogren's syndrome; Sleep apnea; Sotos syndrome; Spasticity; Spina bifida; Spinal cord injury; Spinal cord tumor; Spinal muscular atrophy; Stiff-person syndrome; Stroke; Sturge-Weber syndrome; Subacute sclerosing panencephalitis; Subcortical arteriosclerotic encephalopathy; Sydenham chorea; Syncope; Syringomyelia; Tardive dyskinesia; Tay-Sachs disease; Temporal arteritis; Tethered spinal cord syndrome; Thomsen's disease; Thoracic outlet syndrome; Trigeminal neuralgia; Todd's palsy; Tourette's syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multiple sclerosis); vasculitis including temporal arteritis; von Hippel-Lindau disease; Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash injury; Williams syndrome; Wilson's disease; amyotrophic lateral sclerosis; and Zellweger syndrome. 6. Kit Another aspect of the present disclosure provides a kit comprising a compound of any one of the formulas described above or a pharmaceutical composition comprising a compound of any one of the formulas described above of the present disclosure. The kit may also include a diagnostic or therapeutic agent in addition to a compound of any one of the formulas described above of the present disclosure or a pharmaceutical composition thereof. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes a compound of any one of the formulas described above or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes a compound of any one of the formulas described above or a pharmaceutical composition thereof.

[0118] In yet another embodiment, the present disclosure comprises a kit suitable for use in carrying out the method of treatment described herein.In one embodiment, the kit contains a first dosage form containing one or more of the compounds of the present disclosure in an amount sufficient to carry out the method of the present disclosure.In another embodiment, the kit comprises one or more compounds of the present disclosure in an amount sufficient to carry out the method of the present disclosure, and a container for the dosage amount. 7. Preparation The compounds of any one of the formulas described above can be prepared by the general and specific methods described below using the common general knowledge of those skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books, such as Comprehensive Organic Chemistry, edited by Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience). The starting materials used herein are commercially available or can also be prepared by conventional methods known in the art.

[0119] It is noted that in the preparation of compounds of any one of the formulas described above, some of the preparative methods described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls in precursors of any one of the formulas described above). The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. The need for such protection will be readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill of the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0120] For example, certain compounds contain primary amine or carboxylic acid functional groups that, if left unprotected, may interfere with reaction elsewhere in the molecule. Therefore, such functional groups can be protected with appropriate protecting groups that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (e.g., Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are generally chemically unreactive under the described reaction conditions and can generally be removed without chemically altering other functional groups in a compound of any one of the formulas described above.

[0121] The schemes described below are intended to provide a general description of the methodology utilized in the preparation of the compounds of the present disclosure. Some of the compounds of the present disclosure may contain single or multiple chiral centers, with the stereochemical designation (R) or (S). It will be apparent to those skilled in the art that all of the synthetic transformations can be carried out in a similar manner whether the materials are enantiomerically enriched or racemic. Furthermore, resolution into the desired optically active materials can be carried out at any desired point in the reaction sequence using well-known methods, such as those described herein and in the chemical literature. [Example]

[0122] General Procedure All reactions were performed under anhydrous conditions using dry solvents under a nitrogen atmosphere unless otherwise specified. Low-resolution mass spectrometry (LC-MS) was used to monitor reaction progress and recorded on a Waters ACQUITY UPLC equipped with an SQ detector, using a Waters CORTEC SC18 column (2.7 μm, 4.6 × 30 mm) and the following gradient elution method: Solvent A: 0.1% formic acid in water; Solvent B: 0.1% formic acid in CH3CN; 5% solvent B to 95% solvent B for 1.0 min, hold for 1.0 min, equilibrate to 5% solvent B in 0.5 min; flow rate: 1.8 mL / min; column temperature: 40 °C. Purification of the final product was performed by preparative HPLC using a Waters Xbridge C18 column (5 μm, 150 × 19 mm) equipped with a QDA detector and a gradient elution method. Abbreviation AcOH acetic acid Ac2O acetic anhydride DCE 1,2-dichloroethane DIBAL-H Diisobutylaluminum hydride DIPEA N-ethyl-N-isopropylpropan-2-amine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphino)ferrocene EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EtOH ethanol EtOAc ethyl acetate HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HOBT 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography Preparative HPLC Preparative High Performance Liquid Chromatography LC-MS Liquid Chromatography-Mass Spectrometry MeOH Methanol MsCl methanesulfonyl chloride NBS N-Bromosuccinimide Pd(dppf)Cl2 Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium PPTS 4-methylbenzenesulfonic acid TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride T3P Propyl phosphonate anhydride Xphos Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene tBuXphos 2-di-t-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl % weight weight percentage rac racemic Acid Intermediates Acid intermediate 1

[0123] [ka]

[0124] Step 1 To a stirred solution of 1-chloro-2-nitro-4-(trifluoromethyl)benzene (28.0 g, 18.2 mL, 124 mmol) in t-BuOH (30.0 mL) was added K0t-Bu (27.9 g, 248 mmol) and diethylpropanedioate (39.8 g, 37.5 mL, 248 mmol) sequentially at 25 °C. The reaction mixture was warmed to 90 °C and stirred at that temperature for 6 h. The reaction mixture was cooled to 25 °C, quenched with water (50 mL), and then extracted with EtOAc (200 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-30% EtOAc) within 20 min to give diethyl 2-[2-nitro-4-(trifluoromethyl)phenyl]propanedioate (28.9 g, 66% yield) as a yellow oil. LC-MS: m / z [M+H] + 350.1. Step 2 To a stirred solution of diethyl 2-[2-nitro-4-(trifluoromethyl)phenyl]propanedioate (28.9 g, 82.8 mmol) in DMSO (100 mL) and water (30.0 mL) was added NaCl (14.5 g, 248 mmol) at 25° C. The reaction mixture was warmed to 120° C. and stirred at that temperature for 16 hours. The reaction mixture was cooled to 0° C., quenched with water (200 mL), and stirred at that temperature for 30 minutes. The precipitate was collected by filtration and dried under vacuum to give ethyl 2-[2-nitro-4(trifluoromethyl)phenyl]acetate (15.0 g, 65% yield) as a yellow solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 278.0. Step 3 To a stirred solution of ethyl 2-[2-nitro-4-(trifluoromethyl)phenyl]acetate (15.0 g, 54.1 mmol) in toluene (50.0 mL) was added Pd / C (5.76 g, 10 wt%, 5.43 mmol) and AcO (27.6 g, 25.6 mL, 271 mmol) sequentially at 25 °C. The reaction mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 16 h, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (containing 0-30% EtOAc) within 20 min to give ethyl 2-[2-acetamido-4-(trifluoromethyl)phenyl]acetate (10.0 g, 64% yield) as a white solid. LC-MS: m / z [M+H] + 290.1. Step 4 To a stirred solution of ethyl 2-[2-acetamido-4-(trifluoromethyl)phenyl]acetate (10.0 g, 34.6 mmol) in acetic acid (30.0 mL) was added tert-butyl nitrite (7.10 g, 8.20 mL, 69.1 mmol) at 25° C. The reaction mixture was warmed to 90° C. and stirred at that temperature for 16 hours. The mixture was cooled to 25° C., poured into ice water (100 mL), and stirred at that temperature for 1 hour. The precipitate was collected by filtration and dried under vacuum to give ethyl 6-(trifluoromethyl)-1H-indazole-3-carboxylate (8.40 g, 94% yield) as a white solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 259.0. Step 5 To a stirred solution of methyl 6-(trifluoromethyl)-1H-indazole-3-carboxylate (200 mg, 0.819 mmol) in CHCN (5.0 mL) was added 2-iodopropane (279 mg, 1.60 mmol) and KCO (679 mg, 4.91 mmol) sequentially at 25 °C. The reaction mixture was stirred at that temperature for 16 h, after which it was quenched with water (10 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0–30% EtOAc) within 20 min to afford ethyl 1-isopropyl-6-(trifluoromethyl)indazole-3-carboxylate (130 mg, 53% yield) as a colorless oil. LC-MS: m / z [M+H] + 301.1. Step 6 To a stirred solution of ethyl 1-isopropyl-6-(trifluoromethyl)indazole-3-carboxylate (130 mg, 0.433 mmol) in THF (3.0 mL) was added aqueous NaOH (2.20 mL, 2.0 M, 4.40 mmol) at 25 °C. The reaction mixture was warmed to 40 °C and stirred at that temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove most of the THF. The mixture was acidified to pH = 3 with aqueous HCl (2.0 M), and then extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 1-isopropyl-6-(trifluoromethyl)indazole-3-carboxylic acid (102 mg, 87% yield) as a white solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 273.1.

[0125] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in Acid Intermediate 1. Their corresponding characterization data are listed in the table below.

[0126] [Table 1]

[0127] Acid intermediate 5

[0128] [ka]

[0129] Step 1 To a stirred solution of 6-bromo-1H-indazole-3-carbaldehyde (503 mg, 2.20 mmol) in THF (8.0 mL) was added CHCl (381 mg, 167 μL, 2.70 mmol) and CsCO (452 ​​mg, 3.27 mmol) sequentially at 25 °C. The mixture was stirred at that temperature for 16 h before it was quenched with water (20 mL) and then extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (containing 1% to 82% EtOAc) within 25 min to give 6-bromo-1-methyl-indazole-3-carbaldehyde (313 mg, 58% yield) as a white solid. LC-MS: m / z [M+H] + 240.0. Step 2 To a stirred solution of 6-bromo-1-methyl-indazole-3-carbaldehyde (313 mg, 1.30 mmol) in CHCN (10.0 mL) was added aqueous KMnO (2.0 mL, 1.1 M, 2.2 mmol) at 25 °C. The mixture was stirred at that temperature for 4 h, then poured into ice-water (40 mL) and filtered through a pad of Celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (40 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (containing 1% to 96% EtOAc) within 20 min to give 6-bromo-1-methyl-indazole-3-carboxylic acid (171 mg, 51% yield) as a white solid. LC-MS: m / z [M+H] + 255.0. Acid intermediate 6

[0130] [ka]

[0131] To a stirred solution of 1-methylindazole-3-carboxylic acid (200 mg, 1.14 mmol) in AcOH (5.0 mL) was added bromine (544 mg, 175 μL, 3.40 mmol) at 0°C. The reaction mixture was stirred at that temperature for 3 h before it was quenched with water (50 mL) and then extracted with EtOAc (40 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (containing 1% to 54% EtOAc) within 30 min to give 5-bromo-1-methyl-indazole-3-carboxylic acid (250 mg, 86% yield) as a white solid. LC-MS: m / z [M+H] + 255.1. Acid intermediate 7

[0132] [ka]

[0133] Step 1 To a stirred solution of 5-(trifluoromethyl)-1H-indole (302 mg, 1.60 mmol) in acetone (10.0 mL) was added aqueous NaNO (1.5 mL, 8.0 M, 12 mmol) and aqueous HCl (1.0 mL, 2.0 M, 2.0 mmol) sequentially at 0 °C. The resulting mixture was warmed to 25 °C and stirred at that temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to afford 5-(trifluoromethyl)-2H-indazole-3-carbaldehyde (328 mg, 96% yield) as a dark oil, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 215.0. Step 2 To a stirred solution of 6-(trifluoromethyl)-1H-indazole-3-carbaldehyde (50.0 mg, 0.233 mmol) in CHCN (1.0 mL) was added aqueous NaHPO (500 μL, 0.7 M, 0.350 mmol) and aqueous NaClO (500 μL, 1.0 M, 0.500 mmol) sequentially at 0 °C. The resulting mixture was warmed to 25 °C and stirred at that temperature for 2 h. The reaction mixture was diluted with water (10 mL), treated with aqueous NaOH (1.0 mL, 2.0 M), and then extracted with EtOAc (20 mL). The aqueous phase was separated, acidified to pH = 3 with aqueous HCl (1.0 M), and then extracted with CHCl (15 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 6-(trifluoromethyl)-1H-indazole-3-carboxylic acid (46.0 mg, 85% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 231.1. Acid intermediate 8

[0134] [ka]

[0135] Step 1 To a stirred solution of methyl 6-bromo-1H-indazole-3-carboxylate (500 mg, 2.00 mmol) in CHCN (10.0 mL) was added 3,4-dihydro-2H-pyran (329 mg, 357 μL, 3.90 mmol) and PPTS (33.8 mg, 0.196 mmol) sequentially at 25° C. The reaction mixture was warmed to 95° C. and stirred at that temperature for 1 h. The reaction mixture was cooled to 25° C., quenched with water (20 mL), and then extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-30% EtOAc) within 20 min to give methyl 6-bromo-1-tetrahydropyran-2-yl-indazole-3-carboxylate (600 mg, 90% yield) as a white solid. LC-MS: m / z [M+Na] + 361.0. Step 2 To a stirred solution of methyl 6-bromo-1-tetrahydropyran-2-yl-indazole-3-carboxylate (120 mg, 0.354 mmol) in 1,4-dioxane (4.0 mL), morpholine (46.2 mg, 46.2 μL, 0.531 mmol), NaOt-Bu (102 mg, 1.10 mmol), Xphos (33.7 mg, 0.0708 mmol), and Pd(dba) (32.4 mg, 0.0354 mmol) were added sequentially at 25 °C. The reaction mixture was warmed to 110 °C and stirred at that temperature for 3 h. The reaction mixture was cooled to 25 °C, treated with water (20 mL), and then washed with EtOAc (10 mL × 2). The aqueous layer was separated, acidified to pH = 3 with aqueous HCl (1.0 M), and then extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 6-morpholino-1-tetrahydropyran-2-yl-indazole-3-carboxylic acid (60.0 mg, 51% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 332.1. Acid intermediate 9

[0136] [ka]

[0137] Step 1 To a stirred solution of methyl 6-bromo-2H-indazole-3-carboxylate (300 mg, 1.20 mmol) in 1,4-dioxane (8.0 mL) and water (2.0 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (344 mg, 1.60 mmol), Pd(dppf)Cl (125 mg, 0.170 mmol), and KPO (1.60 g, 7.41 mmol) were added sequentially at 25 °C. The reaction mixture was warmed to 100 °C and stirred at that temperature for 2 hours. The reaction mixture was cooled to 25 °C, poured into water (20 mL), and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-20% EtOAc) within 25 min to give methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate (124 mg, 41% yield) as a white solid. LC-MS: m / z [M+H] + 259.1. Step 2 To a stirred solution of methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate (44.0 mg, 0.170 mmol) in MeOH (25.0 mL) was added Pd / C (9.0 mg, 10 wt%, 0.0085 mmol) at 25° C. The reaction mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 12 hours. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to yield methyl 6-tetrahydropyran-4-yl-1H-indazole-3-carboxylate (48.0 mg) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 261.1. Step 3 To a stirred solution of methyl 6-tetrahydropyran-4-yl-1H-indazole-3-carboxylate (48.0 mg, 0.184 mmol) in 1,4-dioxane (2.0 mL) was added aqueous NaOH (2.0 mL, 0.9 M, 1.8 mmol) at 25° C. The reaction mixture was warmed to 100° C. and stirred at that temperature for 4 hours. The reaction mixture was cooled to 25° C., diluted with water (15 mL), and extracted with EtOAc (10 mL). The aqueous phase was separated, acidified to pH = 3 with aqueous HCl (1.0 M), and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to produce 6-tetrahydropyran-4-yl-1H-indazole-3-carboxylic acid (31.0 mg, 68% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 247.1.

[0138] Additional intermediates of the present disclosure were prepared from corresponding materials using similar procedures as disclosed in Acid Intermediate 9. Their corresponding characterization data are listed in the table below.

[0139] [Table 2]

[0140] Acid intermediate 11

[0141] [ka]

[0142] Step 1 To a stirred solution of methyl 6-bromo-1H-indazole-3-carboxylate (150 mg, 0.588 mmol) in THF (10.0 mL) was added EtN (146 mg, 200 μL, 1.44 mmol), CuI (11.2 mg, 0.0588 mmol), Pd(PPh)Cl (41.3 mg, 0.0588 mmol), and ethynyl(trimethyl)silane (86.6 mg, 124 μL, 0.882 mmol) sequentially at 25 °C. The reaction mixture was warmed to 90 °C and stirred at that temperature for 16 h. The reaction mixture was cooled to 25 °C and filtered through a pad of Celite. The filtrate was quenched with water (100 mL) and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (containing 1% to 56% EtOAc) within 20 min to give methyl 6-(2-trimethylsilylethynyl)-1H-indazole-3-carboxylate (150 mg, 94% yield) as a brown solid. LC-MS: m / z [M+H] + 273.1. Step 2 To a stirred solution of methyl 6-(2-trimethylsilylethynyl)-1H-indazole-3-carboxylate (50.0 mg, 0.184 mmol) in THF (2.0 mL) was added aqueous NaOH (0.5 mL, 1.0 M, 0.5 mmol) at 25 °C. The reaction mixture was warmed to 50 °C and stirred at that temperature for 16 h. The reaction mixture was cooled to 25 °C, diluted with EtOAc (10 mL), and then extracted with water (10 mL × 2). The combined aqueous phase was acidified to pH = 3 with aqueous HCl (1.0 M) and extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 6-ethynyl-1H-indazole-3-carboxylic acid (34.0 mg, 99% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 187.1. Acid intermediate 12

[0143] [ka]

[0144] Step 1 To a stirred solution of 2,4-difluorobenzaldehyde (2.00 g, 14.1 mmol) and pyridin-4-ol (1.47 g, 15.4 mmol) in DMSO (10.0 mL) was added K2CO3 (5.84 g, 42.2 mmol) at 25 °C. The reaction mixture was stirred at that temperature for 16 h. The mixture was quenched with water (50 mL) and then extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (containing 1% to 75% EtOAc) within 25 min to give 2-fluoro-4-(4-pyridyloxy)benzaldehyde (1.00 g, 33% yield) as a brown solid. LC-MS: m / z [M+H] + 218.1. Step 2 To a stirred solution of 2-fluoro-4-(4-pyridyloxy)benzaldehyde (1.00 g, 4.60 mmol) in 1,4-dioxane (15.0 mL) was added hydrazine hydrate (690 mg, 670 μL, 78 wt%, 10.8 mmol) at 25°C. The reaction mixture was warmed to 115°C and stirred at that temperature for 48 h. The reaction mixture was cooled to 25°C, quenched with water (100 mL), and then extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1% to 95% EtOAc) within 20 min to give 6-(4-pyridyloxy)-1H-indazole (260 mg, 27% yield) as a brown solid. LC-MS: m / z [M+H] + 212.0. Step 3 To a stirred solution of 6-(4-pyridyloxy)-1H-indazole (250 mg, 1.18 mmol) in DMF (5.0 mL) was added I2 (449 mg, 1.77 mmol) and KOH (265 mg, 4.72 mmol) sequentially at 25 °C. The reaction mixture was stirred at that temperature for 2 h. The mixture was quenched with saturated aqueous Na2SO3 (20 mL) and extracted with EtOAc (40 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / CHCl2 (containing 1% to 10% MeOH) within 20 min to give 3-iodo-6-(4-pyridyloxy)-1H-indazole (180 mg, 45% yield) as a white solid. LC-MS: m / z [M+H] + 338.9. Step 4 To a stirred solution of 3-iodo-6-(4-pyridyloxy)-1H-indazole (180 mg, 0.533 mmol) in toluene (2.0 mL) and MeOH (2.0 mL) was added Pd(dppf)Cl (39.1 mg, 0.053 mmol), dppf (29.6 mg, 0.053 mmol), and EtN (162 mg, 222 μL, 1.60 mmol) at 25° C. The reaction mixture was warmed to 75° C. and stirred at that temperature for 14 h under a CO atmosphere (balloon). The reaction mixture was cooled to 25° C., quenched with water (100 mL), and then extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (containing 1% to 86% EtOAc) within 20 min to give methyl 6-(4-pyridyloxy)-1H-indazole-3-carboxylate (120 mg, 83% yield) as an off-white solid. LC-MS: m / z [M+H] + 270.1. Step 5 To a stirred solution of methyl 6-(4-pyridyloxy)-1H-indazole-3-carboxylate (120 mg, 0.445 mmol) in THF (2.0 mL), MeOH (2.0 mL), and water (1.0 mL) was added LiOH·HO (56.1 mg, 1.34 mmol) at 25 °C. The reaction mixture was stirred at that temperature for 16 h. The mixture was acidified to pH = 5 with aqueous HCl (1.0 M) and then extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 6-(4-pyridyloxy)-1H-indazole-3-carboxylic acid (100 mg, 88% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 256.0. Acid intermediate 13

[0145] [ka]

[0146] Step 1 To a stirred solution of 6-bromo-5-fluoro-1H-indole (2.00 g, 9.34 mmol) in DMF (15.0 mL) was added TFAA (5.89 g, 3.95 mL, 28.0 mmol) at 0° C. The reaction mixture was warmed to 25° C. and stirred at that temperature for 12 hours. The reaction mixture was poured into ice water (200 mL) and the precipitate was collected by filtration to yield 1-(6-bromo-5-fluoro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (2.89 g, 99% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 310.0. Step 2 To a stirred solution of 1-(6-bromo-5-fluoro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (2.60 g, 8.39 mmol) in EtOH (20.0 mL) and water (20.0 mL) was added KOH (2.35 g, 41.9 mmol) at 25 °C. The reaction mixture was warmed to 100 °C and stirred at that temperature for 16 hours. The mixture was cooled to 25 °C, diluted with water (50 mL), and extracted with EtOAc (50 mL × 2). The aqueous phase was separated, acidified to pH = 3 with aqueous HCl (1.0 M), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to produce 6-bromo-5-fluoro-1H-indole-3-carboxylic acid (1.60 g, 74% yield) as a gray solid. This was used directly in the next step without further purification. LC-MS: m / z [M+H] + 258.1. Acid intermediate 14

[0147] [ka]

[0148] Step 1 To a stirred solution of 6-(trifluoromethyl)-1H-indole (500 mg, 2.70 mmol) in DMF (3.0 mL) was added POCl (828 mg, 503 μL, 5.40 mmol) at 0 °C. The reaction mixture was stirred at that temperature for 1 h before it was quenched with water (10 mL) and then extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-50% EtOAc) within 20 min to give 6-(trifluoromethyl)-1H-indole-3-carbaldehyde (141 mg, 24% yield) as a white solid. LC-MS: m / z [M+H] + 214.0. Step 2 To a stirred solution of 6-(trifluoromethyl)-1H-indole-3-carbaldehyde (141 mg, 0.662 mmol) in CHCN (5.0 mL) was added aqueous KMnO (1.2 mL, 1.0 M, 1.2 mmol) at 25 °C. The mixture was stirred at that temperature for 16 h, and then it was diluted with water (10 mL). The mixture was filtered through a pad of Celite and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by pre-TLC (MeOH / CHCl = 1:10) to give 6-(trifluoromethyl)-1H-indole-3-carboxylic acid (70.0 mg, 46% yield) as a white solid. LC-MS: m / z [M+H] + 230.0. Acid intermediate 15

[0149] [ka]

[0150] Step 1 To a stirred solution of tert-butyl 6-fluoro-2H-pyrazolo[3,4-b]pyridine-3-carboxylate (550 mg, 2.32 mmol) in THF (10.0 mL) was added sodium hydride (266 mg, 60 wt%, 6.96 mmol) and 2,2,2-trifluoroethanol (695 mg, 500 μL, 6.95 mmol) sequentially at 0° C. The reaction mixture was stirred at that temperature for 10 minutes, then warmed to 70° C. and stirred at that temperature for 8 hours. The reaction mixture was cooled to 25° C., quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-50% EtOAc) within 25 min to give tert-butyl 6-(2,2,2-trifluoroethoxy)-2H-pyrazolo[3,4-b]pyridine-3-carboxylate (300 mg, 41% yield) as a yellow oil. LC-MS: m / z [M+H] +318.1. Step 2 To a stirred solution of tert-butyl 6-(2,2,2-trifluoroethoxy)-2H-pyrazolo[3,4-b]pyridine-3-carboxylate (180 mg, 0.567 mmol) in CHCl (5.0 mL) was added TFA (323 mg, 210 μL, 2.84 mmol) at 25° C. The reaction mixture was stirred at that temperature for 16 h, and then it was concentrated under reduced pressure to give 6-(2,2,2-trifluoroethoxy)-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (130 mg, 88% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 262.1. Acid intermediate 16

[0151] [ka]

[0152] Step 1 To a stirred solution of 6-(trifluoromethyl)-1H-indole (3.00 g, 16.2 mmol) in DMF (20.0 mL) was added TFAA (3.91 g, 2.33 mL, 18.6 mmol) at 0° C. The resulting mixture was stirred at that temperature for 1 hour and then poured into ice water (100 mL). The precipitate was collected by filtration and dried under vacuum to give 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (4.40 g, 96% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 282.0. Step 2 To a stirred solution of 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (4.00 g, 14.2 mmol) in DMF (20.0 mL) was added KCO (5.90 g, 42.6 mmol) and CHI (4.10 g, 1.80 mL, 28.9 mmol) sequentially at 25 °C. The reaction mixture was warmed to 40 °C and stirred at that temperature for 3 h. The reaction mixture was cooled to 25 °C, quenched with water (30 mL), and then extracted with EtOAc (100 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-30% EtOAc) within 20 min to give 2,2,2-trifluoro-1-[1-methyl-6-(trifluoromethyl)indol-3-yl]ethanone (3.40 g, 80% yield) as an off-white solid. LC-MS: m / z [M+H] + 296.0. Step 3 To a stirred solution of 2,2,2-trifluoro-1-[1-methyl-6-(trifluoromethyl)indol-3-yl]ethanone (3.40 g, 11.5 mmol) in MeOH (60.0 mL) was added aqueous NaOH (6.0 mL, 3.0 M, 18 mmol) at 25° C. The reaction mixture was warmed to 105° C. and stirred at that temperature for 10 hours. The reaction mixture was cooled to 25° C. and extracted with EtOAc (100 mL). The aqueous phase was separated and acidified to pH=4 with aqueous HCl (1.0 M), then extracted with EtOAc (200 mL×2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-58% EtOAc) within 40 min to give 1-methyl-6-(trifluoromethyl)indole-3-carboxylic acid (2.50 g, 89% yield) as a white solid. LC-MS: m / z [M+Na] + 266.0.

[0153] Additional intermediates of the present disclosure were prepared from corresponding materials using similar procedures as disclosed in Acid Intermediate 16. Their corresponding characterization data are listed in the table below.

[0154] [Table 3]

[0155] Acid intermediate 20

[0156] [ka]

[0157] Step 1 To a stirred solution of (3R)-tetrahydrofuran-3-ol (88.0 mg, 0.998 mmol) in CHCl (5.0 mL) was added EtN (303 mg, 416 μL, 3.00 mmol) and MsCl (171 mg, 1.50 mmol) sequentially at 0 °C. The reaction mixture was warmed to 25 °C and stirred at that temperature for 16 h. The reaction mixture was quenched with water (10 mL) and then extracted with CHCl (20 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was dried in vacuo to yield [(3R)-tetrahydrofuran-3-yl]methanesulfonate (140 mg, 84% yield) as a yellow oil, which was used directly in the next step without further purification. Step 2 To a Schlenk pressure tube, 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (150 mg, 0.533 mmol), [(3R)-tetrahydrofuran-3-yl]methanesulfonate (133 mg, 0.800 mmol), K2CO3 (221 mg, 1.60 mmol), and DMF (4.0 mL) were added sequentially at 25 °C. The mixture was sealed, warmed to 100 °C, and stirred at that temperature for 16 hours. The mixture was cooled to 25 °C and poured into water (50 mL). The precipitate was collected by filtration to give 2,2,2-trifluoro-1-[1-[(3S)-tetrahydrofuran-3-yl]-6-(trifluoromethyl)indol-3-yl]ethanone (120 mg, 64% yield) as a light brown solid. This was used directly in the next step without further purification. LC-MS: m / z [M+H] + 351.1. Step 3 To a stirred solution of 2,2,2-trifluoro-1-[1-[(3S)-tetrahydrofuran-3-yl]-6-(trifluoromethyl)indol-3-yl]ethanone (120 mg, 0.341 mmol) in MeOH (6.0 mL) was added aqueous NaOH (5.2 mL, 1.0 M, 5.2 mmol) at 25° C. The reaction mixture was warmed to 100° C. and stirred at that temperature for 2 hours. The reaction mixture was cooled to 25° C. and extracted with EtOAc (10 mL). The aqueous phase was separated and acidified to pH=3 with aqueous HCl (1.0 M). The precipitate was collected by filtration to yield 1-[(3S)-tetrahydrofuran-3-yl]-6-(trifluoromethyl)indole-3-carboxylic acid (85.0 mg, 83% yield) as a light brown solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 300.1.

[0158] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in acid intermediate 20. Their corresponding characterization data are listed in the table below.

[0159] [Table 4]

[0160] Acid intermediate 22

[0161] [ka]

[0162] Step 1 To a stirred solution of methyl 5-fluoro-1H-indole-6-carboxylate (800 mg, 4.14 mmol) in DMF (5.0 mL) was added POCl (2.22 g, 1.35 mL, 14.5 mmol) at 0 °C. The reaction mixture was stirred at that temperature for 1 hour, and then it was poured into saturated aqueous NaHCO (30 mL) and stirred at 25 °C for 5 hours. The precipitate was collected by filtration and dried in vacuo to give methyl 5-fluoro-3-formyl-1H-indole-6-carboxylate (830 mg, 91% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 222.1. Step 2 In a Schlenk pressure tube, 5-fluoro-3-formyl-1H-indole-6-carboxylate (250 mg, 1.13 mmol), CHI (240 mg, 105 μL, 1.70 mmol), CsCO (1.10 g, 3.39 mmol), and DMF (3.0 mL) were added sequentially at 25 °C. The mixture was sealed, warmed to 85 °C, and stirred at that temperature for 16 hours. The mixture was cooled to 25 °C and poured into ice water (50 mL). The precipitate was collected by filtration and dried in vacuo to yield 6-bromo-5-fluoro-1-methyl-indole-3-carbaldehyde (530 mg, 99% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 236.1. Step 3 To a stirred solution of methyl 5-fluoro-3-formyl-1-methyl-indole-6-carboxylate (250 mg, 1.06 mmol) in THF (10.0 mL) and t-BuOH (4.0 mL) was added 2-methylbut-2-ene (745 mg, 892 μL, 10.6 mmol) and a solution of NaClO (481 mg, 5.31 mmol) and NaHPO (382 mg, 3.19 mmol) in water (4.0 mL) at 0 °C. The resulting mixture was warmed to 25 °C and stirred at that temperature for 16 h. The mixture was diluted with water (50 mL) and then extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / CH2Cl2 (containing 0–10% MeOH) within 20 min to give 5-fluoro-6-methoxycarbonyl-1-methyl-indole-3-carboxylic acid (240 mg, 90% yield) as a yellow solid. LC-MS: m / z [M+H] + 252.1.

[0163] Additional intermediates of the present disclosure were prepared from corresponding materials using similar procedures as disclosed in acid intermediate 22. Their corresponding characterization data are listed in the table below.

[0164] [Table 5]

[0165] Acid intermediate 26

[0166] [ka]

[0167] Step 1 To a stirred solution of 6-(trifluoromethyl)-1H-indole (2.00 g, 10.8 mmol) in DMF (15.0 mL) was added TFAA (2.61 g, 1.80 mL, 12.4 mmol) at 0 °C. The reaction mixture was warmed to 25 °C and stirred at that temperature for 12 hours. The reaction mixture was poured into ice water (200 mL). The precipitate was collected by filtration and dried under vacuum to produce 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (2.53 g, 83% yield) as a pale yellow solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 282.0. Step 2 To a stirred solution of 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (1.00 g, 3.56 mmol) in DCE (25.0 mL) was added cyclopropylboronic acid (916 mg, 10.7 mmol), 2,2'-bipyridine (611 mg, 3.91 mmol), Cu(OAc) (711 mg, 3.91 mmol), and NaCO (1.13 g, 10.7 mmol) sequentially at 25 °C. The resulting mixture was warmed to 95 °C and stirred at that temperature under air (balloon) for 6 h. The mixture was cooled to 25 °C, quenched with water (80 mL), and extracted with CHCl (50 mL × 2). The combined organic phase was washed with brine (80 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-50% EtOAc) within 25 min to give 1-[1-cyclopropyl-6-(trifluoromethyl)indol-3-yl]-2,2,2-trifluoroethanone (504 mg, 44% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 322.0. Step 3 To a stirred solution of 1-[1-cyclopropyl-6-(trifluoromethyl)indol-3-yl]-2,2,2-trifluoro-ethanone (494 mg, 1.54 mmol) in MeOH (5.0 mL) and water (5.0 mL) was added NaOH (308 mg, 7.69 mmol) at 25° C. The resulting mixture was warmed to 100° C. and stirred at that temperature for 4 hours. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with diethyl ether (40 mL×2). The aqueous layer was separated and acidified to pH=6 with aqueous HCl (1.0 M), then extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 1-cyclopropyl-6-(trifluoromethyl)indole-3-carboxylic acid (349 mg, 84% yield) as a white solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 270.0. Acid intermediates 27 and 28

[0168] [ka]

[0169] Step 1 To a stirred solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (150 mg, 0.712 mmol) in DMF (6.0 mL) was added NaH (113 mg, 60 wt%, 2.85 mmol) at 0 °C. The mixture was stirred at that temperature for 10 minutes, and then CHCl (303 mg, 133 μL, 2.14 mmol) was added. The mixture was stirred at 0 °C for 1 hour, after which it was quenched with water (20 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0% to 50% EtOAc) within 25 min to give methyl 6-chloro-1-methyl-pyrrolo[2,3-b]pyridine-3-carboxylate (157 mg, 98% yield) as a white solid. LC-MS: m / z [M+H] + 225.0. Step 2 To a stirred solution of methyl 6-chloro-1-methyl-pyrrolo[2,3-b]pyridine-3-carboxylate (147 mg, 0.654 mmol) in 1,4-dioxane (3.0 mL) was added 2,2,2-trifluoroethanol (196 mg, 141 μL, 1.96 mmol), Pd(dba) (119 mg, 0.130 mmol), Xantphos (151 mg, 0.261 mmol), and CsCO (852 mg, 2.62 mmol) sequentially at 25 °C. The resulting mixture was warmed to 110 °C and stirred at that temperature for 6 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-35% EtOAc) within 25 min to give methyl 1-methyl-6-(2,2,2-trifluoroethoxy)pyrrolo[2,3-b]pyridine-3-carboxylate (115 mg, 61% yield) as a yellow solid. LC-MS: m / z [M+H] + 289.0. Step 3 To a stirred solution of methyl 1-methyl-6-(2,2,2-trifluoroethoxy)pyrrolo[2,3-b]pyridine-3-carboxylate (115 mg, 0.399 mmol) in EtOH (10.0 mL) was added aqueous NaOH (5.0 mL, 1.2 M, 6.0 mmol) at 25 °C. The resulting mixture was warmed to 100 °C and stirred at that temperature for 5 h. The mixture was cooled to 25 °C, diluted with water (50 mL), and extracted with diethyl ether (50 mL × 2). The aqueous phase was separated, acidified to pH = 6 with aqueous HCl (1.0 M), and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 1-methyl-6-(2,2,2-trifluoroethoxy)pyrrolo[2,3-b]pyridine-3-carboxylic acid (103 mg, 94% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 275.0. Step 4 To a stirred solution of methyl 6-chloro-1-methyl-pyrrolo[2,3-b]pyridine-3-carboxylate (188 mg, 0.837 mmol) in THF (8.0 mL) was added aqueous LiOH (2.0 mL, 6.0 M, 12 mmol) at 25 °C. The mixture was stirred at that temperature for 72 h, after which it was diluted with water (50 mL) and extracted with diethyl ether (50 mL × 2). The aqueous phase was separated and acidified to pH = 6 with aqueous HCl (1.0 M), then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to produce 6-chloro-1-methyl-pyrrolo[2,3-b]pyridine-3-carboxylic acid (175 mg, 99% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H]+ 211.0. Acid intermediate 29

[0170] [ka]

[0171] Step 1 To a stirred solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.50 g, 7.12 mmol) in DCE (25.0 mL) was added cyclopropylboronic acid (1.84 g, 21.4 mmol), 2,2'-bipyridine (1.33 g, 8.55 mmol), Cu(OAc) (1.55 g, 8.55 mmol), and NaCO (2.26 g, 21.4 mmol) sequentially at 25 °C. The reaction mixture was warmed to 95 °C and stirred at that temperature under air (balloon) for 8 h. The mixture was cooled to 25 °C, diluted with CHCl (100 mL), and then washed sequentially with water (80 mL) and brine (80 mL). The organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc / petroleum ether (0-40% EtOAc) within 20 min to give methyl 6-chloro-1-cyclopropyl-pyrrolo[2,3-b]pyridine-3-carboxylate (1.06 g, 60% yield) as a white solid. LC-MS: m / z [M+H] + 251.0. Step 2 To a stirred solution of methyl 6-chloro-1-cyclopropyl-pyrrolo[2,3-b]pyridine-3-carboxylate (150 mg, 0.598 mmol) in 1,4-dioxane (4.0 mL) was added 2,2,2-trifluoroethanol (180 mg, 129 μL, 1.80 mmol), Pd(dba) (110 mg, 0.120 mmol), Xantphos (138 mg, 0.239 mmol), and CsCO (780 mg, 2.39 mmol) sequentially at 25 °C. The reaction mixture was warmed to 110 °C and stirred at that temperature for 6 h. The reaction mixture was cooled to 25 °C, diluted with CHCl (100 mL), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc / petroleum ether (0-30% EtOAc) within 20 min to give methyl 1-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyrrolo[2,3-b]pyridine-3-carboxylate (156 mg, 83% yield) as a yellow solid. LC-MS: m / z [M+H]+ 315.0. Step 3 To a stirred solution of methyl 1-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyrrolo[2,3-b]pyridine-3-carboxylate (156 mg, 0.496 mmol) in MeOH (10.0 mL) was added aqueous NaOH (5.0 mL, 0.6 M, 3.0 mmol) at 25 °C. The resulting mixture was warmed to 100 °C and stirred at that temperature for 5 h. The mixture was cooled to 25 °C, diluted with water (50 mL), and extracted with diethyl ether (50 mL × 2). The aqueous phase was separated, acidified to pH = 6 with aqueous HCl (1.0 M), and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 1-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyrrolo[2,3-b]pyridine-3-carboxylic acid (106 mg, 71% yield) as a pale yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 301.1.

[0172] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in acid intermediate 29. Their corresponding characterization data are listed in the table below.

[0173] [Table 6]

[0174] Acid intermediate 33

[0175] [ka]

[0176] Step 1 To a stirred solution of 6-bromo-1H-indole-3-carboxylic acid (3.00 g, 12.5 mmol) in DMF (20.0 mL) was added NaH (1.50 g, 60 wt%, 37.5 mmol) in small batches at 0 °C. The resulting mixture was stirred at that temperature for 30 min, and then CHCl (5.32 g, 2.33 mL, 37.4 mmol) was added. The resulting mixture was warmed to 25 °C and stirred at that temperature for 16 h. The reaction was poured into ice water (150 mL) and stirred for 30 min. The precipitate was collected by filtration and dried under vacuum to give methyl 6-bromo-1-methyl-indole-3-carboxylate (2.95 g, 88% yield) as a gray solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 267.1. Step 2 To a stirred solution of methyl 6-bromo-1-methyl-indole-3-carboxylate (1.30 g, 4.85 mmol) in 1,4-dioxane (20.0 mL) and water (8.0 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.32 g, 6.30 mmol), Pd(dppf)Cl (354 mg, 0.484 mmol), and KPO (3.09 g, 14.5 mmol) were added sequentially at 25 °C. The mixture was warmed to 100 °C and stirred at that temperature for 50 minutes. The reaction mixture was cooled to 25 °C, diluted with water (25 mL), and extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-65% EtOAc) within 25 min to give methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-indole-3-carboxylate (1.10 g, 83% yield) as a brown solid. LC-MS: m / z [M+H] + 272.1. Step 3 To a stirred solution of methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-indole-3-carboxylate (600 mg, 2.21 mmol) in 1,4-dioxane (6.0 mL) was added aqueous NaOH (3.0 mL, 3.5 M, 10.5 mmol) at 25 °C. The resulting mixture was warmed to 90 °C and stirred at that temperature for 3 hours. The mixture was cooled to 25 °C, acidified to pH = 5 with aqueous HCl (1.0 M), and then extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give 6-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-indole-3-carboxylic acid (500 mg, 87% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 258.1. Step 4 To a suspension of 6-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-indole-3-carboxylic acid (75.0 mg, 0.291 mmol) in THF (5.0 mL) and MeOH (5.0 mL) was added Pd / C (31.0 mg, 10 wt%, 0.0292 mmol) at 25° C. The resulting mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 1 hour, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give 1-methyl-6-tetrahydropyran-4-yl-indole-3-carboxylic acid (70.0 mg, 93% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 260.1.

[0177] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in acid intermediate 33. Their corresponding characterization data are listed in the table below.

[0178] [Table 7]

[0179] Acid intermediate 36

[0180] [ka]

[0181] Step 1 To a stirred solution of 6-bromo-5-fluoro-1H-indole (1.00 g, 4.67 mmol) in DMF (6.0 mL) was added POCl (2.51 g, 1.52 mL, 16.4 mmol) at 0 °C. The resulting mixture was stirred at that temperature for 2 h before it was treated with aqueous NaOH (2.0 M, 10.0 mL). The mixture was warmed to 25 °C and stirred at that temperature for 1 h. The precipitate was collected by filtration to give 6-bromo-5-fluoro-1H-indole-3-carbaldehyde (1.13 g, 100% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 241.9. Step 2 Into a Schlenk pressure tube, 6-bromo-5-fluoro-1H-indole-3-carbaldehyde (505 mg, 2.09 mmol), CHI (444 mg, 195 μL, 3.13 mmol), CsCO (2.04 g, 6.26 mmol), and DMF (12.0 mL) were added sequentially at 25 °C. The mixture was sealed, warmed to 85 °C, and stirred at that temperature for 12 hours. The mixture was cooled to 25 °C and poured into ice water (50 mL). The precipitate was collected by filtration to yield 6-bromo-5-fluoro-1-methyl-indole-3-carbaldehyde (530 mg, 99% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 255.9. Step 3 To a stirred solution of 6-bromo-5-fluoro-1-methyl-indole-3-carbaldehyde (330 mg, 1.29 mmol) in 1,4-dioxane (6.0 mL) was added (3S)-3-methylmorpholine (391 mg, 3.87 mmol), Pd(dba) (236 mg, 0.258 mmol), tBuXphos (219 mg, 0.515 mmol), and CsCO (1.26 g, 3.87 mmol) sequentially at 25 °C. The reaction mixture was warmed to 110 °C and stirred at that temperature for 12 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc / petroleum ether (0-70% EtOAc) within 25 min to give 5-fluoro-1-methyl-6-[(3S)-3-methylmorpholin-4-yl]indole-3-carbaldehyde (82.0 mg, 23% yield) as a yellow solid. LC-MS: m / z [M+H] + 277.1. Step 4 To a stirred solution of 5-fluoro-1-methyl-6-[(3S)-3-methylmorpholin-4-yl]indole-3-carbaldehyde (82.0 mg, 0.297 mmol) in THF (5.0 mL) and t-BuOH (1.5 mL) was added 2-methylbut-2-ene (208 mg, 250 μL, 2.97 mmol) and a solution of NaClO (134 mg, 1.48 mmol) and NaHPO (107 mg, 0.890 mmol) in water (1.5 mL) sequentially at 25 °C. The reaction mixture was stirred at that temperature for 48 h before being quenched with saturated aqueous NaHSO (10 mL). The mixture was concentrated under reduced pressure to remove most of the solvent, diluted with EtOAc (50 mL), and washed with brine (50 mL). The organic layer was separated, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc / petroleum ether (0-70% EtOAc) within 25 min to give 5-fluoro-1-methyl-6-[(3S)-3-methylmorpholin-4-yl]indole-3-carboxylic acid (60.0 mg, 69% yield) as a yellow solid. LC-MS: m / z [M+H] + 293.1.

[0182] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in acid intermediate 36. Their corresponding characterization data are listed in the table below.

[0183] [Table 8]

[0184] Acid intermediate 38

[0185] [ka]

[0186] Step 1 To a stirred solution of 3-(trifluoromethyl)pyridine (3.00 g, 20.4 mmol) in CHCN (15.0 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (4.90 g, 24.8 mmol) at 25° C. The resulting mixture was warmed to 40° C. and stirred at that temperature for 15 hours. The mixture was cooled and concentrated to yield 3-(trifluoromethyl)pyridin-1-ium-1-amine (8.00 g) as a white solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 163.1. Step 2 To a stirred suspension of 3-(trifluoromethyl)pyridin-1-ium-1-amine (8.00 g, 49.0 mmol) in DMF (35.0 mL) was added methyl propiolate (1.80 g, 1.90 mL, 20.8 mmol) and K2CO3 (10.1 g, 73.0 mmol) sequentially at 25 °C. The resulting mixture was stirred at that temperature for 2 h before it was quenched with HO (100 mL) and then extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc / petroleum ether (containing 0–30% EtOAc) within 20 min to afford methyl 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (423 mg, 8% yield) as a yellow solid. LC-MS: m / z [M+H] + 245.1. Step 3 To a stirred solution of methyl 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (310 mg, 1.30 mol) in THF (5.0 mL) was added aqueous LiOH (2.0 mL, 9.5 M, 19 mmol) at 25 °C. The resulting mixture was stirred at that temperature for 72 h, after which it was diluted with water (50 mL) and extracted with diethyl ether (50 mL × 2). The aqueous phase was separated and acidified to pH = 6 with aqueous HCl (1.0 M) and then extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to yield 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (290 mg, 99% yield) as a yellow solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 231.1. Acid intermediate 39

[0187] [ka]

[0188] Step 1 To a stirred solution of 6-bromo-5-fluoro-1H-indole (5.00 g, 23.4 mmol) in DMF (25.0 mL) was added NaH (1.32 g, 60 wt%, 30.4 mmol) at 0 °C. The mixture was stirred at that temperature for 10 minutes, and then iodomethane (3.65 g, 25.7 mmol, 1.60 mL) was added. The mixture was stirred at 0 °C for 2 hours, after which it was quenched with water (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with EtOAc / petroleum ether (v / v = 2:1, 20 mL) for 2 hours and filtered to produce 6-bromo-5-fluoro-1-methyl-indole (4.80 g, 90% yield) as a brown solid. LC-MS: m / z [M+H] + 227.0. Step 2 To a stirred solution of 6-bromo-5-fluoro-1-methyl-indole (2.20 g, 9.65 mmol) in DMA (25.0 mL) was added KFe(CN) (2.04 g, 4.82 mmol), Pd(dppf)Cl CHCl (197 mg, 0.241 mmol), and NaCO (1.12 g, 10.6 mmol) sequentially at 25 °C. The resulting mixture was warmed to 120 °C and stirred at that temperature for 2 h. The reaction mixture was cooled to 25 °C and filtered through a pad of Celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-50% EtOAc) within 25 min to give 5-fluoro-1-methyl-indole-6-carbonitrile (1.20 g, 71% yield) as a brown solid. LC-MS: m / z [M+H] + 175.1. Step 3 A solution of phosphoryl trichloride (1.10 g, 7.20 mmol) in DMF (5.0 mL) was stirred at 0 °C for 30 minutes, and then a solution of 5-fluoro-1-methyl-indole-6-carbonitrile (1.14 g, 6.55 mmol) in DMF (15.0 mL) was added. The reaction mixture was warmed to 25 °C and stirred at that temperature for 1 hour, after which it was poured into saturated aqueous NaHCO (20 mL) and stirred at that temperature for 2 hours. The precipitate was collected by filtration and dried in vacuo to give 5-fluoro-3-formyl-1-methyl-indole-6-carbonitrile (1.00 g, 76% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 203.1. Step 4 To a stirred suspension of 5-fluoro-3-formyl-1H-indole-6-carbonitrile (2.50 g, 13.3 mmol) in THF (40.0 mL) and t-BuOH (10.0 mL) was added 2-methylbut-2-ene (7.45 g, 106 mmol, 11.3 mL) and a solution of NaClO (4.81 g, 53.2 mmol) and NaHPO (8.29 g, 53.2 mmol) in water (40.0 mL) sequentially at 0 °C. The resulting mixture was warmed to 25 °C and stirred at that temperature for 48 h. The mixture was diluted with water (50 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 6-cyano-5-fluoro-1H-indole-3-carboxylic acid (2.00 g, 74% yield) as a yellow solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 219.1. Acid intermediate 40

[0189] [ka]

[0190] Step 1 To a stirred solution of 5-fluoro-1-methyl-indole-6-carbonitrile (500 mg, 2.87 mmol) in THF (5.0 mL) was added MeMgBr (3.83 mL, 3.0 M in THF-MeTHF, 11.5 mmol) at 25 °C. The resulting mixture was warmed to 40 °C and stirred at that temperature for 12 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0–50% EtOAc) within 20 min to give 1-(5-fluoro-1-methyl-indol-6-yl)ethanone (482 mg, 89% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 192.1. Step 2 A solution of phosphoryl trichloride (425 mg, 2.77 mmol) in DMF (2.0 mL) was stirred at 0 °C for 30 minutes, and then a solution of 1-(5-fluoro-1-methyl-indol-6-yl)ethanone (482 mg, 2.52 mmol) in DMF (10.0 mL) was added. The reaction mixture was warmed to 25 °C and stirred at that temperature for 3 hours. It was then poured into saturated aqueous NaHCO (20 mL) and stirred at 25 °C for 2 hours. The precipitate was collected by filtration and dried in vacuo to give 6-acetyl-5-fluoro-1-methyl-indole-3-carbaldehyde (480 mg, 87% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 220.1. Step 3 To a stirred suspension of 6-acetyl-5-fluoro-1-methyl-indole-3-carbaldehyde (480 mg, 2.19 mmol) in THF (8.0 mL) and t-BuOH (2.0 mL) was added 2-methylbut-2-ene (1.23 g, 17.5 mmol, 1.80 mL) and a solution of NaClO (792 mg, 8.76 mmol) and NaHPO (1.37 g, 8.76 mmol) in water (8.0 mL) at 0 °C. The resulting mixture was warmed to 25 °C and stirred at that temperature for 48 h. The mixture was diluted with water (50 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / CHCl (containing 0-10% MeOH) within 20 min to give 6-acetyl-5-fluoro-1-methyl-indole-3-carboxylic acid (410 mg, 80% yield) as a yellow solid. LC-MS: m / z [M+H] + 236.1. Amine Intermediates Amine intermediate 1

[0191] [ka]

[0192] Step 1 To a stirred solution of AgNO (1.70 g, 10.0 mmol) in CHCN (50.0 mL) was added sequentially NBS (1.78 g, 10.0 mmol) and a solution of 6-fluoro-1H-indole (1.35 g, 10.0 mmol) in CHCN (10.0 mL) at 80 °C. The mixture was stirred at that temperature for 2 h, then cooled to 25 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (containing 1% to 26% EtOAc) within 25 min to give 6-fluoro-3-nitro-1H-indole (440 mg, 24% yield) as a brown solid. LC-MS: m / z [M+H] + 181.0. Step 2 To a stirred solution of 6-fluoro-3-nitro-1H-indole (35.0 mg, 0.194 mmol) in MeOH (6.0 mL) was added Pd / C (20.6 mg, 10 wt%, 0.0194 mmol) at 25° C. The reaction mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 2 hours, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give 6-fluoro-1H-indol-3-amine (23.3 mg, 80% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 151.1.

[0193] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in Amine Intermediate 1, and their corresponding characterization data are listed in the table below.

[0194] [Table 9]

[0195] Amine intermediate 6

[0196] [ka]

[0197] Step 1 To a stirred solution of NBS (1.40 g, 7.60 mmol) in CHCN (50.0 mL) was added AgNO (1.30 g, 7.60 mmol) and a solution of 5-bromo-1H-indole (1.50 g, 7.60 mmol) in CHCN (5.0 mL) sequentially at 80 °C. The reaction mixture was stirred at that temperature for 3 h, after which it was cooled to 25 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (containing 1% to 56% EtOAc) within 20 min to give 5-bromo-3-nitro-1H-indole (700 mg, 38% yield) as a brown solid. LC-MS: m / z [M+H] + 241.1. Step 2 To a stirred solution of 5-bromo-3-nitro-1H-indole (100 mg, 0.414 mmol) in AcOH (2.0 mL) was added SnCl (78.7 mg, 0.415 mmol) at 25 °C. The resulting mixture was warmed to 85 °C and stirred at that temperature for 2 h. The mixture was cooled to 25 °C and concentrated under reduced pressure to give 5-bromo-1H-indol-3-amine (80.0 mg, 92% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 211.1. Amine intermediate 7

[0198] [ka]

[0199] Step 1 To a stirred solution of 1H-indole-5-carbonitrile (2.00 g, 14.1 mmol) and AgNO3 (2.63 g, 15.5 mmol) in CH3CN (40.0 mL) was slowly added a solution of acetyl chloride (1.21 g, 0.942 mL, 15.5 mmol) in CH3CN (10.0 mL) at -10 °C. The reaction mixture was stirred at that temperature for 1 h, and then quenched with saturated aqueous NaHCO3 solution (50 mL). The mixture was extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with petroleum ether / EtOAc = 1.5:1 (30 mL) and filtered to produce 3-nitro-1H-indole-5-carbonitrile (2.20 g, 84% yield) as an orange solid. LC-MS: m / z [M+H] + 188.0. Step 2 To a solution of 3-nitro-1H-indole-5-carbonitrile (60.0 mg, 0.321 mmol) in MeOH (5.0 mL) was added Pd / C (13.0 mg, 10 wt%, 0.012 mmol) at 25° C. The reaction mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 2 hours, and then it was filtered through a pad of Celite. The filtrate was treated with HCl (2.0 M in EtOAc, 10 mL) at 25° C., stirred at that temperature for 10 minutes, and concentrated under reduced pressure to produce 3-amino-1H-indole-5-carbonitrile hydrochloride (61.4 mg, 99% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 158.1.

[0200] Additional intermediates of the present disclosure were prepared from corresponding materials using procedures similar to those disclosed in amine intermediate 7, and their corresponding characterization data are listed in the table below.

[0201] [Table 10]

[0202] Amine intermediate 13

[0203] [ka]

[0204] Step 1 To a stirred solution of 3-nitro-1H-indole-5-carbonitrile (190 mg, 1.00 mmol) in NH₃·H₂O (3.0 mL) was added hydrogen peroxide (653 mg, 30 wt%, 5.70 mmol) at 25 °C. The resulting mixture was stirred at that temperature for 16 h before it was quenched with saturated aqueous Na₂S₂O₃ (20 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0–100% EtOAc) within 25 min to give 3-nitro-1H-indole-5-carboxamide (200 mg, 96% yield) as a white solid. LC-MS: m / z [M+H] + 206.1. Step 2 To a stirred solution of 3-nitro-1H-indole-5-carboxamide (200 mg, 0.974 mmol) in MeOH (10.0 mL) was added Pd / C (50.0 mg, 10 wt%, 0.0472) at 25° C. The resulting mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 16 hours, after which it was filtered through a pad of Celite. The filtrate was treated with HCl (1.0 mL, 4.0 M in 1,4-dioxane) and concentrated under reduced pressure to give 3-amino-1H-indole-5-carboxamide hydrochloride (150 mg, 88%) as a black solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 176.1. Amine intermediate 14

[0205] [ka]

[0206] Step 1 To a stirred solution of 5-iodo-1H-indole (1.00 g, 4.11 mmol) in 1,4-dioxane (20.0 mL), tert-butyl 3-oxopiperazine-1-carboxylate (1.24 g, 6.17 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (234 mg, 1.65 mmol), CuI (156 mg, 0.822 mmol), and KPO (2.62 g, 12.3 mmol) were added sequentially at 25 °C. The resulting mixture was warmed to 110 °C and stirred at that temperature for 4 hours. The mixture was cooled to 25 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-100% EtOAc) within 25 min to give tert-butyl 4-(1H-indol-5-yl)-3-oxo-piperazine-1-carboxylate (230 mg, 17% yield) as a white solid. LC-MS: m / z [M+H] + 316.1. Step 2 To a stirred solution of NBS (129 mg, 0.729 mmol) in CHCN (5.0 mL) was added sequentially AgNO (123 mg, 0.729 mmol) and a solution of tert-butyl 4-(1H-indol-5-yl)-3-oxo-piperazine-1-carboxylate (230 mg, 0.729 mmol) in CHCN (3.0 mL) at 80 °C. The resulting mixture was stirred at that temperature for 3 h, after which it was cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-100% EtOAc) within 25 min to give tert-butyl 4-(3-nitro-1H-indol-5-yl)-3-oxo-piperazine-1-carboxylate (50.0 mg, 19% yield) as a yellow solid. LC-MS: m / z [M+H] + 305.0. Step 3 To a suspension of tert-butyl 4-(3-nitro-1H-indol-5-yl)-3-oxo-piperazine-1-carboxylate (50.0 mg, 0.138 mmol) in MeOH (5.0 mL) was added Pd / C (14.7 mg, 10 wt %, 0.0139 mmol) at 25 °C. The mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 8 hours, and then it was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-amino-1H-indol-5-yl)-3-oxo-piperazine-1-carboxylate (45.0 mg) as a black solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 331.2. Amine intermediate 15

[0207] [ka]

[0208] Step 1 To a stirred solution of 1H-indole-5-carbaldehyde (1.00 g, 6.89 mmol) in MeOH (10.0 mL) was added MeNH (1.43 g, 30 wt% in MeOH, 13.8 mmol) at 25 °C. The resulting mixture was stirred at that temperature for 30 min, and then NaBH(OAc) (1.59 g, 7.50 mmol) was added. The reaction mixture was stirred at 25 °C for 3 h, and then it was quenched with saturated aqueous NaHCO (20 mL). The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The solvent was evaporated in vacuo to give 1-(1H-indol-5-yl)-N-methylmethanamine (1.01 g, 91% yield) as a brown solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 161.0. Step 2 To a stirred solution of 1-(1H-indol-5-yl)-N-methylmethanamine (1.00 g, 6.25 mmol) in CHCl (20.0 mL) was added (Boc)O (1.36 g, 1.44 mL, 6.25 mmol) and EtN (632 mg, 869 μL, 6.25 mmol) sequentially at 0 °C. The resulting mixture was stirred at that temperature for 1 h before it was quenched with saturated aqueous NaHCO (20 mL). The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The solvent was evaporated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-60% EtOAc) within 20 min to give tert-butyl ((1H-indol-5-yl)methyl)(methyl)carbamate (1.30 g, 80% yield) as a white solid. LC-MS: m / z [M+H] + 205.0. Step 3 To a stirred solution of NBS (822 mg, 4.62 mmol) in CHCN (20.0 mL) was added sequentially AgNO (785 mg, 4.62 mmol) and a solution of tert-butyl ((1H-indol-5-yl)methyl)(methyl)carbamate (1.20 g, 4.62 mmol) in CHCN (5.0 mL) at 80 °C. The resulting mixture was stirred at that temperature for 2 h. The mixture was cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (containing 0–50% EtOAc) within 25 min to give tert-butyl methyl ((3-nitro-1H-indol-5-yl)methyl)carbamate (276 mg, 20% yield) as a yellow solid. LC-MS: m / z [M+H] + 250.9. Step 4 To a suspension of tert-butyl 4-(3-nitro-1H-indol-5-yl)-3-oxo-piperazine-1-carboxylate (250 mg, 0.820 mmol) in MeOH (10.0 mL) was added Pd / C (43.5 mg, 10 wt %, 0.041 mmol) at 25° C. The mixture was stirred at that temperature under a hydrogen atmosphere (balloon) for 8 hours, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give tert-butyl ((3-amino-1H-indol-5-yl)methyl)(methyl)carbamate (145 mg, 64% yield) as a black solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 276.9. Amine intermediate 16

[0209] [ka]

[0210] Step 1 To a stirred solution of 5-iodo-1H-indole (500 mg, 2.00 mmol) in DMF (10.0 mL) was added sequentially dimethylphosphine oxide (176 mg, 2.20 mmol), Pd(OAc) (92.3 mg, 0.411 mmol), Xantphos (476 mg, 0.822 mmol), and KPO (1.30 g, 6.10 mmol) at 25 °C. The resulting mixture was warmed to 120 °C and stirred at that temperature for 12 h. The mixture was cooled to 25 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / CHCl (containing 0–5% MeOH) within 15 min to afford 5-dimethylphosphoryl-1H-indole (200 mg, 50% yield) as a yellow solid. LC-MS: m / z [M+H] + 194.1. Step 2 To a stirred solution of NBS (184 mg, 1.04 mmol) in CHCN (5.0 mL) was added sequentially AgNO (175 mg, 1.00 mmol) and a solution of 5-dimethylphosphoryl-1H-indole (200 mg, 1.40 mmol) in CHCN (2.0 mL) at 80 °C. The reaction mixture was stirred at 80 °C for 3 h, after which it was cooled to 25 °C and filtered through a pad of Celite. The filtrate was diluted with water (30 mL) and then extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0–56% EtOAc) within 20 min to give 5-dimethylphosphoryl-3-nitro-1H-indole (35.0 mg, 14% yield) as a yellow solid. LC-MS: m / z [M+H] + 239.1. Step 3 To a stirred solution of 5-dimethylphosphoryl-3-nitro-1H-indole (65.0 mg, 0.272 mmol) in MeOH (5.0 mL) was added Pd / C (50.0 mg, 10 wt%, 0.0472 mmol). The reaction mixture was stirred under a hydrogen atmosphere (balloon) at 25° C. for 16 hours, after which it was filtered. The filtrate was concentrated under reduced pressure to give 5-dimethylphosphoryl-1H-indol-3-amine (40.0 mg, 71% yield) as a brown solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 209.1. Amine intermediate 17

[0211] [ka]

[0212] Step 1 To a stirred solution of 5-iodo-1H-indole (1.50 g, 6.17 mmol) in DMSO (10.0 mL) was added sodium methanesulfinate (819 mg, 8.02 mmol), CuI (235 mg, 1.23 mmol), and L-proline (284 mg, 2.47 mmol) sequentially at 25 °C. The resulting mixture was warmed to 110 °C and stirred at that temperature for 24 h. The mixture was cooled to 25 °C, quenched with NH4Cl (35 mL), and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0–30% EtOAc) within 20 min to give 5-methylsulfonyl-1H-indole (550 mg, 46% yield) as a yellow solid. LC-MS: m / z [M+H] + 196.0. Step 2 To a stirred solution of NBS (638 mg, 3.59 mmol) in CHCN (20.0 mL) was added sequentially AgNO (609 mg, 3.59 mmol) and a solution of 5-methylsulfonyl-1H-indole (700 mg, 3.59 mmol) in CHCN (5.0 mL) at 80 °C. The reaction mixture was stirred at 80 °C for 3 h, after which it was cooled to 25 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (containing 1% to 16% EtOAc) within 20 min to give 5-methylsulfonyl-3-nitro-1H-indole (550 mg, 63% yield) as a yellow solid. LC-MS: m / z [M+H] + 241.0. Step 3 To a stirred solution of 5-methylsulfonyl-3-nitro-1H-indole (99.6 mg, 0.414 mmol) in HOAc (2.0 mL) was added SnCl (78.7 mg, 0.414 mmol) at 25° C. The resulting mixture was warmed to 85° C. and stirred at that temperature for 2 h. The mixture was cooled to 25° C. and concentrated under reduced pressure to give 5-methylsulfonyl-1H-indol-3-amine (50.0 mg, 58%) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 211.0. Synthesis Examples Example 1

[0213] [ka]

[0214] To a stirred solution of 1-methyl-6-(trifluoromethyl)indazole-3-carboxylic acid (22.0 mg, 0.0901 mmol) in DMF (3.0 mL) was added sequentially T3P (115 mg, 50 wt% in EtOAc, 0.180 mmol), DMAP (2.2 mg, 0.018 mmol), DIPEA (35 mg, 48 μL, 0.27 mmol), and 1H-indol-3-amine (13.1 mg, 0.0991 mmol) at 25° C. The resulting mixture was warmed to 40° C. and stirred at that temperature for 2 h. The mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 45% to 75% CH3CN) within 8 min to give N-(1H-indol-3-yl)-1-methyl-6-(trifluoromethyl)indazole-3-carboxamide (9.0 mg, 28% yield) as a white solid. LC-MS: m / z [M+H] + 359.1.

[0215] The following compounds were prepared using procedures similar to those disclosed in Synthesis Example 1, and their corresponding characterization data are presented in the table below.

[0216] [Table 11-1]

[0217] [Table 11-2]

[0218] [Table 11-3]

[0219] Example 25

[0220] [ka]

[0221] To a stirred suspension of 5-fluoro-6-methoxycarbonyl-1-methyl-indole-3-carboxylic acid (150 mg, 0.597 mmol) in CHCl (5.0 mL) was added oxalyl dichloride (227 mg, 151 μL, 1.79 mmol) and DMF (19.0 mg, 20.0 μL, 0.260 mmol) sequentially at 25 °C. The resulting mixture was stirred at that temperature for 1 h, and then concentrated in vacuo to give the crude acid chloride. To a stirred solution of 5-fluoro-1H-indol-3-amine (100 mg, 0.667 mmol) in CHCl (5.0 mL) was added DIPEA (287 mg, 367 μL, 2.23 mmol) and the acid chloride prepared above sequentially at 25 °C. The reaction mixture was stirred at that temperature for 16 hours before it was quenched with water (30 mL) and then extracted with CHCl (30 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-50% EtOAc) within 25 minutes to give methyl 5-fluoro-3-[(5-fluoro-1H-indol-3-yl)carbamoyl]-1-methyl-indole-6-carboxylate (200 mg, 94% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 384.1.

[0222] Using a procedure similar to that disclosed in Synthesis Example 25, the following compounds were prepared, the corresponding characterization data of which are presented in the table below.

[0223] [Table 12-1]

[0224] [Table 12-2]

[0225] [Table 12-3]

[0226] [Table 12-4]

[0227] [Table 12-5]

[0228] Example 60

[0229] [ka]

[0230] Step 1 To a stirred solution of 6-morpholino-1-tetrahydropyran-2-yl-indazole-3-carboxylic acid (60.0 mg, 0.181 mmol) in DMF (3.0 mL) was added DMAP (2.2 mg, 0.018 mmol), DIPEA (94.1 mg, 120 μL, 0.728 mmol), HATU (208 mg, 0.543 mmol), and 5-fluoro-1H-indol-3-amine (32.6 mg, 0.217 mmol) at 25 °C. The reaction mixture was stirred at that temperature for 1 hour, after which it was quenched with water (10 mL) and then extracted with EtOAc (15 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (EtOAc / petroleum ether=1:2) to give N-(5-fluoro-1H-indol-3-yl)-6-morpholino-1-tetrahydropyran-2-yl-indazole-3-carboxamide (40.0 mg, 48% yield) as a yellow solid. LC-MS: m / z [M+H] + 464.1. Step 2 To a stirred solution of N-(5-fluoro-1H-indol-3-yl)-6-morpholino-1-tetrahydropyran-2-yl-indazole-3-carboxamide (40.0 mg, 0.0863 mmol) in EtOAc (2.0 mL) was added HCl (1.0 mL, 1.0 M in EtOAc, 1.0 mmol) at 25 °C. The reaction mixture was stirred at that temperature for 36 h, and then it was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CHCN / water (containing 25% to 55% CHCN) within 8 min to give N-(5-fluoro-1H-indol-3-yl)-6-morpholino-1H-indazole-3-carboxamide (7.0 mg, 19% yield) as a yellow solid. LC-MS: m / z [M+H] + 380.1.

[0231] The following compounds were prepared using procedures similar to those disclosed in Synthesis Example 60, and their corresponding characterization data are presented in the table below.

[0232] [Table 13]

[0233] Example 67

[0234] [ka]

[0235] To a stirred solution of 1-cyclopropyl-6-(trifluoromethyl)indole-3-carboxylic acid (120 mg, 0.446 mmol) in DMF (5.0 mL) was added 5-fluoro-1H-indol-3-amine hydrochloride (108 mg, 0.579 mmol), EDCI (256 mg, 1.34 mmol), HOBT (181 mg, 1.34 mmol), and DIPEA (461 mg, 590 μL, 3.57 mmol) sequentially at 25 °C. The reaction mixture was stirred at that temperature for 12 h before it was quenched with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0–50% EtOAc) within 25 min to yield the crude product. This was further purified by preparative HPLC eluting with CH3CN / water (containing 50%-80% CH3CN) within 8 min to give 1-cyclopropyl-N-(5-fluoro-1H-indol-3-yl)-6-(trifluoromethyl)indole-3-carboxamide (90.0 mg, 50% yield) as a white solid. LC-MS: m / z [M+H] + 402.0.

[0236] The following compounds were prepared using procedures similar to those disclosed in Synthesis Example 67, and their corresponding characterization data are presented in the table below.

[0237] [Table 14-1]

[0238] [Table 14-2]

[0239] [Table 14-3]

[0240] Post-amidation transformation Example 86

[0241] [ka]

[0242] To a stirred solution of 6-bromo-N-(1H-indol-3-yl)-1-methyl-indazole-3-carboxamide (27.0 mg, 0.0731 mmol) in DMF (3.0 mL) was added Zn(CN) (20.0 mg, 0.170 mmol) and Pd(PPh) (10.0 mg, 0.00865 mmol) at 25 °C. The resulting mixture was warmed to 110 °C and stirred at that temperature for 12 hours. The mixture was cooled to 25 °C, poured into water (30 mL), and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 45%-75% CH3CN) within 8 min to give 6-cyano-N-(1H-indol-3-yl)-1-methyl-indazole-3-carboxamide (5.8 mg, 23% yield) as a yellow solid. LC-MS: m / z [M+H] + 316.1.

[0243] Example 87

[0244] [ka]

[0245] To a stirred solution of methyl 3-[[1-methyl-6-(trifluoromethyl)indole-3-carbonyl]amino]-1H-indole-5-carboxylate (50.0 mg, 0.120 mmol) in THF (2.0 mL) was added aqueous NaOH (1.0 mL, 0.6 M, 0.60 mmol) at 25 °C. The reaction mixture was stirred at that temperature for 16 h, after which it was acidified to pH = 4 with aqueous HCl (1.0 M) and then concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CHCN / water (containing 35% to 65% CHCN) within 8 min to give 3-[[1-methyl-6-(trifluoromethyl)indole-3-carbonyl]amino]-1H-indole-5-carboxylic acid (14.4 mg, 29% yield) as a white solid. LC-MS: m / z [M+H] + 402.1.

[0246] Examples 88-89

[0247] [ka]

[0248] Step 1, Example 88 To a stirred solution of methyl 3-[(5-fluoro-1H-indol-3-yl)carbamoyl]-1H-indazole-6-carboxylate (41.0 mg, 0.116 mmol) in 1,4-dioxane (1.0 mL) was added an aqueous solution of LiOH (700 μL, 1.0 M, 0.700 mmol) at 25° C. The resulting mixture was warmed to 50° C. and stirred at that temperature for 30 minutes. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL). The aqueous phase was separated, acidified to pH = 3 with aqueous HCl (1.0 M), and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford 3-[(5-fluoro-1H-indol-3-yl)carbamoyl]-1H-indazole-6-carboxylic acid (32 mg, 81% yield) as a white solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 339.0. Step 2, Example 89 To a stirred solution of 3-[(5-fluoro-1H-indol-3-yl)carbamoyl]-1H-indazole-6-carboxylic acid (28.0 mg, 0.0828 mmol) in CHCl (4.0 mL), DIPEA (49.0 mg, 62.7 μL, 0.379 mmol), DMAP (3.0 mg, 0.025 mmol), T3P (124 mg, 50% wt. in EtOAc, 0.195 mmol), and 2,2,2-trifluoroethanamine (13.0 mg, 0.131 mmol) were added sequentially at 25 °C. The resulting mixture was warmed to 40 °C and stirred at that temperature for 2 h. The mixture was cooled to 25 °C, quenched with water (10 mL), and extracted with CHCl (10 mL × 3). The combined organic layer was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (EtOAc / petroleum ether=1:2) to produce N-(6-fluoro-1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)-1H-indazole-3,6-dicarboxamide (10.4 mg, yield 30%) as a gray solid. LC-MS: m / z [M+H] + 420.0.

[0249] Examples 90 to 92

[0250] [ka]

[0251] Step 1, Example 90 To a stirred solution of methyl 5-fluoro-3-[(5-fluoro-1H-indol-3-yl)carbamoyl]-1-methyl-indole-6-carboxylate (200 mg, 0.0521 mmol) in THF (8.0 mL) was added DIBAL-H (2.09 mL, 1.0 M in THF, 2.09 mmol) at 25 °C. The resulting mixture was stirred at that temperature for 16 hours, after which it was quenched with saturated aqueous potassium sodium tartrate (10.0 mL), diluted with EtOAc (20 mL), and stirred at 25 °C for 30 minutes. The aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH / CHCl (containing 0-15% MeOH) within 20 min to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-6-(hydroxymethyl)-1-methyl-indole-3-carboxamide (60.0 mg, 33% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 356.1. Step 2, Example 91 To a stirred solution of 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-6-(hydroxymethyl)-1-methyl-indole-3-carboxamide (50.0 mg, 0.140 mmol) in THF (2.0 mL) was added DIPEA (42.7 mg, 54.6 μL, 0.422 mmol) and MsCl (24.2 mg, 16.3 μL, 0.211 mmol) sequentially at 0 °C. The resulting mixture was warmed to 25 °C and stirred at that temperature for 1 h. The mixture was concentrated in vacuo to give the crude methanesulfonate salt as a yellow oil. To the methanesulfonate salt prepared above was added 2,2,2-trifluoroethan-1-amine (177 mg, 140 μL, 1.79 mmol) at 25 °C. The resulting mixture was stirred at that temperature for 16 hours, after which it was quenched with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC eluting with CHCN / water (containing 18%-28% CHCN) within 6 minutes to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-[(2,2,2-trifluoroethylamino)methyl]indole-3-carboxamide (7.4 mg, 19% yield) as a white solid. LC-MS: m / z [M+H] + 437.1. Step 3, Example 92 To a stirred solution of 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-[(2,2,2-trifluoroethylamino)methyl]indole-3-carboxamide (10.0 mg, 0.0223 mmol) in MeCN (5.0 mL) was added formaldehyde (69 mg, 2.3 mmol, 0.063 mL) and NaBH(OAc) (14.6 mg, 0.0688 mmol) sequentially at 25 °C. The reaction mixture was stirred at that temperature for 12 hours, after which it was quenched with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was first purified by silica gel chromatography eluting with EtOAc / petroleum ether (with 0-100% EtOAc) within 20 min, and then by preparative HPLC eluting with CH3CN / water (with 5%-95% CH3CN) within 10 min to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-[[methyl(2,2,2-trifluoroethyl)amino]methyl]indole-3-carboxamide (3.0 mg, 29% yield) as a white solid. LC-MS: m / z [M+H] + 451.7.

[0252] The following compounds were prepared using procedures similar to those disclosed in Synthesis Example 91, and their corresponding characterization data are presented in the table below.

[0253] [Table 15]

[0254] Example 97

[0255] [ka]

[0256] Step 1 To a stirred suspension of 6-cyano-5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-indole-3-carboxamide (25.0 mg, 0.0714 mmol) in water (3.0 mL), HOAc (3.0 mL), and pyridine (6.0 mL), NaHPO·H0 (14.8 mg, 143 mmol) and Raney nickel (30 mg, 0.36 mmol) were added sequentially at 25 °C. The mixture was warmed to 45 °C and stirred at that temperature for 3 h. The reaction mixture was filtered through a pad of Celite and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0-100% EtOAc) within 20 min to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-6-formyl-1-methyl-indole-3-carboxamide (15 mg, 59% yield) as a yellow solid. LC-MS: m / z [M+H] + 354.1. Step 2 To a stirred solution of 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-6-formyl-1-methyl-indole-3-carboxamide (5.0 mg, 0.014 mmol) in DCE (2.0 mL) was added 3,3,3-trifluoropropan-1-amine (25.0 mg, 0.221 mmol) and NaBH(OAc) (28.1 mg, 0.133 mmol) sequentially at 25 °C. The reaction mixture was stirred at that temperature for 12 hours, after which it was quenched with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 5% to 95% CH3CN) within 10 min to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-[(3,3,3-trifluoropropylamino)methyl]indole-3-carboxamide (2.0 mg, 10% yield) as a white solid. LC-MS: m / z [M+H]+ 451.7.

[0257] Using procedures similar to those disclosed in Synthesis Example 97, the following compounds were prepared:

[0258] [Table 16-1]

[0259] [Table 16-2]

[0260] Example 107

[0261] [ka]

[0262] To a stirred solution of 6-acetyl-5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-indole-3-carboxamide (5.0 mg, 0.014 mmol) in 1,4-dioxane (2.0 mL), 2,2,2-trifluoroethanamine (6.7 mg, 0.068 mmol, 5.4 μL) and TiCl (27 μL, 1.0 M in CHCl, 0.027 mmol) were added sequentially at 25 °C. The resulting mixture was stirred at that temperature for 3 hours, and then filtered. The filtrate was diluted with methanol (2.0 mL), and NaBH (5.0 mg, 0.13 mmol) was added at 25 °C. The resulting mixture was stirred at that temperature for 5 minutes, and then quenched with saturated aqueous NaHCO (5.0 mL). The mixture was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 5% to 95% CH3CN) within 10 min to give rac-5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-[1-(2,2,2-trifluoroethylamino)ethyl]indole-3-carboxamide (1.6 mg, 26% yield) as a white solid. LC-MS: m / z [M+H] + 451.7.

[0263] Examples 108 and 109

[0264] [ka]

[0265] Step 1, Example 108 To a stirred solution of tert-butyl 4-[3-[[1-methyl-6-(trifluoromethyl)indole-3-carbonyl]amino]-1H-indol-5-yl]-3-oxo-piperazine-1-carboxylate (20.0 mg, 0.0360 mmol) in EtOAc (2.0 mL) was added HCl (2.0 mL, 4.0 M in EtOAc, 8.0 mmol) at 25 °C. The mixture was stirred at that temperature for 2 h, and then it was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CHCN / water (containing 35% to 65% CHCN) within 8 min to give 1-methyl-N-[5-(2-oxopiperazin-1-yl)-1H-indol-3-yl]-6-(trifluoromethyl)indole-3-carboxamide (13.0 mg, 79% yield) as a yellow solid. LC-MS: m / z [M+H] + 456.0. Step 2, Example 109 To a stirred solution of 1-methyl-N-[5-(2-oxopiperazin-1-yl)-1H-indol-3-yl]-6-(trifluoromethyl)indole-3-carboxamide (5.0 mg, 0.011 mmol) in CHCN (1.0 mL) was added aqueous formaldehyde (200 μL, 37 wt%, 2.71 mmol) at 25 °C. The mixture was stirred at that temperature for 2 h, and then NaBH(OAc) (7.0 mg, 0.033 mmol) was added. The resulting mixture was stirred at 25 °C for 3 h, after which it was quenched with saturated aqueous NaHCO (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 5% to 95% CH3CN) within 10 min to yield N-(5-fluoro-1H-indol-3-yl)-6-[(2,2,2-trifluoroethylamino)methyl]-1H-indazole-3-carboxamide (2.3 mg, 45% yield) as a white solid. LC-MS: m / z [M+H] + 470.8.

[0266] Examples 110 and 111

[0267] [ka]

[0268] Step 1, Example 110 To a stirred solution of tert-butyl methyl ((3-(1-methyl-6-(trifluoromethyl)-1H-indole-3-carboxamido)-1H-indol-5-yl)methyl)carbamate (17.0 mg, 0.0340 mmol) in CHCl (2.0 mL) was added TFA (307 mg, 200 μL, 2.69 mmol) at 25 °C. The mixture was stirred at that temperature for 2 h, and then it was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CHCN / water (containing 5% to 95% CHCN) within 10 min to give 1-methyl-N-(5-((methylamino)methyl)-1H-indol-3-yl)-6-(trifluoromethyl)-1H-indole-3-carboxamide (10.0 mg, 77% yield) as a yellow solid. LC-MS: m / z [M+H] + 401.8. Step 2, Example 111 To a stirred solution of 1-methyl-N-(5-((methylamino)methyl)-1H-indol-3-yl)-6-(trifluoromethyl)-1H-indole-3-carboxamide (5.0 mg, 0.013 mmol) in CHCN (1.0 mL) was added aqueous formaldehyde (200 μL, 37 wt%, 2.71 mmol) at 25 °C. The mixture was stirred at that temperature for 2 h, and then NaBH(OAc) (8.0 mg, 0.0377 mmol) was added. The resulting mixture was stirred at 25 °C for 3 h, after which it was quenched with saturated aqueous NaHCO (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 5% to 95% CH3CN) within 10 min to yield N-(5-((dimethylamino)methyl)-1H-indol-3-yl)-1-methyl-6-(trifluoromethyl)-1H-indole-3-carboxamide (2.1 mg, 41% yield) as a white solid. LC-MS: m / z [M+H] + 415.8.

[0269] Example 112

[0270] [ka]

[0271] To a stirred solution of 6-bromo-N-(5-cyano-1H-indol-3-yl)-5-fluoro-1-(oxetan-3-yl)indole-3-carboxamide (160 mg, 0.353 mmol) in 1,4-dioxane (5.0 mL) and water (3.0 mL) were added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (96.4 mg, 0.458 mmol), Pd(dppf)Cl (25.8 mg, 0.0353 mmol), and KPO (224 mg, 1.06 mmol) sequentially at 25° C. The resulting mixture was warmed to 100° C. and stirred at that temperature for 50 minutes. The mixture was cooled to 25°C, diluted with water (25 mL), and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 35% to 65% CH3CN) within 8 min to give N-(5-cyano-1H-indol-3-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-1-(oxetan-3-yl)indole-3-carboxamide (22.0 mg, 14% yield) as a light brown solid. LC-MS: m / z [M+H] + 457.1.

[0272] Examples 113 and 114

[0273] [ka]

[0274] Step 1, Example 113 To a stirred solution of tert-butyl 3-[3-[(5-fluoro-1H-indol-3-yl)carbamoyl]-6-(trifluoromethyl)indol-1-yl]azetidine-1-carboxylate (170 mg, 0.329 mmol) in CHCl (5.0 mL) was added HCl (1.00 mL, 2.0 M in EtOAc, 2.00 mmol) at 25 °C. The reaction mixture was stirred at that temperature for 2 h, and then it was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CHCN / water (containing 20% ​​to 50% CHCN) within 8 min to give 1-(azetidin-3-yl)-N-(5-fluoro-1H-indol-3-yl)-6-(trifluoromethyl)indole-3-carboxamide (135 mg, 90% yield) as a white solid. LC-MS: m / z [M+H] + 417.1. Step 2, Example 114 To a stirred solution of 1-(azetidin-3-yl)-N-(5-fluoro-1H-indol-3-yl)-6-(trifluoromethyl)indole-3-carboxamide (100 mg, 0.240 mmol) in MeOH (10.0 mL) was added formaldehyde (43.3 mg, 1.44 mmol) and NaBH (109 mg, 2.88 mmol) sequentially at 25 °C. The mixture was stirred at that temperature for 48 hours, after which it was quenched with water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / CHCl (containing 0-10% MeOH) within 20 min to give the crude product, which was further purified by pre-TLC (100% EtOAc) to give N-(5-fluoro-1H-indol-3-yl)-1-(1-methylazetidin-3-yl)-6-(trifluoromethyl)indole-3-carboxamide (16.0 mg, 15% yield) as a white solid. LC-MS: m / z [M+H] + 431.1.

[0275] Examples 115 and 116

[0276] [ka]

[0277] Step 1, Example 115 To a stirred solution of 6-bromo-5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-indole-3-carboxamide (175 mg, 0.435 mmol) in 1,4-dioxane (4.0 mL) and water (1.0 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (173 mg, 0.779 mmol), NaCO (137 mg, 1.30 mmol), and Pd(dppf)Cl·CHCl (70.7 mg, 0.086 mmol) were added sequentially at 25 °C. The resulting mixture was warmed to 100 °C and stirred at that temperature for 6 h. The reaction mixture was cooled to 25 °C and quenched with water (15 mL). The precipitate was collected by filtration and further purified by preparative HPLC eluting with CH3CN / water (containing 10%-40% CH3CN) within 8 min to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)indole-3-carboxamide (65.0 mg, 36% yield) as a yellow solid. LC-MS: m / z [M+H] + 421.1. Step 2, Example 116 To a solution of 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)indole-3-carboxamide (50.0 mg, 0.118 mmol) in MeOH (2.0 mL) and THF (2.0 mL) was added Pd / C (5.0 mg, 10 wt%, 0.0047 mmol) at 25° C. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at that temperature for 50 minutes and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 15% to 45% CH3CN) within 8 min to give 5-fluoro-N-(5-fluoro-1H-indol-3-yl)-1-methyl-6-(1-methyl-4-piperidyl)indole-3-carboxamide (10.2 mg, 20% yield) as a yellow solid. LC-MS: m / z [M+H] + 423.1.

[0278] The following compounds were prepared using procedures similar to those disclosed in Synthesis Example 116, and their corresponding characterization data are presented in the table below.

[0279] [Table 17]

[0280] Examples 119 and 120

[0281] [ka]

[0282] Step 1, Example 119 To a stirred solution of 6-bromo-5-chloro-N-(5-cyano-1H-indol-3-yl)-1-methyl-indole-3-carboxamide (140 mg, 0.327 mmol) in 1,4-dioxane (8.0 mL) and water (2.0 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (131 mg, 0.589 mmol), Pd(dppf)Cl·CHCl (53.4 mg, 0.0655 mmol), and KPO (208 mg, 0.982 mmol) were added sequentially at 25 °C. The resulting mixture was warmed to 100 °C and stirred at that temperature for 1 h. The reaction mixture was cooled to 25 °C and diluted with water (15 mL). The precipitate was collected by filtration and further purified by preparative HPLC eluting with CH3CN / water (containing 15%-45% CH3CN) within 8 min to give 5-chloro-N-(5-cyano-1H-indol-3-yl)-1-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)indole-3-carboxamide (93.1 mg, 64% yield) as a yellow solid. LC-MS: m / z [M+H] + 444.1. Step 2, Example 120 To a solution of 5-chloro-N-(5-cyano-1H-indol-3-yl)-1-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)indole-3-carboxamide (70.0 mg, 0.157 mmol) in MeOH (2.0 mL) and THF (2.0 mL) was added PtO (3.6 mg, 0.016 mmol) at 25 °C. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at that temperature for 20 hours, and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with CH3CN / water (containing 22%-32% CH3CN) within 8 min to give 5-chloro-N-(5-cyano-1H-indol-3-yl)-1-methyl-6-(1-methyl-4-piperidyl)indole-3-carboxamide (1.5 mg, 2% yield) as a yellow solid. LC-MS: m / z [M+H] + 446.1. Biological Example 1 THP1 cells were used to measure STING pathway inactivation by the compounds described herein. THP1 cells (obtained from ATCC, Cat#TIB-202) were maintained in RPMI-1640 (Gibco, Cat#22400105), 10% FBS, 1% Pen-Strep, and 0.05 mM 2-mercaptoethanol. For STING activation, 2'3'-cGAMP (MW718.38, obtained from Invivogen) was used and prepared in serum-free RPMI-1640 medium. Growth medium: RPMI-1640 (HEPES, glutamine), 10% FBS, 1% Pen-Strep, and 0.05 mM 2-mercaptoethanol. Assay medium: RPMI-1640 (HEPES, glutamine), 0.5% FBS. 2'3'-cGAMP: Dissolve 2'3'-cGAMP to a 10 mM stock in HO. IFNβ reporter assay: Cells were prepared and seeded at 100K in 90 μL / well with assay medium (Greiner 655180) in cell culture plates. Compounds were added to 96-well tissue culture plates at final concentrations of 0.00137-3 μM in Tecan D300e.

[0283] Lipo2000 / 3000 and 2'3'-cGAMP stock solutions were diluted in serum-free RPMI-1640 medium. The diluted 2'3'-cGAMP and Lipo (V / V = 1:1) were mixed and allowed to stand at room temperature for 15 minutes. 10 μL of 2,3-cGAMP / Lipofectamine (10x) was transferred to a 96-well assay plate for a final 2'3'-cGAMP concentration of 5 μM. After overnight incubation at 37°C and 5% CO2, the cell plate was centrifuged at 1000 rpm for 5 minutes.

[0284] All reagents (Human IFN beta kit, Cisbio 62HIFNBPEG) were warmed to room temperature for at least 30 minutes before the assay. Detection medium was prepared according to the kit's instructions. 14 μL of cell supernatant was transferred to their designated wells in a 384-well plate. 2 μL of activation reagent solution and 4 μL of mixed antibody solution were then added to all wells. The plate was sealed and incubated at room temperature for 3 hours.

[0285] HTRF signals were read on an Envision (PerkinElmer). IFN-beta reporter activity was then measured. The calculated ratio was the signal at 615 nm / signal at 665 nm. IC was calculated using standard methods known in the art. 50 values ​​were calculated.

[0286] The following table shows the IFNβ secretion inhibitory activity of compounds in the IFNβ reporter assay: <0.05 μM = "++++"; >0.05 and <0.2 μM = "+++"; >0.2 and <1.0 μM = "++"; >1.0 μM = "+". "-" = not available.

[0287] [Table 18-1]

[0288] [Table 18-2]

[0289] [Table 18-3]

[0290] [Table 18-4]

[0291] [Table 18-5]

[0292] Table 18-6

[0293] Table 18-7

[0294] Table 18-8

[0295] Table 18-9

[0296] Table 18-10

[0297] Table 18-11

[0298] Table 18-12

[0299] Table 18-13

[0300] Table 18-14

[0301] Table 18-15

[0302] Table 18-16

Claims

1. A compound represented by structural formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof [In the formula, (i) A ２ If C, then A １ is CH or N, and B ２ is NR １ and B １ is N or CH, and the partial structure in structural formula (I) of the following formula: 【Chemistry 2】 is B １ or B １ is C, and the partial structure in structural formula (I) of the following formula: 【Transformation 3】 is B １ is bonded to (ii) A ２ If N, then A １ is CH and B ２ is N, B １ is CH, and the partial structure in structural formula (I) of the following formula: 【Chemistry 4】 is B １ attached to the carbon atom next to B １ is C, and the partial structure in structural formula (I) of the following formula: 【Transformation 5】 is bound to R １ is H, C １～６ Alkyl, C １～６ Haloalkyl, -(CH ２ ) （０または１） -C ３～７ Cycloalkyl, -(CH ２ ) （０または１） -C ４～７ cycloalkenyl, or -(CH ２ ) （０または１） -3 to 7-membered heterocyclyl, and R １ The cycloalkyl, cycloalkenyl, or heterocyclyl represented by the formula (I) is selected from halogen, —OH, oxo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, and NR １１ R １２ and optionally substituted with one or more substituents independently selected from the group consisting of: R ３ is H, halogen, CN, OH, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, —C(O)R １１ , -C(O)OR １１ , —C(O)NR １１ R １２ , -NR １１ C(O)C １～６ Alkyl, NR １１ R １２ , -P(=O)R １１ R １２ , -S(O) ２ R １１ , -S(O) ２ NR １１ R １２ , -O （０または１） -C ３～７ cycloalkyl, —O （０または１） -C ４～７ cycloalkenyl, —O （０または１） -3 to 7-membered heterocyclyl, -O （０または１） -6 to 10-membered aryl, -O （０または１） -5 to 8-membered heteroaryl, -(CH ２ ) （０または１） -C ３～７ Cycloalkyl, -(CH ２ ) （０または１） -C ４～７ Cycloalkenyl, -(CH ２ ) （０または１） -3 to 7-membered heterocyclyl, or -(CH ２ ) （０または１） -aryl, and R ３ or R ３ The alkyl, alkenyl, alkynyl, aryl, or heteroaryl in the group represented by the formula (I) is not a halogen, —OH, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —NR １１ R １２ , and -N(R １１ )C(O)OR １２ and R is optionally substituted with one or more substituents independently selected from the group consisting of ３ or R ３ The cycloalkyl, cycloalkenyl, or heterocyclyl in the group represented by the formula (I) is selected from halogen, —OH, oxo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —C(O)OC １～６ Alkyl, and NR １１ R １２ and optionally substituted with one or more substituents independently selected from the group consisting of: R ４ , R ５ , and R ６ are independently H, halogen, CN, OH, C １～６ Alkyl, C １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, —C(O)R １１ , -C(O)OR １１ , —C(O)NR １１ R １２ , -NR １１ C(O)C １～６ Alkyl, NR １１ R １２ , -P(=O)R １１ R １２ , -S(O) ２ R １１ , -S(O) ２ NR １１ R １２ , -O （０または１） -C ３～７ cycloalkyl, —O （０または１） -C ４～７ cycloalkenyl, —O （０または１） -3 to 7-membered heterocyclyl, -O （０または１） -6 to 10-membered aryl, -O （０または１） -5 to 8-membered heteroaryl, -(CH ２ ) （０または１） -C ３～７ Cycloalkyl, -(CH ２ ) （０または１） -C ４～７ Cycloalkenyl, -(CH ２ ) （０または１） -3 to 7-membered heterocyclyl, or -(CH ２ ) （０または１） -aryl, and R ４ , R ５ , or R ６ or R ４ , R ５ , or R ６ The alkyl, alkenyl, alkynyl, alkoxy, aryl, or heteroaryl in the group represented by the formula (I) is not a halogen, —OH, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —NR １１ R １２ , and -N(R １１ )C(O)OR １２ and R is optionally substituted with one or more substituents independently selected from the group consisting of ４ , R ５ , or R ６ or R ４ , R ５ , or R ６ The cycloalkyl, cycloalkenyl, or heterocyclyl in the group represented by the formula (I) is selected from halogen, —OH, oxo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —C(O)OC １～６ Alkyl, and NR １１ R １２ and optionally substituted with one or more substituents independently selected from the group consisting of: R ３ , R ４ , R ５ , and R ６ At least one of the is not hydrogen, R ７ and R ８ are independently H, halogen, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ haloalkoxy, R １１ and R １２ each independently represents H, C １～６ Alkyl, C １～６ haloalkyl, or —C(O)OC １～６ alkyl].

2. Structural formula (IA): 【Transformation 6】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof (wherein A 1 , R 1 , and R 3 to R 8 are defined as in claim 1).

3. Structural Formula (IB-1) or (IB-2): 【Transformation 7】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof (wherein A 1 , R 1 , and R 3 to R 8 are defined as in claim 1).

4. Structural Formula (IC-1) or (IC-2): 【Transformation 8】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof (wherein R 3 to R 8 are defined as in claim 1).

5. R1 is H, C １～４ Alkyl, -(CH ２ ) （０または１） -C ３～４ cycloalkyl, or 3- to 6-membered heterocyclyl, and R １ The cycloalkyl or heterocyclyl represented by the formula: １～４ 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally substituted with one or more substituents independently selected from the group consisting of alkyl.

6. R ７ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R and R are independently H or halogen.

7. R ３ and R ５ each independently represents H, a halogen, C １～６ Alkyl, or C １～６ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which is haloalkyl.

8. R4 is independently H, halogen, CN, OH, C １～６ Alkyl, C １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, —C(O)R １１ , -C(O)OR １１ , —C(O)NR １１ R １２ , -NR １１ C(O)C １～６ Alkyl, NR １１ R １２ , -S(O) ２ R １１ , -S(O) ２ NR １１ R １２ , C ３～７ Cycloalkyl, -(CH ２ ) （０または１） -3 to 7-membered heterocyclyl, -O （０または１） -3 to 7-membered heterocyclyl, phenyl, or -O （０または１） - 5- to 6-membered heteroaryl, R ４ or R ４ In the group represented by the formula (I), the alkyl, alkoxy, phenyl, or heteroaryl is halogen, —OH, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —NR １１ R １２ , and -N(R １１ )C(O)OR １２ and R is optionally substituted with one or more substituents independently selected from the group consisting of ４ The cycloalkyl or heterocyclyl represented by the formula (I) is selected from the group consisting of halogen, —OH, oxo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —C(O)OC １～６ Alkyl, and NR １１ R １２ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally substituted with one or more substituents independently selected from the group consisting of:

9. R6 is independently H, halogen, CN, OH, C １～６ Alkyl, C １～６ Alkoxy, —C(O)R １１ , -C(O)OR １１ , —C(O)NR １１ R １２ , -NR １１ C(O)C １～６ Alkyl, NR １１ R １２ , -P(=O)R １１ R １２ , -S(O) ２ R １１ , -S(O) ２ NR １１ R １２ , C ３～７ cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, or —O （０または１） - 5- to 6-membered heteroaryl, R ６ or R ６ In the group represented by the formula (I), the alkyl, alkoxy, phenyl, or heteroaryl is halogen, —OH, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —NR １１ R １２ , and -N(R １１ )C(O)OR １２ and R is optionally substituted with one or more substituents independently selected from the group consisting of ６ The cycloalkyl or heterocyclyl represented by the formula (I) is selected from the group consisting of halogen, —OH, oxo, CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, —C(O)OC １～６ Alkyl, and NR １１ R １２ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally substituted with one or more substituents independently selected from the group consisting of:

10. R1 is H, C １～４ Alkyl, -(CH ２ ) （０または１） -C ３～４ 10. The compound of any one of claims 1 to 3 and 5 to 9, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which is cycloalkyl, or 4-6 membered oxygen-containing heterocyclyl.

11. 11. The compound of any one of claims 1 to 3 and 5 to 10, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein A1 is CH.

12. R ７ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R and R are independently H or F.

13. R ３ and R ５ are independently H, F, Cl, or CF ３ 13. The compound of any one of claims 1 to 12, wherein:

14. R4 is independently H, halogen, CN, C １～４ Alkyl (OH or -NR １１ R １２ optionally substituted with), C １～４ Haloalkyl, C １～４ Alkoxy (C １～４ optionally substituted with alkoxy), C １～４ Haloalkoxy, C ２～４ Alkynyl, —C(O)OR １１ , —C(O)NR １１ R １２ , -S(O) ２ R １１ , -(CH ２ ) （０または１） -5- to 6-membered heterocyclyl, -O （０または１） -5- to 6-membered heterocyclyl, or -O-5- to 6-membered heteroaryl, and R ４ The heteroaryl in the group represented by １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy; ４ The heterocyclyl represented by the formula (I) is selected from halogen, —OH, oxo, CN, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, —C(O)OC １～４ Alkyl, and NR １１ R １２ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally substituted with one or more substituents independently selected from the group consisting of:

15. R6 is independently H, halogen, CN, C １～４ Alkyl (-NR １１ R １２ optionally substituted with), C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, —C(O)OR １１ , —C(O)NR １１ R １２ , -P(=O)R １１ R １２ , -S(O) ２ R １１ or 5- to 6-membered heterocyclyl, and R ６ The heterocyclyl represented by the formula (I) is selected from halogen, —OH, oxo, CN, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, —C(O)OC １～４ Alkyl, and NR １１ R １２ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally substituted with one or more substituents independently selected from the group consisting of:

16. R4 is independently H, halogen, CN, C １～４ Alkyl (-NR １１ R １２ optionally substituted with), C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkynyl, —C(O)NR １１ R １２ or a 5- to 6-membered oxygen-containing heterocyclyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

17. R6 is independently H, halogen, C １～４ Alkyl, C １～４ haloalkyl, or —C(O)OC １～４ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R is alkyl;

18. The compound shown below: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

19. A compound represented by the following formula: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

20. 20. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

21. 21. The pharmaceutical composition of claim 20 for treating a subject with an autoimmune disease, a disorder involving inflammation, or an infectious disease.

22. 22. The pharmaceutical composition of claim 21, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), or ulcerative colitis (UC).

23. 21. The pharmaceutical composition of claim 20 for treating a subject with cancer.

24. 24. The pharmaceutical composition of claim 23, wherein the cancer is melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

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