5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases

Abstract

To provide 5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases.SOLUTION: The present disclosure relates to compounds and compositions for inhibition of Bcr-Abl tyrosine kinases, methods of preparing the compounds and compositions, and their use in the treatment of various cancers, such as chronic myeloid leukemia (CML). Provided herein are compounds and compositions that selectively inhibit Bcr-Abl tyrosine kinases and that are useful for treating disorders mediated by Bcr-Abl tyrosine kinases.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 087,763, filed October 5, 2020, and U.S. Provisional Application No. 63 / 224,236, filed July 21, 2021, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] Provided herein are compounds and compositions for the inhibition of Bcr-Abl tyrosine kinase, methods for preparing said compounds and compositions, and their use in the treatment of various cancers, such as chronic myeloid leukemia (CML). [Background technology]

[0003] A cytogenetic abnormality known as the Philadelphia chromosome is highly associated with the development of numerous hematological malignancies, including most cases of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (Ph+ ALL). The Philadelphia chromosome is the product of a translocation between the breakpoint cluster region (BCR) gene on chromosome 22 and the Abelson (ABL) tyrosine kinase gene on chromosome 9, resulting in the oncogenic fusion gene product Bcr-Abl. The resulting fusion protein is overexpressed and possesses constitutive kinase activity, which then drives the activation of multiple intracellular signaling cascades, inducing uncontrolled cell proliferation, division, and survival associated with oncogenic transformation. Therefore, therapeutic intervention with inhibitors of the Bcr-Abl tyrosine kinase is an essential component of the current treatment paradigm for patients with Philadelphia-positive neoplastic diseases.

[0004] Imatinib (STI-571), a small-molecule Bcr-Abl tyrosine kinase inhibitor (Bcr-Abl TKI), was developed in the early 1990s as a highly effective treatment for CML. Imatinib remains the first-line treatment for CML today. However, in more aggressive cases of CML, patients often relapse due to the development of resistance. The primary mechanism of resistance results from various on-target genetic alterations that either drive aberrant overexpression of Bcr-Abl fusions or, more commonly, introduce amino acid mutations within the Abl kinase domain that reduce the binding affinity of imatinib to the active site, thereby significantly reducing its inhibitory activity. These alterations can occur stochastically, either as a subpopulation within the initial tumor cell population or under the selective pressure of inhibitor treatment. One of the major on-target Bcr-Abl resistance mutations is caused by a point mutation (T315I) that introduces an isoleucine residue in place of threonine at position 315 within the Abl kinase domain, also known as the "gatekeeper" position. This mutant form of Bcr-Abl exhibits significant resistance to all second-generation Bcr-Abl TKIs (nilotinib, dasatinib, bosutinib, and radotinib) in addition to imatinib. Currently, the only treatment option for patients harboring the T315I mutation is ponatinib, a third-line Bcr-Abl TKI. While ponatinib is effective in treating patients with T315I CML, it suffers from low selectivity for Bcr-Abl compared to many other protein kinases. Accordingly, ponatinib has been reported to induce significant dose-limiting toxicities, thereby limiting its ability to effectively bind to its target to achieve clinical efficacy.

[0005] In addition to on- or off-target resistance, intolerance to Bcr-Abl TKIs also poses a major clinical challenge. Over 50% of Ph+ leukemia patients experience adverse events. Dose modifications are necessary due to these adverse effects. In fact, approximately 30% of patients undergo dose reductions within the first six months of treatment. While side effects associated with these drugs appear early in the treatment period and are manageable in most cases, toxicity persists, significantly impacting patients' quality of life and leading to poor compliance. Therefore, approximately 40% of patients discontinue first- and second-generation Bcr-Abl TKIs within the first five years of treatment. All currently approved Bcr-Abl targeted therapies inhibit other tyrosine kinases, which can potentially result in debilitating side effects. Specifically, potent inhibition of VEGFR, PDGFR, c-Kit, and / or c-Src family kinases can result in dose-limiting side effects in patients. To address these adverse effects, dose reductions, interruptions, and even discontinuation are often required during treatment, but such treatment regimens ultimately result in suboptimal therapeutic effects.

[0006] Thus, there remains a substantial unmet medical need for Bcr-Abl TKIs with improved selectivity for improved tolerability and enhanced efficacy against multiple resistance mechanisms in Philadelphia-positive disease. Summary of the Invention [Means for solving the problem]

[0007] Provided herein are compounds and compositions that selectively inhibit Bcr-Abl tyrosine kinase and are useful for treating disorders mediated by Bcr-Abl tyrosine kinase.

[0008] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X is NR 3’ or CR 3 and Y is NR 2 or CR 4 and X is NR 3’ If Y is CR 4 and Y is CR 5 and X is CR 5 or X has a single bond to CR 3 If Y is NR 2 and Y is CR 5 and X has a single bond to CR 5 having a double bond to R 0 teeth, [ka] is the basis of m is an integer from 0 to 3, Each R 1 are independently -D, -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 1 wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; R 2 is —H, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl, or -CN; R 4 is —H, C1-C3 alkyl, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, R 6 is -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, C1-C6 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; R 7’ and R 8’ Each pair, together with the nitrogen atom to which they are attached, independently forms a 3- to 8-membered complex. forming a heterocyclic ring, the heterocyclic ring optionally containing 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , -NR 7 R 8 , C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CN, S(O) n C1-C3 alkyl, or S(O) n C3-C6 cycloalkyl, n is an integer from 0 to 2, Each R 10 are independently -H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl, C1-C3 alkoxy, and / or 1 to 6 deuterium atoms, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0009] In another embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X is NR 3’ or CR 3 and Y is NR 2 or CR 4 and X is NR 3’ If Y is CR 4 and Y is CR 5 and X is CR 5 or X has a single bond to CR 3If Y is NR 2 and Y is CR 5 and X has a single bond to CR 5 having a double bond to R 0 teeth, [ka] is the basis of m is an integer from 0 to 3, Each R 1 are independently -D, -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 1 The alkyl, alkylene, cycloalkylene, and the heterocycloalkylene moiety is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; R 2is —H, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl, or -CN; R 4 is —H, C1-C3 alkyl, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, R 6 is -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, C1-C6 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , -NR 7 R 8 , C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CN, S(O) n C1-C3 alkyl, or S(O) n C3-C6 cycloalkyl, n is an integer from 0 to 2, Each R 10are independently -H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl, C1-C3 alkoxy, and / or 1 to 6 deuterium atoms, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0010] In some embodiments, the compound of Formula (I) has the formula (IA): [ka] is a compound of

[0011] In some embodiments, the compound of Formula (I) has Formula (IAi) or Formula (IA-ii): [ka] A compound of the formula: m is an integer of 0 or 2, Each R 1 are independently -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’R 8’ and R 1 wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; R 2 is -H, -CH3, CD3, -CHF2, or -CH2CH3, R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl, or -CN; R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein: [ka] represents a single bond or a double bond, and the C6 to C 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, Each R 7 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl, and each R 8 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl; R 7’and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl, or -CN; Each R 10 are independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl and / or C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0012] In some embodiments that may be combined with any of the preceding embodiments, each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, and R 1 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl. In other embodiments that may be combined with any of the preceding embodiments, R 5 is phenyl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein: [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 In still other embodiments which may be combined with any of the preceding embodiments, R 2 is -CH3, CD3, or -CH2CH3, and R 3 is -H, -F, -CH3, or -CN, and R 3’ is -H or -CH3, and R 4 is -H, -F, or -CH. In still other embodiments that may be combined with any of the preceding embodiments, each R 9 are independently -F, -Cl, -OR 10 , -CH3, or -CN, and each R 10 are independently -H, -CH3, -CD3, or -CH2CH3, wherein the -CH3 or the -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0013] In still other embodiments that may be combined with any of the preceding embodiments, the compound of formula (I) has formula (IAi) or formula (IA-ii): [ka] A compound of the formula: m is an integer of 0 or 1, R 1 -F, C1-C3 alkylene -NR 7’ R 8’ or C1-C3 alkylene-OH, R 2 is -CH3, CD3, or -CH2CH3, R 3 is -H, -F, -CH3, or -CN, R 3’ is -H or -CH3, R 4 is -H, -F, or -CH3, R 5is phenyl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] is selected from the group consisting of [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 optionally substituted with a group, R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl; Each R 9 are independently -F, -Cl, -OR 10 , -CH3, or -CN; Each R 10 are independently -H, -CH3, -CD3, or -CH2CH3, wherein the -CH3 or the -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3. In still other embodiments that may be combined with any of the preceding embodiments, the compound of formula (I) is a compound of formula (IAi) or formula (IA-ii): [ka] A compound of the formula: m is an integer of 0 or 1, R 1 is -F, R 2 is -CH3, R 3 is -H or -CH3, R 3’ is -H or -CH3, R 4is -CH3, R 5 is a 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 optionally substituted with a group, Each R 9 are independently -F or -OR 10 and Each R 10 are independently —H or —CH 3 .

[0014] In other embodiments of this aspect of the invention, the compound of formula (I) has the formula (IB): [ka] is a compound of

[0015] In some of the foregoing embodiments, the compound of formula (I) has formula (IBi) or formula (IB-ii): [ka] A compound of the formula: R 2 is -H, -CH3, CD3, -CHF2, or -CH2CH3, R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl, or -CN; R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] is selected from the group consisting of [ka] represents a single bond or a double bond, and the C6 to C 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, R 6 is C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkylene-NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently selected from C1 to C3 alkyl, C3 to C6 cycloalkyl, C2 to C3 haloalkyl, C and optionally substituted with C2-C3 alkylene-CN, or C2-C3 heteroalkyl, and each R 7are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl, and each R 8 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl; R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl, or -CN; Each R 10 are independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl and / or C1-C3 alkoxy.

[0016] In some embodiments that may be combined with any of the preceding embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ and R 6 R 7 ' and R 8’each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In other embodiments that may be combined with any of the preceding embodiments, R 5 is phenyl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein the phenyl or the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 In still other embodiments that may be combined with any of the preceding embodiments, each R 9 are independently -F, -OR 10 , -CH3, and each R 10 is independently -H, -CH, -CD, -CFH, or -CF. In still other embodiments that may be combined with any of the preceding embodiments, R 2 is -H or -CH3, and R 3 is -H, and R 3’ is -H, and R 4 is -H or -CH3.

[0017] In some embodiments that may be combined with any of the preceding embodiments, the compound of Formula (I) has Formula (IBi) or Formula (IB-ii): [ka] A compound of the formula: R 2 is -H or -CH3, R 3 is -H, R 3’ is -H, R 4is -H or -CH3, R 5 is phenyl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein the phenyl or the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 optionally substituted with a group, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ and R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently -F, -OR 10 , -CH3, Each R 10 are independently -H, -CH3, -CD3, -CF2H, or -CF3.

[0018] In this specification, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Also provided is a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0019] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I), as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0020] In yet another aspect, the present disclosure provides a method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell to an effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0021] In still yet another aspect, provided herein is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed phenotype acute leukemia in a human in need thereof, the method comprising administering to said human a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0022] In some embodiments of this aspect of the invention, the leukemia is refractory leukemia. In certain embodiments, the resistant leukemia is associated with a mutation in the Bcr-Abl tyrosine kinase gene resulting in a specific amino acid substitution selected from the group consisting of M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I. In still other embodiments of the foregoing, the resistant leukemia is associated with a mutation in the Bcr-Abl tyrosine kinase gene that results in the specific amino acid substitution T315I. In still other embodiments that may be combined with any preceding embodiment of this aspect of the invention, the method further comprises administering one or more pharmaceutical agents including an anti-microtubule therapy, a topoisomerase inhibitor, an alkylating agent, a nucleotide synthesis inhibitor, a DNA synthesis inhibitor, a protein synthesis inhibitor, a developmental signaling pathway inhibitor, a pro-apoptotic agent, an Abl myristoyl pocket binding inhibitor, a MEK1 / 2 inhibitor, an AKT inhibitor, a PI3K inhibitor, and / or radiation. DETAILED DESCRIPTION OF THE INVENTION

[0023] The following description sets forth example methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of representative embodiments.

[0024] I. Definition As used herein, the following definitions shall apply unless otherwise specified. Furthermore, if any term or symbol used herein is not defined below, it has its ordinary meaning in the art.

[0025] As used herein, the term "excipient" refers to an inactive or non-active substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet containing a compound of the present disclosure as an active ingredient. The term excipient can encompass a variety of substances, including, but not limited to, binders, disintegrants, coatings, compression / encapsulation aids, creams or lotions, lubricants, parenteral solutions, chewable tablet materials, sweeteners or flavoring agents, suspending / gelling agents, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression aids / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, Examples of suitable lubricants include maltodextrin, carrageenan, etc.; lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tableting agents include dextrose, fructose dc, lactose (monohydrate; optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0026] The terms "individual," "subject," and "patient" refer to mammals, and include human and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, and the like. In some embodiments, patient refers to a human.

[0027] As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0028] "Pharmaceutically acceptable" refers to safe and non-toxic and suitable for in vivo or human administration.

[0029] As used herein, unless otherwise stated, the term "alkyl," alone or as part of another substituent, means a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms (e.g., C1-C6 means 1 to 6 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term "alkyl" can encompass C1-C6 alkyl, C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3 alkyl, C2-C3 alkyl, or C1-C2 alkyl.

[0030] The terms "cycloalkyl," "carbocyclic," or "carbocycle" refer to a hydrocarbon ring having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3 to 6 carbons) and which is fully saturated or has no more than one double bond between the ring vertices. As used herein, "cycloalkyl," "carbocyclic," or "carbocycle" refers to, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norbornene, spirocyclic C 5~12It is also intended to refer to bicyclic, polycyclic, and spirocyclic hydrocarbon rings such as alkanes. In some embodiments, "cycloalkyl" includes C3-C7 cycloalkyl, C4-C7 cycloalkyl, C5-C7 cycloalkyl, C5-C7 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6 cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl. In addition, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (which moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, but 1,2,3,4-tetrahydronaphthalen-5-yl (which moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group.

[0031] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight- or branched-chain hydrocarbon radical consisting of the specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. "Heteroalkyl" may contain up to three unsaturated units and also encompasses mono- and polyhalogenated variants, or combinations thereof. Examples are -CH2-CH2-O-CH3, -CH2-CH2-O-CF3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH 3)3, -CH2-CH=N-OCH3, and -CH=CH=N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0032] The terms "heterocycloalkyl," "heterocyclic," or "heterocycle" refer to a cycloalkyl radical group having the indicated number of ring atoms (e.g., a 5- or 6-membered heterocycloalkyl), including 1 to 5 heteroatoms selected from the group consisting of N, O, and S, where the nitrogen and sulfur ring atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Unless otherwise specified, a "heterocycloalkyl ring," "heterocycle," or "heterocycle" can be a monocyclic, bicyclic, bridged or fused ring system, spirocyclic, or polycyclic ring system. Non-limiting examples of "heterocycloalkyl rings," "heterocycles," or "heterocycles" include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, etc. A "heterocycloalkyl," "heterocycle," or "heterocycle" group may be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.In some embodiments, "heterocycloalkyl" includes 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered heterocycloalkyl, 7-10 membered heterocycloalkyl, 8-10 membered heterocycloalkyl, 9-10 membered heterocycloalkyl, 3-9 membered heterocycloalkyl, 4-9 membered heterocycloalkyl, 5-9 membered heterocycloalkyl, 6-9 membered heterocycloalkyl, 7-9 membered heterocycloalkyl, 8-9 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered heterocycloalkyl, 6-8 membered heterocycloalkyl, 7-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heterocycloalkyl, 6-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 4-5 membered heterocycloalkyl, or 3-4 membered heterocycloalkyl. In other embodiments, "heterocycloalkyl" may be characterized by the number of carbon atoms in the ring, provided that the ring contains at least one heteroatom. For example, in some embodiments, "heterocycloalkyl" includes C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, C-C heterocycloalkyl, or C-C heterocycloalkyl. It is to be understood that "heterocycloalkyls" described by the number of ring atoms can also be described by the number of carbon atoms in the ring.For example, a piperazinyl ring may be described as a C4 heterocycloalkyl ring or a 6-membered heterocycloalkyl ring, and an azetidinyl or oxetanyl ring may be described as a C3 heterocycloalkyl ring or a 4-membered heterocycloalkyl ring, respectively.

[0033] The term "alkylene," by itself or as part of another substituent, means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms. In embodiments, the alkyl (or alkylene) group has 10 or fewer carbon atoms.

[0034] The term "heteroalkylene," by itself or as part of another substituent, means a saturated or unsaturated or polyunsaturated divalent radical derived from heteroalkyl, as exemplified by -CH-CH-S-CHCH-, -CH-S-CH-CH-NH-CH-, -O-CH-CH=CH-, -CH-CH=C(H)CH-O-CH-, and -S-CH-C≡C-. In heteroalkylene groups, heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0035] The term "heterocycloalkylene," alone or as part of another substituent, means a saturated, unsaturated, or polyunsaturated divalent radical derived from a heterocycloalkyl. In a heterocycloalkylene group, heteroatoms can occupy either or both of the chain termini.

[0036] The terms "alkoxy" and "alkylamino" are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule through an oxygen atom or an amino group, respectively.

[0037] The term "heterocycloalkoxy" refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein.

[0038] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C4 haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0039] The term "haloalkyl-OH" refers to a haloalkyl group, as defined above, that is also substituted with one or more hydroxyl groups. The term "haloalkyl-OH" is intended to include haloalkyl substituted with one hydroxyl group and haloalkyl substituted with multiple hydroxyl groups. For example, the term "haloalkyl-OH" includes -CH(F)OH, -CHCFHCHOH, -CH(OH)CF, and the like.

[0040] The term "alkyl-OH" refers to an alkyl substituted with one or more hydroxyl groups. The term "alkyl-OH" is intended to encompass alkyl substituted with one hydroxyl group and alkyl substituted with multiple hydroxyl groups. For example, the term "alkyl-OH" includes -CHOH, -CH(OH)CH, -CHCHOH, -C(CH)OH, etc.

[0041] The term "alkyl-CN" refers to an alkyl substituted with one or more cyano groups. The term "alkyl-CN" is intended to include alkyl substituted with one cyano group and alkyl substituted with multiple cyano groups. For example, the term "alkyl-CN" includes -CHCN, -CHCHCN, -CH(CN)CH, etc.

[0042] The term "aryl," unless otherwise specified, refers to a polyunsaturated hydrocarbon group, typically an aromatic hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together. In some embodiments, "aryl" refers to a C6-C 14 Aryl, C8-C 14 Aryl, C 10 ~C 14 Aryl, C 12 ~C 14 Aryl, C6-C 12 Aryl, C8-C 12 Aryl, C 10 ~C 12 Aryl, C6-C 10 Aryl, C8-C 10 Aryl or C6-C8 aryl. In some embodiments, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other embodiments, a polycyclic aryl group can include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, in some embodiments, a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) would be considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) would not be considered an aryl group. Similarly, in some embodiments, a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) would be considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) would not be considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl," as defined herein, regardless of point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some embodiments, aryl is phenyl or naphthyl. In certain embodiments, aryl is phenyl.

[0043] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from the group consisting of N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule through a carbon atom or a heteroatom, where valency allows. In some embodiments, both rings of a polycyclic heteroaryl group are aromatic. In other embodiments, a polycyclic heteroaryl group can include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in an aromatic ring. For example, in some embodiments, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (which moiety is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while a 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl group (which moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group.

[0044] Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl. , indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. In some embodiments, the term "heteroaryl" includes 5-10 membered heteroaryl, 6-10 membered heteroaryl, 7-10 membered heteroaryl, 8-10 membered heteroaryl, 9-10 membered heteroaryl, 5-9 membered heteroaryl, 6-9 membered heteroaryl, 7-9 membered heteroaryl, 8-9 membered heteroaryl, 5-8 membered heteroaryl, 6-8 membered heteroaryl, 7-8 membered heteroaryl, 5-7 membered heteroaryl, 6-7 membered heteroaryl, or 5-6 membered heteroaryl.

[0045] In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") encompass both substituted and unsubstituted forms of the indicated radical. The term "substituted" means that the specified group or moiety bears one or more substituents, including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, and the like. The term "unsubstituted" means that the specified group bears no substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any position permitted by the valences of the system. When a group or moiety bears two or more substituents, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituted group or moiety has 1 to 5 substituents. In some embodiments, a substituted group or moiety has one substituent. In some embodiments, a substituted group or moiety has two substituents. In some embodiments, a substituted group or moiety has three substituents. In some embodiments, a substituted group or moiety has four substituents. In some embodiments, a substituted group or moiety has five substituents.

[0046] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description encompasses instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group that contains one or more substituents, it will be understood by those of skill in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical, and / or inherently unstable. When a group or moiety is optionally substituted, it will also be understood that the present disclosure encompasses both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

[0047] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0048] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0049] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0050] As used herein, a wavy line crossing a bond in a chemical structure [ka] indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the rest of the molecule or the rest of a molecular fragment.

[0051] As used herein, the group within the brackets (e.g., X a ) followed by a subscript to represent an integer range (e.g., (X a ) 0~1) means that the group can have the number of occurrences indicated by the integer range. For example, (X a ) 0~1 is X a It means that the group may be absent or may occur once.

[0052] "Diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate using high-resolution analytical procedures such as electrophoresis and chromatography.

[0053] "Enantiomer" refers to a compound of two stereoisomers which are non-superimposable mirror images of one another.

[0054] Stereochemical definitions and conventions used herein are generally those set forth in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley. & Sons, Inc., New York, 1994. The compounds of the present disclosure may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present disclosure, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, e.g., racemic mixtures, are intended to be part of this disclosure. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0055] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0056] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. Certain compounds of the present disclosure may exist in solvated forms, including unsolvated and hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure.

[0057] As used herein, the term "cocrystal" refers to a solid that is a crystalline single-phase substance composed of two or more different molecular or ionic compounds, generally in a stoichiometric ratio, that are not solvates or simple salts. A cocrystal consists of two or more components that form a unique crystal structure with unique properties. Typically, a cocrystal is characterized by a crystal structure that is usually held together by freely reversible non-covalent interactions. As used herein, a cocrystal refers to a crystal structure refers to a compound of the present disclosure and at least one other component in a predetermined stoichiometric ratio to form

[0058] As used herein, the term "protecting group" refers to a substituent typically employed to block or protect a particular functional group in a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see P. G. M. Butts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.

[0059] As used herein, the term "pharmaceutically acceptable salts" is intended to encompass salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present disclosure has a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholinium, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. In cases where a compound of the present disclosure possesses a relatively basic functionality, an acid addition salt may be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids, such as arginine acid, and organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0060] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this disclosure.

[0061] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; all racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are intended to be encompassed within the scope of the present disclosure.

[0062] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more atomic positions that constitute such compounds.For example, the present disclosure also encompasses the isotopically labeled variants of the present disclosure, which are identical to those detailed herein, except that one or more atoms are replaced with atoms that have atomic mass or mass number different from the primary atomic mass or mass number of the atom that is usually found in nature.All isotopes of any specified specific atom or element are intended to be within the scope of the compounds of the present disclosure, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example, 2 H("D"), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O.18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of the present disclosure, such as 3 H or 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Heavier isotopes, such as deuterium (i.e., 2 Further substitution with positron-emitting isotopes, such as H, may afford certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. 15 O. 13 N, 11 C, and 18 F is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can be prepared following procedures analogous to those disclosed in the following schemes and / or examples herein, generally by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0063] "Treating" a disease in a patient or "treatment" of a patient's disease refers to inhibiting or reducing the onset of the disease; or ameliorating or causing regression of the disease. As used herein, "treatment" or "treating" is an effort to achieve a beneficial or desired result, including a clinical outcome. In accordance with the scope of this disclosure, a beneficial or desired result includes, but is not limited to, one or more of the following: reducing one or more symptoms resulting from a disease or disorder, attenuating the severity of a disease or disorder, stabilizing a disease or disorder (e.g., preventing or delaying worsening of a disease or disorder), delaying the onset or recurrence of a disease or disorder, delaying or slowing the progression of a disease or disorder, improving the condition of a disease or disorder, causing remission (whether partial or complete) of a disease or disorder, reducing the dose of one or more other drugs required to treat the disease or disorder, enhancing the effectiveness of another drug used to treat a disease or disorder, delaying the progression of a disease or disorder, increasing the quality of life, and / or extending the survival of a patient. Reduction of the pathological consequences of a disease or disorder is also encompassed by "treatment." The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0064] "Preventing" a disease in a patient, "preventing" a disease in a patient, or "prophylaxis" of a disease in a patient refers to preventing the disease from occurring in a patient who is predisposed to developing the disease or who does not yet exhibit symptoms of the disease.

[0065] The phrase "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0066] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0067] It will be understood that certain features of the present disclosure, which are described in separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features of the present invention, which are described in a single embodiment for brevity, may be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables, so long as such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically embraced by the present invention and disclosed herein, just as if every combination were individually and explicitly disclosed. In addition, all subcombinations of chemical groups listed in embodiments describing such variables are also specifically embraced by the present invention and disclosed herein, just as if every such subcombination of chemical groups were individually and explicitly disclosed herein.

[0068] II. Compounds In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X is NR 3’ or CR 3 and Y is NR 2 or CR 4 and X is NR 3’ If Y is CR 4 and Y is CR 5 and X is CR 5 or X has a single bond to CR 3 If Y is NR 2 and Y is CR 5and X has a single bond to CR 5 having a double bond to R 0 teeth, [ka] is the basis of m is an integer from 0 to 3, Each R 1 are independently -D, -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 1wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; R 2 is —H, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl, or -CN; R 4 is —H, C1-C3 alkyl, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, R 6 is -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, C1-C6 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; R 7’ and R 8’ Each pair, together with the nitrogen atom to which they are attached, independently forms a 3- to 8-membered complex. forming a heterocyclic ring, the heterocyclic ring optionally containing 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , -NR 7 R 8 , C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CN, S(O) n C1-C3 alkyl, or S(O) n C3-C6 cycloalkyl, n is an integer from 0 to 2, Each R 10 are independently -H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl, C1-C3 alkoxy, and / or 1 to 6 deuterium atoms, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0069] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X is NR 3’ or CR 3 and Y is NR 2 or CR 4 and X is NR 3’ If Y is CR 4 and Y is CR 5 and X is CR 5 or X has a single bond to CR 3 If Y is NR 2 and Y is CR 5 and X has a single bond to CR 5 having a double bond to R 0 teeth, [ka] is the basis of m is an integer from 0 to 3, Each R 1 are independently -D, -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 1 The alkyl, alkylene, cycloalkylene, and the heterocycloalkylene moiety is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; R 2 is —H, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or -CN; R 3’is -H, C1-C3 alkyl, -C3-C6 cycloalkyl, or -CN; R 4 is —H, C1-C3 alkyl, or halogen, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, R 6 is -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, C1-C6 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl; R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , -NR 7 R 8 , C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CN, S(O) n C1-C3 alkyl, or S(O) n C3-C6 cycloalkyl, n is an integer from 0 to 2, Each R 10 are independently -H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl, C1-C3 alkoxy, and / or 1 to 6 deuterium atoms, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0070] In some embodiments of this aspect of the invention, R 0 teeth, [ka] R0 but [ka] In some embodiments, m is an integer of 0, 1, 2, or 3. In some embodiments, m is 0. In other embodiments, m is 1. In still other embodiments, m is 2. In still other embodiments, m is 3. In other embodiments of this aspect of the invention, R 0 teeth, [ka] is.

[0071] In some embodiments, the compound of Formula (I) has Formula (IA) or Formula (IB): [ka] is a compound of

[0072] In some embodiments, each R 1 are independently -D, -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1~C3A alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’, C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ where R 1 wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl.

[0073] In some embodiments, each R 1 are independently -D, -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ where R 1The alkyl, alkylene, cycloalkylene, and heterocycloalkylene portions of are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, each R 1 are independently -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ where R 1 wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, each R 1 is independently -D, -F, C1-C3 alkyl. In some embodiments, each R 1 are independently C1-C3 alkyl, C1-C3 alkylene-NR 7 R8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, or C1-C3 alkylene-CN. In some embodiments, each R 1 are independently C1-C3 alkylene-NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ In some embodiments, each R 1 are independently C1-C3 alkylene-NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ is 。 In some embodiments, each R 1 is independently C1-C3 alkylene-OH, C1-C3 alkylene-CN, or C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH. 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, where R 1 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 3-8 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, where R 1 R 7’ and R 8 Each pair of R', together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl. In some embodiments, each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH. In certain embodiments, each R 1 is -F. In some embodiments, each R 1are independently C1-C3 alkylene-NR 7’ R 8’ In certain embodiments, each R 1 is independently an optionally substituted -C1-C2 alkylene-N-morpholinyl or an optionally substituted -C1-C2 alkylene-N-piperazinyl. 1 is, independently, arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] or optionally substituted [ka] In certain embodiments, each R 1 is, independently, arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] or optionally substituted [ka] In some embodiments, each R 1 is, independently, [ka] In certain embodiments, each R 1 is, independently, [ka] In certain other embodiments, each R 1 is, independently, [ka] In still other embodiments, each R 1 is, independently, [ka] In some embodiments, each R 1 is independently C1-C3 alkylene-OH. In certain other embodiments, each R 1 is independently -C1-C2 alkylene-OH. In certain embodiments, each R 1 is independently -CHOH, -CHCHOH, -CH(OH)CH, -CHCHCHOH, -CHCH(OH)CH, or -CH(CN)CHCH. In certain other embodiments, each R 1 is independently —CHOH or —CHCHOH.

[0074] In some embodiments of this aspect of the invention, X is CR 3 and Y is NR 2 X is CR 3 and Y is NR 2 In some embodiments, R 2 is —H, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms; R 3is —H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or —CN.

[0075] In some embodiments, R 2 is —H, C1-C3 alkyl, or C3-C6 cycloalkyl, where the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 2 is —H or C1-C3 alkyl, where the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 2 is —H or C-C cycloalkyl. In some embodiments, R 2 is C1-C3 alkyl or C3-C6 cycloalkyl, where the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 2 is —H. In some embodiments, R 2 is a C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 2 is —CH3, —CH2CH3, —CH2CH2CH3, or —CH(CH3)2, where —CH3, —CH2CH3, —CH2CH2CH3, or —CH(CH3)2 is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms. 2 is C-C cycloalkyl. In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0076] In some embodiments, R 2 is -H, -CH, -CD, -CHF, or -CHCH. In some embodiments, R 2is -CH, -CD, -CHF, or -CHCH. In some embodiments, R 2 is -H, -CD, -CHF, or -CHCH. In some embodiments, R 2 is -H, -CH, -CHF, or -CHCH. In some embodiments, R 2 is -H, -CH, -CD, or -CHCH. In some embodiments, R 2 is -H, -CH, -CD, or -CHF. In some embodiments, R 2 is -CH, -CD, or -CHF. In some embodiments, R 2 is —CH, or —CHCH. In some embodiments, R 2 is -H or -CH3.

[0077] In some embodiments, R 3 is -H, C1-C3 alkyl, C3 cycloalkyl, In some embodiments, R 3 is —H, C1-C3 alkyl, C3-C6 cycloalkyl, or halogen. 3 is —H, C1-C3 alkyl, C3-C6 cycloalkyl, or —CN. In some embodiments, R 3 is —H, C1-C3 alkyl, halogen, or —CN. In some embodiments, R 3 is —H, C-C cycloalkyl, halogen, or —CN. In some embodiments, R 3 is C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or -CN. 3 is —H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen, or —CN. In some embodiments, R 3 is -H, -F, -CH, or -CN. In some embodiments, R 3 is -H, -F-, or -CH3. In some embodiments, R 3is -H, -F-, or -CN. In some embodiments, R 3 is —H, —CH, or —CN. In some embodiments, R 3 is -F, -CH, or -CN. In some embodiments, R 3 is -H or -F. In some embodiments, R 3 is —H or —CH. In some embodiments, R 3 is —H or —CN. In some embodiments, R 3 is -F or -CH. In some embodiments, R 3 is -F or -CN. In some embodiments, R 3 is —CH or —CN. In some embodiments, R 3 is —H. In some embodiments, R 3 is -F. In some embodiments, R 3 is —CH. In some embodiments, R 3 is -CN.

[0078] In some embodiments, R 2 is -CH3, CD3, or -CH2CH3, and R 3 is -H, -F, -CH, or -CN. In some embodiments, R 2 is -CH3 and R 3 is -H, -F, -CH, or -CN. In some embodiments, R 2 is -CD3 and R 3 is -H, -F, -CH, or -CN. In some embodiments, R 2 is -CH2CH3, and R 3 is -H, -F, -CH, or -CN. In some embodiments, R 2 is -CH3, -CD3, or -CH2CH3, and R 3 is —H. In some embodiments, R 2 is -CH3, -CD3, or -CH2CH3, and R 3 is -F. In some embodiments, R 2is -CH3, CD3, or -CH2CH3, and R 3 is —CH. In some embodiments, R 2 is -CH3, -CD3, or -CH2CH3, and R 3 is -CN. In some embodiments, R 2 is -CH3, -CD3, or -CH2CH3, and R 3 is -H, -F, -CH, or -CN. In some embodiments, R 2 is -CH3 and R 3 is —H or —CH. In some embodiments, R 2 is -CH3 and R 3 is —H. In some embodiments, R 2 is -CH3 and R 3 is —CH. In some embodiments, R 2 is -H or -CH3, and R 3 is —H. In some embodiments, R 2 is -H, and R 3 is —H. In some embodiments, R 2 is -CH3 and R 3 is -H.

[0079] In another embodiment of this aspect of the invention, X is NR 3’ and Y is CR 4 X is NR 3’ and Y is CR 4 In some embodiments, R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl, or -CN, and R 4 is -H, C1-C3 alkyl, or halogen, where the C1-C3 alkyl is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms.

[0080] In some embodiments, R 3’ is —H, C1-C3 alkyl, or C3-cycloalkyl. In some embodiments, R 3’is —H, C1-C3 alkyl, or —CN. In some embodiments, R 3’ is —H, C cycloalkyl, or —CN. In some embodiments, R 3’ is C1-C3 alkyl, C3 cycloalkyl, or -CN. In some embodiments, R 3’ is -H or C1-C3 alkyl In certain embodiments, R 3’ is —H or —CH. In some embodiments, R 3’ is —H or C cycloalkyl. In some embodiments, R 3’ is —H or —CN. In some embodiments, R 3’ is C1-C3 alkyl or C3 cycloalkyl. In some embodiments, R 3’ is C1-C3 alkyl or -CN. In some embodiments, R 3’ is C cycloalkyl or —CN. In some embodiments, R 3’ is H. In some embodiments, R 3’ is C1-C3 alkyl. In certain embodiments, R 3’ is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In certain embodiments, R 3’ is —CH. In some embodiments, R 3’ is C cycloalkyl. In some embodiments, R 3’ is -CN.

[0081] In some embodiments, R 4 is —H or C1-C3 alkyl, where the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 4 is —H or halogen. In some embodiments, R 4 is a C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms.4 is —H. In some embodiments, R 4 is a C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 4 is —CH3, —CH2CH3, —CH2CH2CH3, or —CH(CH3)2, where —CH3, —CH2CH3, —CH2CH2CH3, or —CH(CH3)2 is optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms. 4 is CH3. In some embodiments, R 4 is halogen. In certain embodiments, R 4 is -F, -Cl, or -Br. In certain other embodiments, R 4 is -F. In some embodiments, R 4 is -H, -F, or -CH. In some embodiments, R 4 is -H, -CH, -CD, -CHF, -CHCH, or halogen. 4 is -H, -CH, -CD, -CHF, or -CHCH. In some embodiments, R 4 is —H, —CH, —CD, —CHF, or halogen. In some embodiments, R 4 is -H, -CH, -CD, -CHCH, or halogen. In some embodiments, R 4 is —H, —CH, —CHF, —CHCH, or halogen. In some embodiments, R 4 is -H, -CD, -CHF, -CHCH, or halogen. In some embodiments, R 4 is —CH, —CD, —CHF, —CHCH, or halogen. In some embodiments, R 4 is —H or halogen. In some embodiments, R 4 is —CH or —CHCH. In some embodiments, R 4is -CH3, -CD3, or -CHF2.

[0082] In some embodiments, R 3’ is -H or -CH3, and R 4 is -H, -F, or -CH. In some embodiments, R 3’ is -H, and R 4 is -H, -F, or -CH. In some embodiments, R 3’ is -CH3 and R 4 is -H, -F, or -CH. In some embodiments, R 3’ is -H or -CH3, and R 4 is —H. In some embodiments, R 3’ is -H or -CH3, and R 4 is -F. In some embodiments, R 3’ is -H or -CH3, and R 4 is -CH3. In certain embodiments, R 3’ is -H, and R 4 is —H. In certain embodiments, R 3’ is -H, and R 4 is -F. In certain embodiments, R 3’ is -H, and R 4 is -CH3. In certain embodiments, R 3’ is -CH3 and R 4 is —H. In certain embodiments, R 3’ is -CH3 and R 4 is -F. In certain other embodiments, R 3’ is -CH3 and R 4 is -CH3.

[0083] In some embodiments, R 5 C6~C 14 aryl or 5-10 membered heteroaryl, wherein the C6-C 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9In some embodiments, R 5 C6~C 14 aryl, wherein the C6 to C 14 Aryl is 1 to 5 R 9 In some embodiments, R 5 is phenyl, wherein the phenyl is selected from 1 to 5 R 9 In some embodiments, R 5 is a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from 1 to 5 R 9 In some embodiments, R 5 teeth, [ka] is a 5-10 membered heteroaryl selected from the group consisting of: [ka] represents a single bond or a double bond, and the C6 to C 14 Aryl or the 5- to 10-membered heterocyclic The aryl group is a group consisting of 1 to 5 R 9 In some embodiments, R 5 teeth, [ka] is a 5-10 membered heteroaryl selected from the group consisting of: [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 In some embodiments, R 5 teeth, [ka] is a 5-10 membered heteroaryl selected from the group consisting of: [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 In some embodiments, R 5 teeth, [ka] wherein the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 In some embodiments, R 5 teeth, [ka] wherein the phenyl or the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 is optionally substituted with a group.

[0084] In some embodiments, R 5 teeth, [ka] is a 5-10 membered heteroaryl selected from the group consisting of: [ka] represents a single bond or a double bond, and the C6 to C 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 In some embodiments, R 5 is phenyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is [ka] wherein: [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 In some embodiments, R 5 is phenyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is [ka] wherein the phenyl or the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 is optionally substituted with a group.

[0085] In some embodiments, R 6 is -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, C1-C6 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl.

[0086] In some embodiments, R 6 is -H, C1-C6 alkyl, C3-C6 cycloalkyl C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, C1-C6 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl.

[0087] In some embodiments, R6 is C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkylene-NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 The alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions of are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. 6 is C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkylene-NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’, C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 The alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions of are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, or C1-C6 alkylene-CN. In some embodiments, R 6 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ In some embodiments, R 6 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ In some embodiments, R 6 is C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C6 alkylene-OH, or C1-C6 alkylene-CN. In some embodiments, R 6 is C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4-8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C3-C7 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ In some embodiments, R 6 is C1-C6 alkylene-NR 7 R 8 , C1-C6 alkylene-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ In other embodiments, R 6 is C1-C6 alkylene-OH or C1-C6 alkylene-CN. In some embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ In certain embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ And this So, R 6 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 3-8 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In certain other embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ where R 6 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocyclic ring, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, R 6 is C1-C3 alkyl. In certain embodiments, R 6 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In certain other embodiments, R 6 is -CH2CH3. In some embodiments, R 6 is C1-C3 alkylene-NR 7’ R 8 ’ In certain embodiments, each R 6 is independently an optionally substituted -C1-C2 alkylene-N-morpholinyl or an optionally substituted -C1-C2 alkylene-N-piperazinyl. 6 is, independently, arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] or optionally substituted [ka] In certain embodiments, each R 6 is, independently, [ka] arbitrarily substituted [ka] arbitrarily substituted [ka] or optionally substituted [ka] In some embodiments, each R 6 is, independently, [ka] In certain embodiments, each R 6 is, independently, [ka] In certain other embodiments, each R 6is, independently, [ka] In still other embodiments, each R 6 is, independently, [ka] is.

[0088] In some embodiments, each R 7 is independently —H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl. 7 is independently —H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl. 7 is independently —H. In some embodiments, each R 7 is independently C1-C3 alkyl. In certain embodiments, each R 7 is independently -CH, -CHCH, -CHCHCH, or -CH(CH). In some embodiments, each R 7 is independently C-C cycloalkyl. In certain embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 7 is independently C2-C3 haloalkyl. In certain embodiments, each R 7 is independently a C2-C3 haloalkyl, where each halogen atom in each C2-C3 haloalkyl is independently -F, -Cl, or -Br. 7 is independently C2-C3 alkylene-CN. In certain embodiments, each R 7is independently —CH2CH2CN, —CH(CN)CH3, —CH2CH2CH2CN, —CH2CH(CN)CH3, —CH(CN)CH2CH3, or —CH(CH2CN)CH3. In some embodiments, each R 7 is independently C2-C3 heteroalkyl. In certain embodiments, each R 7 are independently -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, or -CH(OH)CH2CH3, -CH2OCH3, -CH2OCH2CH3, -C H2CH2OCH3, -CH(OCH3)CH3, -CH(CH2OH)CH3, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2, -CH2CH(NH2)CH3, or -CH(NH2)CH2CH3, -CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH3, -CH(NHCH 3) CH3, -CH(CH2NH2CH3, -CH2CH2SH, -CH(SH)CH3, -CH2CH2CH2SH, -CH2CH(SH)CH3, or -CH(SH)CH2CH3, -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, -CH(SCH3)CH3, or -CH(CH2SH)CH3.

[0089] In some embodiments, each R 8 is independently —H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN, or C1-C6 heteroalkyl. 8 is independently —H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl. 8 is independently —H. In some embodiments, each R 8 is independently C1-C3 alkyl. In certain embodiments, each R 8 is independently -CH, -CHCH, -HCHCH, or -CH(CH). In some embodiments, each R 8is independently C-C cycloalkyl. In certain embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R 8 is independently C2-C3 haloalkyl. In certain embodiments, each R 8 is independently a C2-C3 haloalkyl, where each halogen atom in each C2-C3 haloalkyl is independently -F, -Cl, or -Br. 8 is independently C2-C3 alkylene-CN. In certain embodiments, each R 8 is independently —CH2CH2CN, —CH(CN)CH3, —CH2CH2CH2CN, —CH2CH(CN)CH3, —CH(CN)CH2CH3, or —CH(CH2CN)CH3. In some embodiments, each R 8 is independently C2-C3 heteroalkyl. In certain embodiments, each R 8 are independently -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, or -CH(OH)CH2CH 3、 -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH(OCH3)CH3, -CH(CH2OH)CH3, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2, -CH2CH(NH2)CH3, or -CH(NH2)CH2CH 3, -CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH3, -CH(NHCH3)CH3, -CH(CH2NH2CH3, -CH2CH2SH, -CH(SH)CH3, -CH2CH2CH2SH, -CH2CH(SH)CH3, or -CH(SH)CH2CH 3、 -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, -CH(SCH3)CH3, or -CH(CH2SH)CH3.

[0090] In some embodiments, R 7’ and R 8’each pair, together with the nitrogen atom to which they are attached, independently form a 3-8 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. In some embodiments, R 1 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 3-8 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl. 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, which optionally contains 1 to 2 additional heteroatoms selected from the group consisting of N, O, and S. Each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl. 1 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocycle, which optionally contains 1 to 2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl.

[0091] In some embodiments, each R 9 are independently halogen, -OR 10 , -NR 7 R 8 , C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -CN, S(O)n C1-C3 alkyl, or S(O) n C3-C6 cycloalkyl, where n is an integer from 0 to 2. In some embodiments, each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, —CF2H, —CF3, C3-C6 cycloalkyl, or —CN. In some embodiments, each R 9 are independently -F, -Cl, -OR 10 , —CH, or —CN. In some embodiments, each R 9 are independently -F, -OR 10 or -CH3. In some embodiments, each R 9 are independently -F or -OR 10 In certain embodiments, each R 9 are independently -F, -OH, -OCH3, or -OCD3.

[0092] In some embodiments, each R 10 are independently -H, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl, C1-C3 alkoxy, and / or 1 to 6 deuterium atoms. 10 are independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl and / or C1-C3 alkoxy and / or 1 to 6 deuterium atoms. 10 is independently -H, -CH, -CD, -CHCH, or cyclopropyl, wherein the -CH or the -CHCH is optionally substituted with hydroxyl and / or -OCH. 10 is independently -H, -CH, -CD, or -CHCH, wherein the -CH or the -CHCH is optionally substituted with hydroxyl and / or -OCH. 10is independently -H, -CH, -CD, -CFH, or -CF. In some embodiments, each R 10 are independently -H or -CH3.

[0093] In some embodiments, the compound of Formula (I) has the formula (IA): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0094] In some embodiments, the compound of Formula (I) or Formula (IA) has Formula (IAi) or (IA-ii): [ka] A compound of the formula: m is an integer of 0 or 2, Each R 1 are independently -F, C1-C3 alkyl, C1-C3 alkylene -NR 7 R 8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 1wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; and R 2 is -H, -CH3, CD3, -CHF2, or -CH2CH3, R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl, or -CN; R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] is selected from the group consisting of [ka] represents a single bond or a double bond, and the C6 to C 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, Each R 7 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl, and each R 8 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl; R 7’ and R 8’each pair, together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocycle, which optionally contains 1 to 2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently selected from C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 aryl, optionally substituted with alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl, or -CN; Each R 10 are independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl and / or C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0095] In some embodiments, each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, where R 1 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocycle, which optionally contains 1 to 2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl.

[0096] In some embodiments, R 5 is phenyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is [ka] is selected from the group consisting of [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 is optionally substituted with a group.

[0097] In some embodiments, R 2 is -CH3, CD3, or -CH2CH3, and R 3 is -H, -F, -CH3, or -CN, and R 3’ is -H or -CH3, and R 4 is -H, -F, or -CH3.

[0098] In some embodiments, each R 9 are independently -F, -Cl, -OR 10 , -CH3, or -CN, and each R 10 are independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0099] In some embodiments, the compound of Formula (I) is a compound of Formula (IAi) or Formula (IA-ii), wherein m is an integer of 0 or 1, and R 1 -F, C1~C 3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, and R 2 is -CH3, CD3, or -CH2CH3, and R 3 is -H, -F, -CH3, or -CN, and R 3’ is -H or -CH3, and R 4 is -H, -F, or -CH3, and R 5 is phenyl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] is selected from the group consisting of [ka] represents a single bond or a double bond, and the phenyl or the 5- to 10-membered heteroaryl is 9 optionally substituted with R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocycle, which optionally contains 1 to 2 additional heteroatoms selected from the group consisting of N and O, and any primary or secondary amine nitrogen atom present in the heterocycle is optionally substituted with H or C1-C3 alkyl; and each R 9 are independently -F, -Cl, -OR 10 , -CH3, or -CN, and each R 10 are independently -H, -CH3, -CD3, or -CH2CH3, wherein the -CH3 or the -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0100] In some embodiments, the compound of Formula (I) is a compound of Formula (IAi) or Formula (IA-ii), wherein m is an integer of 0 or 1, and R 1 is -F and R 2 is -CH3 and R 3 is -H or -CH3, and R 3’ is -H or -CH3, and R 4 is -CH3 and R 5 is a 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 groups, and each R 9 are independently -F or -OR 10 and each R 10 are independently —H or —CH 3 .

[0101] In some embodiments, the compound of formula (I) has formula (IB): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.

[0102] In some embodiments, the compound of Formula (I) or Formula (IB) has Formula (IBi) or (IB-ii): [ka] A compound of the formula: R 2 is -H, -CH3, CD3, -CHF2, or -CH2CH3, R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen, or -CN; R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl, or -CN; R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R 5 C6~C 14 aryl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] is selected from the group consisting of [ka] represents a single bond or a double bond, and the C6 to C 14 The aryl or the 5- to 10-membered heteroaryl may be substituted with 1 to 5 R 9 optionally substituted with a group, R 6 is C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkylene-NR 7 R8 , C1-C3 alkylene-NR 7’ R 8’ , C1-C3 alkylene-OH, C1-C3 alkylene-CN, C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ and R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene portions are optionally substituted with 1 to 3 fluorine atoms and / or 1 to 6 deuterium atoms, and each heterocyclic nitrogen atom, if present, is independently selected from C1 to C3 alkyl, C3 to C6 cycloalkyl, C2 to C3 haloalkyl, C and optionally substituted with C2-C3 alkylene-CN, or C2-C3 heteroalkyl, and each R 7 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl, and each R 8 are independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN, or C2-C3 heteroalkyl; R 7’ and R 8’each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl, or -CN; Each R 10 are independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxyl and / or C1-C3 alkoxy.

[0103] In some embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ where R 6 R 7’ and R 8’ each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C-C alkyl, C-C cycloalkyl, C-C haloalkyl, C-C alkylene-CN, or C-C heteroalkyl.

[0104] In some embodiments, R 5 is phenyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is [ka] wherein the phenyl or the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 is optionally substituted with a group.

[0105] In some embodiments, each R 9 are independently -F, -OR 10 , -CH3, and each R 10 are independently -H, -CH3, -CD3, -CF2H, or -CF3.

[0106] In some embodiments, R 2 is -H or -CH3, and R 3 is -H, and R 3’ is -H, and R 4 is -H or -CH3.

[0107] In some embodiments, the compound of Formula (I) is a compound of Formula (IBi) or Formula (IB-ii), wherein R 2 is -H or -CH3, and R 3 is -H, and R 3’ is -H, and R 4 is -H or -CH3, and R 5 is phenyl or 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is [ka] wherein the phenyl or the 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 R 9 optionally substituted with R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ and R 7’ and R 8’each pair, together with the nitrogen atom to which they are attached, independently form a 4-6 membered heterocycle, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and each heterocycle nitrogen atom, if present, is independently optionally substituted with C-C alkyl, C-C cycloalkyl, C-C haloalkyl, C-C alkylene-CN, or C-C heteroalkyl; and each R 9 are independently -F, -OR 10 , -CH3, and each R 10 are independently -H, -CH3, -CD3, -CF2H, or -CF3.

[0108] In some embodiments, a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0109] Although certain compounds described in Table 1 are depicted as particular stereoisomers and / or non-stereochemical forms, it is understood that any or all non-stereochemical forms and any or all stereochemical forms are described herein, including any enantiomeric or diastereomeric form, and any tautomeric or other form, of any of the compounds in Table 1. In some embodiments, the compounds described herein are selected from Compound Nos. 1-147.

[0110] The present disclosure also encompasses all salts, such as pharmaceutically acceptable salts, of the compounds referred to herein. The present disclosure also encompasses any enantiomeric or diastereomeric forms of the compounds described, and any tautomeric or other forms, such as N-oxides, solvates, hydrates, or isotopomers, including any or all stereochemical forms. The present disclosure also encompasses cocrystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the depicted compound. In addition, when a specific stereochemical form is depicted, it is understood that other stereochemical forms are also encompassed by the present invention. All forms of the compounds, including crystalline and amorphous forms of the compounds, are also encompassed by the present invention. Compositions comprising the compounds of the present invention, for example, compositions of substantially pure compounds containing a specific stereochemical form, are also contemplated. Compositions comprising mixtures of the compounds of the present invention in any ratio, including mixtures of two or more stereochemical forms of the compounds of the present invention, are also encompassed by the present invention, and thus include racemic, non-racemic, enantiomerically enriched, and scalemic mixtures of the compounds.

[0111] It will be understood that in the description herein, every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of any other moiety, as if every combination of descriptions were specifically and individually recited. For example, R 0 All descriptions, variations, embodiments, or aspects provided herein regarding X, Y, m, R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 7’ , R 8 , R 8’ , R 9 , and / or R 10Furthermore, all descriptions, variations, embodiments, or aspects of formula (I) apply equally to other formulas detailed herein, where applicable, as if every description, variation, embodiment, or aspect were set forth separately and individually for every formula. For example, any description, variation, embodiment, or aspect of formula (I) applies equally to, and is equally described with respect to, any of formulas (IA), (IAi), (IB), (IBi), and (IB-ii), where applicable, detailed herein, as if every description, variation, embodiment, or aspect were separately and individually described for every formula.

[0112] III. General Synthesis Methods The compounds of the present disclosure can be prepared by a number of processes, such as those generally described below and more specifically described in the Examples below (e.g., the schemes provided in the Examples below). In the process descriptions below, the symbols used in the formulas shown should be understood to represent the groups described above in connection with the formulas herein.

[0113] The intermediates described in the following preparations may contain multiple nitrogen-protecting groups, hydroxy-protecting groups, and acid-protecting groups, such as esters. The variable protecting groups may be the same or different in each occurrence, depending on the specific reaction conditions and the specific transformation being performed. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature. See, for example, Greene and Wuts, Protective Groups in Organic Synthesis, (T. Greene and P. Wuts, eds., 2nd ed. 1991).

[0114] Certain stereochemical centers remain unidentified, and certain substituents are omitted in the following schemes for clarity, but are not intended to limit the teachings of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers can be separated or resolved by those skilled in the art by methods such as selective crystallization techniques or chiral chromatography at any convenient point in the synthesis of the compounds of the invention (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds," Wiley-Interscience, 1994).

[0115] The compounds of the present invention, or their pharmaceutically acceptable salts, solvates, hydrates, or co-crystals, or mixtures of any of the foregoing, can be prepared by a variety of procedures known in the art, some of which are illustrated in the following examples. The specific synthetic steps of each of the described routes can be combined in various ways to prepare the compounds of the present disclosure or their salts. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to those skilled in the art. Others can be made by the procedures described in the following examples, including standard techniques of organic and heterocyclic chemistry analogous to the synthesis of known compounds of similar structure, as well as any novel procedures.

[0116] Compounds of formula (I) can be prepared according to Scheme A, Scheme B, Scheme C, Scheme D, Scheme E, Scheme F, Scheme G, Scheme H, Scheme I, and Scheme J, wherein R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R6 and m are as defined for Formula (I) or any applicable variations thereof detailed herein. More specifically, compounds of formula (IA), (IAi), and (IA-ii) can be prepared as described in Scheme A, Scheme B, Scheme E, Scheme F, Scheme I, and Scheme J, and compounds of formula (IB), (IBi), and (IB-ii) can be prepared as described in Scheme A, Scheme B, Scheme C, Scheme D, Scheme E, Scheme F, Scheme G, Scheme H, Scheme I, and Scheme J. [ka] [ka] [ka]

[0117] Compounds of formula (IAi) can be prepared by the general synthetic scheme shown in parts I-III of Scheme A. In part I of Scheme A, a 6-azaindole compound of general formula Aia (wherein LG 1 is a leaving group (e.g., chloro or bromo) when 1 The imidazolyl nitrogen is protected with (e.g., with a Boc or SEM group) R 5 In preparation for the introduction of the moiety, a suitable leaving group LG 2 (e.g., iodine) is added to a protected compound of general formula Aib. The resulting compound of general formula Aic can then be further modified to include the substituent R required to generate intermediate compounds of general formula Aih. 2’ and R 3 As shown in Scheme A, R 2’ is R 2 R as described herein unless is hydrogen. 2 has the same definition as 2’ is a protecting group P1 Similarly, the substituent R 3” is R 3” R, except that does not contain hydrogen. 3 It has the same definition as LG. 3 and L.G. 4 is a leaving group such as chloro, bromo, or iodo.

[0118] In Part II of Scheme A, R 5 The aryl or heteroaryl moiety is LG of a compound of the general formula Aih 2 It is added to the position occupied by R 5 The introduction of the moiety can be achieved, for example, by the two routes shown above. In the first route, a compound of general formula Aih is reacted with the desired R 5 with a suitable boronic acid derivative Aik containing a group, where R A and R B are independently selected from the group consisting of halogen, OH, and O—(C1-C6 alkyl), or R A and R B form a 5- to 10-membered heterocycle together with the boron atom to which they are attached. In the second route, compounds of formula Aih are reacted directly with boronic acids or derivatives thereof to give 6-azaindyl-boronic ester compounds of formula Aii, where R c is a suitable leaving group (e.g., O-C1-C3 alkyl or (i.e., in a diboron compound) another boronic acid or derivative thereof). The resulting boronic ester compound can be reacted with R 5 The compound (Aij) is further reacted with a substrate (Aij) containing

[0119] In part III of Scheme A, a compound of formula Ail is reacted with a suitable cyclopropanecarboxamide of formula Aim to provide a compound of formula IAi. [ka] [ka] [ka]

[0120] Similar to Scheme A, Scheme B describes the preparation of compounds of formula (IA-ii) having a 5-azaindole core. Compounds of formula (IA-ii) can be prepared by the general synthetic scheme shown in parts I-III of Scheme B. In part I of Scheme B, a 5-azaindole compound of general formula A-ii-a (wherein LG 1 is a leaving group (e.g., chloro or bromo) when 1 The imidazolyl nitrogen is protected with (e.g., with a Boc or SEM group) R 5 In preparation for the introduction of the moiety, a suitable leaving group LG 2 (e.g., iodo) is added to a protected compound of general formula A-ii-b. The resulting compound of general formula A-ii-c can then be further modified to include the substituent R required to generate intermediate compounds of general formula A-ii-h. 4’ and R 3’” As shown in Scheme B, the substituent R 3’” is R 3’” R unless is hydrogen 3 has the same definition as 3’” is a protecting group P 1 Similarly, R 4’ is R 4’ R as described herein, except that does not contain hydrogen. 4 It has the same definition as LG. 3 and L.G. 4 is a leaving group such as chloro, bromo, or iodo.

[0121] In Part II of Scheme B, R 5 The aryl or heteroaryl moiety is LG of a compound of general formula A-ii-h2 It is added to the position occupied by R 5 The introduction of the moiety can be achieved, for example, by two routes as shown above. In the first route, a compound of general formula A-ii-h is converted to the desired R 5 with a suitable boronic acid derivative A-ii-k containing a group, wherein R A and R B are independently selected from the group consisting of halogen, OH, and O—(C1-C6 alkyl), or R A and R B form a 5- to 10-membered heterocycle together with the boron atom to which they are attached. In the second route, compounds of formula A-ii-h are reacted directly with boronic acids or derivatives thereof to give 5-azaindolyl-boronic ester compounds of formula A-ii-i, where R c is a suitable leaving group (e.g., O-C1-C3 alkyl or (i.e., in a diboron compound) another boronic acid or its derivative). The resulting boronic ester compound can be deprotected by removing R 5 The compound (A-ii-j) is further reacted with a substrate containing

[0122] In part III of Scheme B, a compound of formula A-ii-l is reacted with a suitable cyclopropanecarboxamide of formula A-ii-m to give a compound of formula IA-ii.

[0123] Compounds of formula (IB) can also be prepared by the general synthetic schemes shown in Scheme C and Scheme D. In Scheme C, a 6-azaindolyl compound of formula A1 obtained by Scheme A (Part I and Part II) is reacted with a suitable urea compound of formula Bim to give compounds of formula IBi. In Scheme D, a 5-azaindolyl compound of formula A-ii-l obtained by Scheme B (Part I and Part II) is reacted with a suitable urea compound of formula B-ii-m to give compounds of formula IB-ii. . [ka] [ka]

[0124] Alternatively, the addition of a cyclopropylcarboxamidyl or urea moiety as described in Scheme A (Part III), Scheme B (Part III), Scheme C, and Scheme D can be substituted in the manner described in Scheme E, Scheme F, Scheme G, and Scheme H, respectively. [ka]

[0125] In Scheme E, an intermediate compound of general formula A1 is aminated (e.g., with diphenylmethanimine) to give a compound of general formula A1. The resulting compound of general formula A1 can then be reacted with cyclopropanecarboxylic acid or its derivative A10 (wherein LG 5 is reacted with -OH, Cl-, -O-C1-C6 alkyl, etc. Similarly, in Scheme F, an intermediate compound of general formula A-ii-l is aminated (e.g., with diphenylmethanimine) to give a compound of general formula A-ii-n. The resulting compound of general formula A-ii-n can then be reacted with cyclopropanecarboxylic acid or its derivative A-ii-o (wherein LG 5 is reacted with -OH, Cl-, -O-C1-C6 alkyl, etc. [ka]

[0126] Compounds of general formula (IB) can also be prepared from compounds of general formula Ain and A-ii-n as described in Schemes G and H. In Scheme G, compounds of general formula Ain are reacted with a carboxylic acid derivative (e.g., phenyl chlorocarbonate) and R to give the desired urea compounds of general formula IBi.6 Similarly, in Scheme H, compounds of general formula A-ii-n are reacted with a carboxylic acid derivative and R to give the desired urea compounds of general formula IB-ii. 6 is reacted in successive steps with the free amine B-ii-o containing [ka] [ka]

[0127] Schemes I and J below describe further alternatives for the preparation of 5- and 6-azaindole intermediate compounds in the synthesis of compounds of general formula (I). In Scheme I, a 3-aminopyridine compound of formula Aip (wherein LG 6 is a leaving group (e.g., iodo), and R 3 and R 5 In Scheme J, a 4-aminopyridine compound of formula A-ii-p is reacted with an ethyne compound of formula Aiq containing R 4 and R 5 is reacted with an ethyne compound of formula A-ii-q containing: which gives an intermediate compound of formula A-ii-r. [ka] [ka]

[0128] The intermediate compounds of formulae Air and A-ii-r may be optionally modified, for example to add or remove any protecting groups or to modify the substituent R prior to coupling to give the cyclopropylcarboxamide final compounds of formulae (IAi) and (IA-ii), or the ureido compounds of formulae (IBi) and (IB-ii) as shown in Schemes A-H. 2 Or R 3can be further reacted to introduce

[0129] IV. Pharmaceutical Compositions and Formulations Any of the compounds described herein can be formulated as a pharmaceutically acceptable composition.

[0130] Pharmaceutical compositions of any of the compounds detailed herein are encompassed by the present disclosure. Thus, the present disclosure encompasses pharmaceutical compositions comprising the compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, for example, a salt formed with an inorganic or organic acid. The pharmaceutical composition may be in a form suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0131] The compounds detailed herein may, in one aspect, be in purified form, and compositions comprising the compounds in purified form are described herein. Compositions comprising the compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, e.g., compositions of substantially pure compounds, are provided. In some embodiments, compositions containing the compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, are in substantially pure form. In one variation, "substantially pure" refers to a composition containing 35% or less impurities, where the impurities refer to compounds other than the compound or salt thereof that constitutes the majority of the composition. For example, a composition of a substantially pure compound selected from the compounds of Table 1 refers to a composition containing 35% or less impurities, where the impurities refer to compounds other than the compound of Table 1. In one variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 25% or less impurities. In another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 20% or less impurities. In yet another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 10% or less impurities. In a further variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, A composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 5% or less of impurities. In another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 3% or less of impurities. In yet another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 1% or less of impurities. In a further variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided, wherein the composition contains 0.5% or less of impurities. In yet another variation, a composition of a substantially pure compound means that the composition contains 15% or less, 10% or less, 5% or less, 3% or less, or 1% or less of impurities, which may be different stereochemical forms of the compound. For example, and without limitation, a composition of a substantially pure (S) compound means that the composition contains no more than 15%, or no more than 10%, or no more than 5%, or no more than 3%, or no more than 1% of the (R) form of the compound.

[0132] In one variation, the compound is a synthetic compound described herein prepared for administration to an individual. In another variation, a composition containing the compound in substantially pure form is provided. In another variation, the present disclosure encompasses a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering the compound is provided. Purified forms, pharmaceutical compositions, and methods of administering the compound are suitable for any compound or form detailed herein. In some embodiments, the compounds and compositions provided herein are sterile. Sterilization methods known in the art may be suitable for any compound or form detailed herein and compositions thereof.

[0133] The compounds detailed herein, or pharmaceutically acceptable salts, solvates, hydrates, or co-crystals thereof, or mixtures of any of the foregoing, may be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated with a suitable carrier to provide a delivery form, including, but not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal drops or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions, and elixirs.

[0134] The compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, can be used to prepare formulations, such as pharmaceutical formulations, by combining the compound or compounds, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch or oral tablet), the carrier can be in a variety of forms. In addition, pharmaceutical formulations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Formulations containing compounds can also contain other substances with beneficial therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, M, incorporated herein by reference. ack Publishing Company, Philadelphia, PA, 20th ed. (2000).

[0135] The compounds detailed herein, or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals, or mixtures of any of the foregoing, can be administered to individuals in the form of commonly accepted oral compositions, such as tablets, coated tablets, hard-shell or soft-shell gel capsules, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearates or salts thereof, etc. Acceptable carriers for soft-shell gel capsules include, for example, vegetable oils, waxes, fats and oils, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0136] Any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated into a tablet of any dosage form described, for example, a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet.

[0137] Also described are compositions comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing. In one variation, the composition comprises the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of a substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is used as a human or veterinary medicine. In some embodiments, the composition is used in a method described herein. In some embodiments, the composition is used to treat a disease or disorder described herein.

[0138] Also described are compositions formulated for co-administration of the compounds provided herein and one or more additional pharmaceutical agents. Co-administration can be simultaneous or sequential in any order. The compounds provided herein can be formulated for co-administration with one or more additional pharmaceutical agents in the same dosage form (e.g., a single tablet or a single intravenous administration) or in separate dosage forms (e.g., two separate tablets, two separate intravenous administrations, or one tablet and one intravenous administration). Furthermore, co-administration can be, for example, 1) simultaneous delivery by the same route (e.g., tablet or intravenous administration), 2) sequential delivery on the same day by the same route or different routes, or 3) delivery on different days by the same route or different routes.

[0139] V. How to use The compounds and compositions detailed herein, e.g., a pharmaceutical composition containing a compound of Formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, can be used in the administration and treatment methods provided herein. The compounds and compositions can also be used in in vitro methods, e.g., in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control analyses.

[0140] In one aspect, provided herein are methods for inhibiting Bcr-Abl tyrosine kinase enzymatic activity, comprising contacting the Bcr-Abl tyrosine kinase with an effective amount of a compound or composition provided herein. In some embodiments, provided herein are methods for inhibiting Bcr-Abl tyrosine kinase in a cell, comprising administering to the cell an effective amount of a compound or composition disclosed herein. In some embodiments, provided herein are methods for inhibiting Bcr-Abl tyrosine kinase in an individual in need thereof, comprising administering to the individual an effective amount of a compound or composition disclosed herein. In some variations, the compounds provided herein selectively inhibit Bcr-Abl tyrosine kinase. Thus, in some embodiments, provided herein are methods for selectively inhibiting Bcr-Abl tyrosine kinase over other tyrosine kinases, including, but not limited to, c-KIT, FGFR, PDGFR, SRC, CSFR1, or VEGFR.

[0141] The compounds and compositions described herein can be used in methods for treating diseases or disorders mediated by Bcr-Abl tyrosine kinase activity. In some embodiments, the compounds or compositions are administered according to the dosages described herein.

[0142] In some embodiments, provided herein are methods for treating a disease or disorder mediated by Bcr-Abl tyrosine kinase activity, comprising administering to an individual in need thereof an effective amount of a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing. In some embodiments, the disease or disorder is a cancer mediated by Bcr-Abl tyrosine kinase activity. In some embodiments, the disease or disorder is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In some embodiments, the disease or disorder is a cancer, such as a leukemia. In some variations, the cancer is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia.

[0143] In certain embodiments, the leukemia is chronic myeloid leukemia. Chronic myeloid leukemia can be characterized by a disease progression determined by blast cells. In yet other embodiments, the chronic myeloid leukemia is chronic phase CML, accelerated phase CML, or blast phase CML. In some embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia.

[0144] In some embodiments, the disease or disorder mediated by Bcr-Abl tyrosine kinase activity is refractory or resistant to first-line, second-line, and / or third-line treatments. In certain embodiments, the condition mediated by Bcr-Abl tyrosine kinase activity is refractory or resistant to treatment with one or more Bcr-Abl tyrosine kinase inhibitors selected from the group consisting of imatinib, nilotinib, dasatinib, bafetinib, bosutinib, radotinib, asciminib, and ponatinib. First-line treatments described herein include the use of imatinib, and second-line and third-line treatments described herein include the use of nilotinib, dasatinib, bafetinib, bosutinib, radotinib, asciminib, and / or ponatinib. In some variations of the foregoing, the chronic myeloid leukemia is refractory chronic myeloid leukemia.

[0145] Resistant subtypes of diseases or disorders mediated by Bcr-Abl tyrosine kinase may be associated with a number of Bcr-Abl-dependent or Bcr-Abl-independent resistance mechanisms. In some embodiments, the disease or disorder exhibits resistance to treatment with Bcr-Abl, characterized by one or more Bcr-Abl-dependent resistance mechanisms, including, but not limited to, one or more point mutations resulting in amino acid substitutions at the following positions in Bcr-Abl: M244, L248, G250, G250, Q252, Q252, Y253, Y253, E255, E255, D276, F311, T315, F317, F317, M343, M351, E355, F359, F359, V379, F382, L387, H396, H396, S417, E459, or F486 in the Bcr-Abl tyrosine kinase. In certain variations, the therapy-resistant disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with one or more specific point mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of: M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I. In certain embodiments, the therapy-resistant disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with a mutation resulting in a T315I substitution. In yet other embodiments, the therapy-resistant disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with a T315I mutation at the start of treatment and a I315M mutation after ponatinib. In other embodiments, the therapy-resistant disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with one or more mutations resulting in amino acid substitutions within the P-loop (M244V, G250E, Q252H, Y253H / F, E255K / V).

[0146] In some embodiments, provided are methods of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I) or any variation thereof described herein. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the leukemia is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia is refractory to treatment. In certain embodiments, the leukemia is chronic myeloid leukemia. In yet other embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia. In other embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia is refractory to treatment due to an associated T315I mutation. In certain of the foregoing embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia associated with a T315I mutation.

[0147] In one aspect, provided herein is a method of treating cancer in an individual in need thereof, wherein modulation of Bcr-Abl tyrosine kinase activity inhibits or ameliorates cancer pathology and / or symptomology, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method of treating cancer, wherein modulation of Bcr-Abl tyrosine kinase activity inhibits cancer pathology and / or symptomology in the individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method of treating cancer, wherein modulation of Bcr-Abl tyrosine kinase activity ameliorates cancer pathology and / or symptomology in the individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. Such methods are provided herein, comprising administering to the individual a compound or composition provided herein.

[0148] In another aspect, provided herein are methods for preventing cancer, wherein modulation of Bcr-Abl tyrosine kinase activity prevents cancer pathology and / or symptomology in an individual, comprising administering to said individual a therapeutically effective amount of a compound or composition provided herein. In another aspect, provided herein are methods for delaying the onset and / or development of cancer mediated by Bcr-Abl tyrosine kinase activity in an individual (e.g., a human) at risk of developing cancer. It will be understood that delaying onset can include prevention in cases where the individual has not developed cancer.

[0149] In one aspect, provided herein are methods for delaying the onset and / or development of cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the cancer is leukemia. In certain embodiments, the cancer is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the leukemia is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia is refractory to treatment. In certain embodiments, the leukemia is chronic myeloid leukemia. In still other embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia. In other embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia is refractory to treatment due to an associated T315I mutation. In yet other embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia associated with a T315I mutation. In one aspect, provided herein is a method of delaying the onset and / or development of chronic myeloid leukemia in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound or composition provided herein.In one variation, provided herein is a method of delaying the onset and / or development of treatment-resistant chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound or composition provided herein. In one variation, provided herein is a method of delaying the onset and / or development of treatment-resistant chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia associated with a T315I mutation in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein.

[0150] In one aspect, a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, for use in therapy, or

[0013] Provided herein are any mixtures of the compounds of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the treatment of cancer, or pharmaceutical compositions comprising such compounds.

[0014] Provided herein are any mixtures of the compounds of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the treatment of chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia, or pharmaceutical compositions comprising such compounds.

[0015] Provided herein are any mixtures of the compounds of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the treatment of chronic myeloid leukemia (CML), or pharmaceutical compositions comprising such compounds. In some embodiments, there is provided a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, there is provided a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such a compound, for use in the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia associated with the T315I mutation.

[0151] In another embodiment, provided herein is a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer. In another embodiment, provided herein is a compound of Formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the medicament is for the treatment of chronic myeloid leukemia. In some embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In certain embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia. In other embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia associated with a T315I mutation. In some embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia associated with a T315I mutation.

[0152] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about 18 years old, at least about 21 years old, at least about 30 years old, at least about 50 years old, at least about 60 years old, at least about 65 years old, at least about 70 years old, at least about 75 years old, at least about 80 years old, or at least about 85 years old, or any of about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is at least about 21 years old. The child is under the age of 18, under the age of 15, under the age of 10, under the age of 5, under the age of 4, under the age of 3, under the age of 2, or under the age of 1 year, or is any of the following: under the age of 21, 18, 15, 10, 5, 4, 3, 2, or 1 year.

[0153] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents including anti-microtubule therapy (e.g., paclitaxel, vincristine), topoisomerase inhibitors (e.g., adriamycin), alkylating agents (e.g., busulfan, cyclophosphamide), nucleotide synthesis inhibitors (hydroxyurea), DNA synthesis inhibitors (e.g., cytarabine), protein synthesis inhibitors (e.g., omacetaxine), developmental signaling pathway inhibitors (e.g., sonidegib, Hedgehog pathway), pro-apoptotic agents (e.g., venetoclax), Abl myristoyl pocket binding inhibitors (e.g., asciminib), MEK1 / 2 inhibitors (e.g., trametinib, binimetinib), AKT inhibitors (e.g., ipatasertib), PI3K inhibitors (e.g., alpelisib), and radiation.

[0154] VI. Administration and Methods of Administration The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, administered to an individual (e.g., a human) can vary depending on the particular compound or salt thereof, the method of administration, and the particular cancer being treated, e.g., the type and stage of cancer. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount.

[0155] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be administered to an individual by a variety of routes, including, for example, intravenously, intramuscularly, subcutaneously, orally, or transdermally.

[0156] In one embodiment, an effective amount of a compound can be a dose of about 0.01 to about 100 mg / kg. Effective amounts or dosages of compounds of the present disclosure can be confirmed by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, and the subject's health, condition, and body weight. Exemplary doses range from about 0.7 mg to 7 g per day, or from about 7 mg to 350 mg per day, or from about 350 mg to 1.75 g per day, or from about 1.75 to 7 g per day.

[0157] In one aspect, any of the methods provided herein comprises administering to an individual a pharmaceutical composition containing an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.

[0158] The compounds or compositions provided herein can be administered to an individual according to an effective dosing regimen for a desired time or period of time, e.g., at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months, or for a longer period that can, in some variations, be the lifespan of the individual. In one variation, the compound is administered daily or on an intermittent schedule. The compound can be administered to an individual continuously (e.g., at least once daily) for a period of time. The dosing frequency can be less than once daily, e.g., about once a week. The dosing frequency can be more than once a day, e.g., two or three times a day. The dosing frequency can be intermittent, including "drug holidays" (e.g., any 14-day period, e.g., about 2 months, about 4 months, about 6 months, or more). (7 days of single daily administration followed by 7 days of no administration, repeated for the duration of the above.) Any of the administration frequencies can be used with any of the compounds described herein in any of the dosages described herein.

[0159] VII. ARTICLES OF MANUFACTURE AND KITS The present disclosure further provides an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit doses described herein, in suitable packaging. In certain embodiments, the article of manufacture is used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The article of manufacture may further be sterilized and / or sealed.

[0160] The present disclosure further provides kits for practicing the methods of the present disclosure, comprising one or more compounds described herein or compositions comprising the compounds described herein. The kits may use any of the compounds disclosed herein. In one variation, the kits use a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or any mixture thereof. The kits may be used for any one or more of the applications described herein and may therefore contain instructions for use in treating any of the diseases described herein, for example, cancer, including chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is treatment-resistant acute myeloid leukemia. In certain of the foregoing embodiments, the cancer is treatment-resistant chronic myeloid leukemia associated with the T315I mutation.

[0161] The kit optionally further comprises a container containing one or more additional pharmaceutical agents, and the kit further comprises instructions on or within the package insert for treating a subject with an effective amount of the one or more additional pharmaceutical agents.

[0162] The kit typically includes suitable packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) may be packaged in a separate container, or several components may be combined in one container if cross-reactivity and shelf life permit.

[0163] The kit can be a unit dosage form, bulk package (e.g., multi-dose package), or divided unit dose.For example, a kit can be provided that contains a sufficient dosage of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment to an individual for a long period of time, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer.The kit can also include a plurality of unit doses of the compound and instructions for use, and can be packaged in an amount sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0164] The kit may optionally include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions for use of the component(s) of the disclosed methods are also acceptable. Instructions included with the kit typically include information regarding the components and their administration to an individual. [Example]

[0165] It will be understood that this disclosure has been made by way of example only, and that numerous variations in the combination and arrangement of parts may be employed by those skilled in the art without departing from the spirit and scope of the disclosure.

[0166] Synthesis Example The chemical reactions in the described examples can be easily modified to prepare many other compounds disclosed herein, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds according to the present disclosure that are not exemplified can be successfully carried out with modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by routinely modifying the reaction conditions, reagents, and starting materials. Alternatively, it will be understood that other reactions disclosed herein or known in the art have applicability for preparing other compounds of the present disclosure.

[0167] Abbreviations used in the examples include: ACN: acetonitrile; Brettphos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; dppf: 1,1'-ferrocenediyl-bis(diphenylphosphine); DCM, dichloromethane; DIAD: diisopropyl azodicarboxylate; DIEA, N,N'-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EDA; ethylenediamine; EtOAc: ethyl acetate; EtOH: ethanol or ethyl alcohol; F-TEDA-BF4: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); 1 H NMR: proton nuclear magnetic resonance; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyluronium; LCMS: liquid chromatography mass spectrometry; LDA: lithium diisopropylamide; LiHMDS: lithium hexamethyldisilazide; MeOH: methanol or methyl alcohol; NBS: N-bromosuccinimide; NIS: N-iodosuccinimide; NNMP: N-methyl-2-pyrrolidone; OAc: acetate; Py: pyridine; TBAB: tetra-n-butylammonium bromide; TBAF: tetra-n-butylammonium fluoride; TEA: triethylamine; TFA, trifluoroacetic acid; THF: tetrahydrofuran; and TLC: thin layer chromatography.

[0168] Example S1: Synthesis of N-(2-(2-hydroxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 1) [ka] Step 1: Synthesis of tert-butyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (compound 1b) [ka] To a stirred solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine (6.0 g, 39.34 mmol) in DCM (100.0 mL) was added CsCO (compound 1a) (38.4 g, 117.99 mmol) and BocO (12.8 g, 58.98 mmol). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with HO and extracted with CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 1, v / v) to give tert-butyl 5-chloropyrrolo[2,3-c]pyridine-1-carboxylate (compound 1b) (8.0 g, 80%) as a white solid. LCMS (ESI): [M+H] + = 253.1.

[0169] Step 2: Synthesis of tert-butyl 5-chloro-2-iodopyrrolo[2,3-c]pyridine-1-carboxylate (compound 1c) [ka] To a solution of tert-butyl 5-chloropyrrolo[2,3-c]pyridine-1-carboxylate (Compound 1b) (2.0 g, 7.95 mmol) in THF (10.0 mL) was added LDA (8.0 mL, 16.0 mmol) dropwise at −78° C. under N2. The resulting mixture was stirred at −78° C. under N2 for 1 hour. Then, a solution of iodine (3.0 g, 11.82 mmol) in THF (10.0 mL) was added dropwise at −78° C. to the mixture. The mixture was stirred at −78° C. under N2 for 4 hours. After the reaction was complete, the reaction was quenched with NH4Cl solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give tert-butyl 5-chloro-2-iodopyrrolo[2,3-c]pyridine-1-carboxylate (1.0 g, 13%) (compound 1c) as a white solid. LCMS (ESI): [M+H] + = 379.0.

[0170] Step 3: Synthesis of 5-chloro-2-iodo-1H-pyrrolo[2,3-c]pyridine (compound 1d) [ka] To a stirred solution of tert-butyl 5-chloro-2-iodopyrrolo[2,3-c]pyridine-1-carboxylate (compound 1c) (1.0 g, 2.61 mmol) in CHCl (5.0 mL) was added TFA (3.0 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give 5-chloro-2-iodo-1H-pyrrolo[2,3-c]pyridine (compound 1d) (700.0 mg, 95%) as a white solid. LCMS (ESI): [M+H] + = 278.9.

[0171] Step 4: Synthesis of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 1e) [ka] To a solution of 5-chloro-2-iodo-1H-pyrrolo[2,3-c]pyridine (compound 1d) (970.0 mg, 3.48 mmol) in THF (5.0 mL) was added NaH (167.8 mg, 60%) at 0 °C. The mixture was stirred at 0 °C under N for 2 h. Then, a solution of CHI (70.8 mg, 0.44 mmol) in THF (5.0 mL) was added dropwise to the mixture. The mixture was stirred at 0 °C under N for 2 h. After the reaction was complete, the resulting mixture was diluted with H O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v). 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 1e) (800.0 mg, 79%) was obtained as a white solid. LCMS (ESI): [M+H] + = 292.9.

[0172] Step 5: Synthesis of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]phenol (Compound 1g) [ka] To a stirred solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (200.0 mg, 0.68 mmol) in dioxane (compound 1e) (10.0 mL) and HO (1.0 mL) was added 2-hydroxyphenylboronic acid (compound 1f) (113.7 mg, 0.82 mmol), Pd(dppf)Cl (100.6 mg, 0.13 mmol), and KCO (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 °C under N for 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]phenol (Compound 1g) (130.0 mg, 73%) as a white solid. LCMS (ESI): [M+H] + =259.1.

[0173] Step 6: Synthesis of N-[2-(2-hydroxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 1) [ka] To a stirred solution of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]phenol (Compound 1g) (120.0 mg, 0.46 mmol) in dioxane (5.0 mL) was added cyclopropanecarboxamide (Compound 1h) (118.4 mg, 1.39 mmol), BrettPhos Pd G3 (42.5 mg, 0.05 mmol), BrettPhos (49.9 mg, 0.09 mmol), and Cs2CO3 (453.8 mg, 1.39 mmol). The resulting mixture was stirred at 100 °C under N2 for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-(2-hydroxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 1) (26.8 mg, 19%) as a white solid under the following conditions: Column: YMC-Actus Triart C18, 30 × 250 mm, 5 um; Phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 43% B to 64% B in 7 min; detector: UV 254 nm. LCMS (ESI): [M+H] + =308.0. 1 H NMR (300 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.97 (s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 7.35 - 7.27 (m, 2H), 7.02 - 6.91 (m, 2H), 6.39 (s, 1H), 3.64 (s, 3H), 2.07 - 1.99 (m, 1H), 0.81 - 0.75 (m, 4H).

[0174] Example S2: Synthesis of N-(2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 2) [ka] Step 1: Synthesis of 5-chloro-2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 2b) [ka] To a stirred solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 2a) (200.0 mg, 0.68 mmol) in dioxane (10.0 mL) and HO (1.0 mL) was added 2-methoxyphenylboronic acid (124.9 mg, 0.82 mol) and KCO (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 °C under N for 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v). Purification by column chromatography gave 5-chloro-2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 2b) (170.0 mg, 91%) as a yellow solid. LCMS (ESI): [M+H] + = 273.1.

[0175] Step 2: Synthesis of N-[2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 2) [ka] To a stirred solution of 5-chloro-2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 2b) (170.0 mg, 0.63 mmol) in dioxane (5.0 mL), cyclopropanecarboxamide (compound 2c) (159.5 mg, 1.87 mmol), BrettPhos Pd G3 (56.5 mg, 0.06 mmol), BrettPhos (66.9 mg, 0.15 mmol), and Cs2CO3 (609.8 mg, 1.87 mmol) were added. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions to give N-[2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 2) (63.2 mg, 32%) as a white solid: Column: YMC-Actus Triart C18, 30 x 250 mm, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 40% B in 7 min; Detector: UV 254 / 220 nm. LCMS (ESI): [M+H] + = 322.1. 1 H NMR (300 MHz, DMSO-d): δ 10.52 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.55 - 7.49 (m, 1H), 7.39 - 7.35 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 2.03 - 1.98 (m, 1H), 0.81- 0.76 (m, 4H).

[0176] Example S3: Synthesis of N-[2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 3) [ka] Step 1: Synthesis of 5-chloro-2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 3c) [ka] To a stirred mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 3a) (200.0 mg, 0.68 mmol) and 2-ethoxyphenylboronic acid (compound 3b) (226.9 mg, 1.36 mmol) in 1,4-dioxane / HO (5.0 / 0.5 mL), Pd(dppf)Cl (55.8 mg, 0.06 mmol) and KCO (283.5 mg, 2.05 mmol) were added. The resulting mixture was stirred at 80 °C under N for 12 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give 5-chloro-2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 3c) (170.0 mg, 87%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =287.1.

[0177] Step 2: Synthesis of N-[2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 3) [ka] To a stirred mixture of 5-chloro-2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 3c) (150.0 mg, 0.52 mmol) and cyclopropanecarboxamide (222.5 mg, 2.61 mmol) in dioxane (3.0 mL) was added BrettPhos Pd G3 (47.4 mg, 0.05 mmol), Cs2CO3 (511.2 mg, 1.56 mmol), and BrettPhos (56.1 mg, 0.10 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (Column: Xselect CSH OBD column 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 62% B in 8 min; 254 nm; RT1: 7.47 min) to give N-[2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 3) (59.9 mg, 34%) as a white solid. LCMS (ESI, m / z): [M+H] + =336.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.52 - 7.47 (m, 1H), 7.39 - 7.36 (m, 1H), 7.21 - 7.18 (m, 1H), 7.11 - 7.06 (m, 1H), 6.41 (d, J = 0.6 Hz, 1H), 4.14 - 4.11 (m, 2H), 3.63 (s, 3H), 2.06 - 1.99 (m, 1H), 1.28 - 1.23 (m, 3H), 0.84 - 0.82 (m, 4H).

[0178] Example S4: Synthesis of N-[2-[2-(2-hydroxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 4) [ka] Step 1: Synthesis of [2-(2-bromophenoxy)ethoxy](tert-butyl)dimethylsilane (compound 4c) [ka] To a mixture of 2-bromophenol (compound 4a) (5.0 g, 28.90 mmol) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (compound 4b) (7.6 g, 43.32 mmol) in THF (100.0 mL) was added PPh (11.3 g, 43.35 mmol) at room temperature under N. Then, DIAD (8.7 g, 43.37 mmol) was added dropwise to the mixture at 0 °C under N. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) to give [2-(2-bromophenoxy)ethoxy](tert-butyl)dimethylsilane (compound 4c) (8.0 g, 83%) as a yellow solid.

[0179] Step 2: Synthesis of tert-butyldimethyl[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy]silane (compound 4e) [ka] To a mixture of [2-(2-bromophenoxy)ethoxy](tert-butyl)dimethylsilane (compound 4c) (1.0 g, 3.01 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (compound 4d) (2.3 g, 9.05 mmol) in dioxane (10.0 mL), Pd(dppf)Cl (0.2 g, 0.30 mmol) and KOAc (0.9 g, 9.05 mmol) were added at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) to give tert-butyldimethyl[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy]silane (Compound 4e) (700.0 mg, 61%) as a white solid.

[0180] Step 3: Synthesis of 2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-5-chloro-1-methylpyrrolo[2,3-c]pyridine (compound 4g) [ka] To a mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 4f) (300.0 mg, 1.02 mmol) and tert-butyldimethyl[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy]silane (compound 4e) (1.1 g, 3.07 mmol) in dioxane / HO (10.0 / 1.0 mL) was added Pd(dppf)Cl (75.0 mg, 0.10 mmol) and KCO (425.2 mg, 3.07 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give 2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-5-chloro-1-methylpyrrolo[2,3-c]pyridine (compound 4g) (100.0 mg, 23%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =417.2.

[0181] Step 4: Synthesis of N-[2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 4i) [ka] To a mixture of 2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-5-chloro-1-methylpyrrolo[2,3-c]pyridine (Compound 4g) (80.0 mg, 0.19 mmol) and cyclopropanecarboxamide (Compound 4h) (65.3 mg, 0.76 mmol) in dioxane (2.0 mL) was added Brettphos (20.5 mg, 0.03 mmol), BrettPhos Pd G3 (17.3 mg, 0.02 mmol), and Cs2CO3 (187.5 mg, 0.57 mmol) under N2 at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give N-[2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 4i) (68.0 mg, 76%) as a white solid. LCMS (ESI, m / z): [M+H] + =466.2.

[0182] Step 5: Synthesis of N-[2-[2-(2-hydroxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 4) [ka] A solution of N-[2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 4i) (68.0 mg, 0.14 mmol) in HCl / 1,4-dioxane (2.0 mL, 4 mol / L) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified under the following conditions (column: Xselect CSH OBD column). Purification by preparative HPLC (30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 48% B in 9 min; 220 nm; RT 1:8.03) afforded N-[2-[2-(2-hydroxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 4) (15.1 mg, 29%) as a white solid. LCMS (ESI, m / z): [M+H] + =352.2. 1 H NMR (3 00 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.52 - 7.46 (m, 1H), 7.39 - 7.36 (m, 1H), 7.23 - 7.20 (m, 1H), 7.11 - 7.06 (m, 1H), 6.43 (d, J = 0.6 Hz,1H), 4.82 - 4.79 (m, 1H), 4.09 - 4.06 (m, 2H), 3.67 - 3.62 (m, 5H), 2.04 - 1.97 (m, 1H), 0.84 - 0.73 (m, 4H).

[0183] Example S5: Synthesis of N-(2-(2-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 5) [ka] Step 1: Synthesis of 1-bromo-2-(2-methoxyethoxy)benzene (compound 5c) [ka] To a mixture of 2-bromophenol (compound 5a) (2.0 g, 11.56 mmol), PPh3 (4.5 g, 17.34 mmol), and 2-methoxyethanol (compound 5b) (1.3 g, 17.34 mmol) in THF, DIAD (3.5 g, 17.35 mmol) was added under N2 at 0 °C. The resulting mixture was stirred at room temperature under N2 for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (4 / 1, v / v) to give 1-bromo-2-(2-methoxyethoxy)benzene (compound 5c) (2.3 g, 86%) as a yellow oil.

[0184] Step 2: Synthesis of 2-[2-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 5e) [ka] To a mixture of 1-bromo-2-(2-methoxyethoxy)benzene (compound 5c) (1.1 g, 4.76 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (compound 5d) (3.6 g, 14.29 mmol) in dioxane (20.0 mL), Pd(dppf)Cl (348.2 mg, 0.47 mmol) and KOAc (1.4 g, 14.26 mmol) were added under N at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 1, v / v) to give 2-[2-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 5e) (700.0 mg, 52%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =279.2.

[0185] Step 3: Synthesis of 5-chloro-2-[2-(2-methoxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridine (compound 5g) [ka] To a mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 5f) (200.0 mg, 0.68 mmol) and 2-[2-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 5e) (380.3 mg, 1.36 mmol) in dioxane / HO (4 / 0.4 mL) was added Pd(dppf)Cl (55.8 mg, 0.06 mmol) and KCO (283.5 mg, 2.05 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give 5-chloro-2-[2-(2-methoxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridine (compound 5g) (150.0 mg, 69%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =317.2.

[0186] Step 4: N-(2-(2-(2-methoxyethoxy)phenyl)-1-methyl-1H Synthesis of -pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 5) [ka] To a mixture of 5-chloro-2-[2-(2-methoxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridine (Compound 5g) (150.0 mg, 0.52 mmol) and cyclopropanecarboxamide (Compound 5h) (222.5 mg, 2.61 mmol) in dioxane (4.0 mL), BrettPhos Pd G3 (47.4 mg, 0.05 mmol), Cs2CO3 (511.2 mg, 1.56 mmol), and BrettPhos (56.1 mg, 0.10 mmol) were added at room temperature. The resulting mixture was stirred under N2 at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (Column: Xselect CSH OBD column 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 57% B in 8 min; 254 nm; RT1: 7.3 min) to give N-(2-(2-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 5) (59.9 mg, 34%) as a white solid. LCMS (ESI, m / z): [M+H] + =366.2. 1 H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.52 - 7.47 (m, 1H), 7.39 - 7.37 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.43 (d, J = 0.4 Hz, 1H), 4.18 - 4.16 (m, 2H), 3.64 (s, 3H), 3.60 - 3.58 (m, 2H), 3.18 (s, 3H), 2.08 - 2.00 (m, 1H), 0.87 - 0.84 (m, 4H).

[0187] Example S6: Synthesis of N-[2-(2-cyanophenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 6) [ka] Step 1: Synthesis of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]benzonitrile (compound 6b) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 6a) (200.0 mg, 0.68 mmol) in dioxane / HO (10.0 / 1.0 mL) was added 2-cyanophenylboronic acid (120.7 mg, 0.82 mmol), Pd(dppf)Cl (100.6 mg, 0.17 mmol), and KCO (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 °C under N for 16 h. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]benzonitrile (compound 6b) (130.0 mg, 71%) as a yellow solid. LCMS (ESI): [M+H] + =268.1.

[0188] Step 2: Synthesis of N-[2-(2-cyanophenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 6) [ka] To a solution of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]benzonitrile (compound 6b) (110.0 mg, 0.41 mmol) in dioxane (5.0 mL) was added cyclopropanecarboxamide (compound 6c) (105.0 mg, 1.24 mmol), BrettPhos Pd G3 (37.0 mg, 0.04 mmol), BrettPhos (44.0 mg, 0.08 mmol), and Cs2CO3 (401.6 mg, 1.23 mmol). The resulting mixture was stirred at 100 °C for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-(2-cyanophenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 6) (28.6 mg, 22%) as a white solid: Column: YMC-Actus Triart C18, 30 x 250 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 48% B in 7 min; Detector: UV 254 / 220 nm. LCMS (ESI): [M+H] + =317.0. 1 H NMR (300 MHz, DMSO-d): δ 10.57 (s, 1H), 8.72 (s, 1H), 8.26 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.89 - 7.86 (m, 1H), 7.78 - 7.70 (m, 2H), 6.73 (s, 1H), 3.73 (s, 3H), 2.06 - 1.94 (m, 1H), 0.82 - 0.76 (m, 4H).

[0189] Example S7: Synthesis of N-[2-(3-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 7) [ka] Step 1: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 7c) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (7a) (200.0 mg, 0.68 mmol) in dioxane (10.0 mL) and HO (1.0 mL) was added 3-methoxy-2-methylphenylboronic acid (7b) (136.2 mg, 0.82 mmol), Pd(dppf)Cl (100.0 mg, 0.13 mmol), and KCO (283.5 mg, 2.05 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / MeOH (97 / 3, v / v) to give 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 7c) (150.0 mg, 76%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =287.1.

[0190] Step 2: Synthesis of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylphenol (compound 7d) [ka] To a solution of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 7c) (140.0 mg, 0.49 mmol) in DCM (2.0 mL) was added boron tribromide (1.5 mL, 1.50 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylphenol (compound 7d) (120.0 mg, crude product) as a yellow solid. LCMS (ESI, m / z): [M+H] + =273.1.

[0191] Step 3: Synthesis of N-[2-(3-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 7) [ka] To a solution of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylphenol (compound 7d) (130.0 mg, 0.47 mmol) in dioxane (2.0 mL), cyclopropanecarboxamide (compound 7e) (60.8 mg, 0.71 mmol), Brettphos Pd G3 (86.4 mg, 0.09 mmol), BrettPhos (102.3 mg, 0.19 mmol), and CsCO3 (465.9 mg, 1.43 mmol) were added at room temperature under N2. The resulting mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using the following conditions (column: Xselect CSH Purification by preparative HPLC on an OBD column 30 x 150 mm, 5 µm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 30% B in 8 min; 220 nm) afforded N-[2-(3-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 7) (10.4 mg, 6%) as a white solid. LCMS (ESI, m / z): [M+H] + =322.1. 1 H NMR (300 MHz, DMSO-d6): δ 10.48 (s, 1H), 9.64 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.16 - 7.11 (m, 1H), 6.96 - 6.93 (m, 1H), 6.78 - 6.76 (m, 1H), 6.38 (d, J = 0.6 Hz, 1H), 3.55 (s, 3H), 2.05 - 1.97 (m, 1H), 1.94 (s, 3H), 0.84 - 0.78 (m, 4H).

[0192] Example S8: Synthesis of N-[2-(4-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 8) [ka] Step 1: Synthesis of 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylphenol (compound 8c) [ka] To a stirred mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 8a) (200.0 mg, 0.68 mmol) and 4-hydroxy-2-methylphenylboronic acid (compound 8b) (124.6 mg, 0.82 mmol) in dioxane / HO (2.0 / 0.2 mL), Pd(dppf)Cl (100.0 mg, 0.13 mmol) and KCO (283.5 mg, 2.05 mmol) were added at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 1, v / v) to give 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylphenol (compound 8c) (85.0 mg, 45%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =273.2.

[0193] Step 2: Synthesis of N-[2-(4-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 8) [ka] To a stirred mixture of 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylphenol (compound 8c) (85.0 mg, 0.31 mmol) and cyclopropanecarboxamide (compound 8d) (79.5 mg, 0.93 mmol) in dioxane (2.0 mL), CsCO (304.6 mg, 0.93 mmol), Brettphos (33.4 mg, 0.06 mmol), and BrettPhos Pd G (28.2 mg, 0.03 mmol) were added at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-(4-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 8) (38.0 mg, 37%) as a white solid: Column: YMC-Actus Triart C18, 20 x 250 mm, 5 um, 12 nm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 48% B in 8 min; 254 / 220 nm. LCMS (ESI, m / z): [M+H] + =322.1. 1 H NMR (300 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.67 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.78 - 6.69 (m, 2H), 6.35 (s, 1H), 3.54 (s, 3H), 2.07 (s, 3H), 2.04 - 1.97 (m, 1H), 0.80 - 0.72 (m, 4H).

[0194] Example S9: Synthesis of N-[2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 9) [ka] Step 1: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 9b) [ka] To a stirred solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 9a) (200.0 mg, 0.68 mmol) in dioxane / HO (10.0 / 1.0 mL), 3-methoxy-2-methylphenylboronic acid (136.9 mg, 0.82 mmol), Pd(dppf)Cl (50.3 mg, 0.68 mmol), and KCO (283.5 mg, 2.05 mmol) were added. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 9b) (150.0 mg, 77%) as a yellow solid. LCMS (ESI): [M+H] + =287.1.

[0195] Step 2: Synthesis of N-[2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 9) [ka] To a stirred solution of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 9b) (150.0 mg, 0.53 mmol) in dioxane (5.0 mL), cyclopropanecarboxamide (133.5 mg, 1.59 mmol), BrettPhos Pd G3 (47.2 mg, 0.02 mmol), BrettPhos (56.1 mg, 0.15 mmol), and Cs2CO3 (511.9 mg, 1.59 mmol) were added. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 9) (74.2 mg, 42%) as a white solid: Column: YMC-Actus Triart C18, 30 x 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 25% B in 7 min; Detector: UV 254 / 220 nm. LCMS (ESI): [M+H] + =336.2. 1 H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.34 - 7.30 (m, 1H), 7.12 (d , J = 8.0 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.41 (s, 1H), 3.86 (s, 3H), 3.55 (s, 3H), 2.03 - 1.98 (m, 4H), 0.84 - 0.79 (m, 4H).

[0196] Example S10: Synthesis of N-[2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 10) [ka]

[0197] Step 1: Synthesis of 5-chloro-2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 10b) [ka] To a stirred solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (10a) (200.0 mg, 0.68 mmol) in dioxane (10.0 mL) and HO (1.0 mL) was added 4-methoxy-2-methylphenylboronic acid (136.9 mg, 0.81 mmol) and KCO (283.5 mg, 2.05 mmol). The resulting mixture was stirred under N at 80 °C for 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 5-chloro-2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (10b) (190.0 mg, 97%) as a white solid. LCMS (ESI): [M+H] + =287.1.

[0198] Step 2: Synthesis of N-[2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 10) [ka] To a stirred solution of 5-chloro-2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 10b) (190.0 mg, 0.63 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (Compound 10c) (169.7 mg, 1.98 mmol), BrettPhos Pd G3 (60.6 mg, 0.06 mmol), BrettPhos (71.3 mg, 0.13 mmol), and Cs2CO3 (647.6 mg, 1.98 mmol). The resulting mixture was stirred at 100 °C under N2 for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 10) (115.9 mg, 52%) as a white solid: Column: YMC-Actus Triart C18, 30 x 250 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% B to 55% B in 10 min; Detector: UV 254 nm. LCMS (ESI): [M+H] + = 336.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.38 (s, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 2.13 (s, 3H), 2.07 - 1.99 (m, 1H), 0.81 - 0.75 (m, 4H).

[0199] Example S11: Synthesis of N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 11) [ka] Step 1: 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolidone Synthesis of 2,3-c]pyridine (compound 11c) [ka] To a stirred mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 11a) (200.0 mg, 0.68 mmol) and 2-methoxy-6-methylphenylboronic acid (Compound 11b) (136.0 mg, 0.82 mmol) in dioxane / HO (2.0 / 0.2 mL), Pd(dppf)Cl (100.0 mg, 0.13 mmol) and KCO (283.0 mg, 2.05 mmol) were added at room temperature under N. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 1, v / v) to give 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 11c) (60.0 mg, 30%) as a white solid. LCMS (ESI, m / z): [M+H] + =287.1.

[0200] Step 2: Synthesis of N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 11) [ka] To a stirred mixture of 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 11c) (50.0 mg, 0.17 mmol) and cyclopropanecarboxamide (Compound 11d) (44.5 mg, 0.52 mmol) in dioxane (2.0 mL) was added CsCO (170.4 mg, 0.52 mmol), Brettphos (18.7 mg, 0.03 mmol), and BrettPhos Pd G (15.8 mg, 0.02 mmol). The resulting mixture was stirred at 100 °C under N for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 11) (14.5 mg, 25%) as a white solid: Column: YMC-Actus Triart C18, 30 x 250 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 46% B to 60% B in 8 min; 254 nm. LCMS (ESI, m / z): [M+H] + =336.1. 1 H NMR (300 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.42 - 7.36 (m, 1H), 7.01 - 6.97 (m, 2H), 6.34 (s, 1H), 3.70 (s, 3H), 3.47 (s, 3H), 2.06 - 1.96 (m, 4H), 0.81 - 0.75 (m, 4H).

[0201] Example S12: Synthesis of N-[2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 12) [ka] Step 1: Synthesis of 5-chloro-2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 12c) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 12a) (300.0 mg, 1.06 mmol) in dioxane / HO (10.0 / 1.0 mL) was added 5-fluoro-2-methylphenylboronic acid (compound 12b) (189.8 mg, 1.23 mmol), Pd(dppf)Cl (75.5 mg, 0.13 mmol), and KCO (425.5 mg, 3.77 mmol). The reaction mixture was stirred at 80 °C for 16 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 5-chloro-2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 12c) (200.0 mg, 71%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =275.1.

[0202] Step 2: Synthesis of N-[2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 12) [ka] To a solution of 5-chloro-2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 12c) (180.0 mg, 0.65 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (Compound 12d) (167.3 mg, 1.96 mmol), BrettPhos (35.7 mg, 0.06 mmol), BrettPhos Pd G3 (118.9 mg, 0.13 mmol), and Cs2CO3 (640.4 mg, 1.96 mmol) under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / CHOH (10 / 1, v / v) and then by preparative HPLC under the following conditions (Column: YMC-Actus Triart C18, 30 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 79% B in 7 min; 254 nm) to give N-[2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 12) (42.1 mg, 20%) as a white solid. LCMS (ESI, m / z): [M+H] + =324.2. 1 H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.63 (s, 1H), 8.23 ​​(s, 1H), 7.46 - 7.42 (m, 1H), 7.31 - 7.22 (m, 2H), 6.48 (s, 1H), 3.59 (s, 3H), 2.14 (s, 3H), 2.08 - 1.99 (m, 1H), 0.84 - 0.77 (m, 4H).

[0203] Example S13: Synthesis of N-[1-methyl-2-(4-methyl-2,3-dihydro-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 13) [ka] Step 1: Synthesis of 5-bromo-4-methyl-2,3-dihydro-1H-indole (compound 13b) [ka] To a solution of 5-bromo-4-methyl-1H-indole (compound 13a) (880.0 mg, 4.18 mmol) in HOAc (15.0 mL) was added NaBHCN (1.0 g, 16.72 mmol) under N at 0°C. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the pH of the mixture was adjusted to 9 with NaOH (aq). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using petroleum ether / EtOAc (3 / 1, v / v) to give 5-bromo-4-methyl-2,3-dihydro-1H-indole (compound 13b) (800.0 mg, 90%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =212.0.

[0204] Step 2: 5-Bromo-4-methyl-2,3-dihydroindole-1-carboxylic acid Synthesis of ert-butyl (compound 13c) [ka] To a mixture of 5-bromo-4-methyl-2,3-dihydro-1H-indole (800.0 mg, 3.77 mmol) and BocO (2.5 g, 11.32 mmol) in DCM (20.0 mL) was added DMAP (460.8 mg, 3.72 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with HO and extracted with CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / EtOAc (8 / 1, v / v) to afford tert-butyl 5-bromo-4-methyl-2,3-dihydroindole-1-carboxylate (780.0 mg, 66%) as a white solid. LCMS (ESI, m / z): [M+H] + =312.1.

[0205] Step 3: Synthesis of tert-butyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroindole-1-carboxylate (compound 13e) [ka] To a mixture of tert-butyl 5-bromo-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13c) (740.0 mg, 2.3 mmol) and bis(pinacolato)diboron (Compound 13d) (1.8 g, 7.12 mmol) in dioxane (20.0 mL) was added KOAc (697.8 mg, 7.12 mmol) and Pd(dppf)Cl (173.4 mg, 0.23 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give tert-butyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroindole-1-carboxylate (compound 13e) (750.0 mg, 88%) as a white solid. LCMS (ESI, m / z): [M+H] + =360.2.

[0206] Step 4: Synthesis of tert-butyl 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13g) [ka] To a mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (300.0 mg, 1.02 mmol) and tert-butyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroindole-1-carboxylate (442.1 mg, 1.21 mmol) in dioxane / HO (5.0 / 0.5 mL) was added Pd(PPh) (118.5 mg, 0.10 mmol) and KCO (425.2 mg, 3.07 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give tert-butyl 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (170.0 mg, 41%) as a white solid. LCMS (ESI, m / z): [M+H] + =398.2.

[0207] Step 5: Synthesis of tert-butyl 5-[5-cyclopropanamido-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13i) [ka] To a mixture of tert-butyl 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13g) (150.0 mg, 0.37 mmol) and cyclopropanecarboxamide (Compound 13h) (128.3 mg, 1.50 mmol) in dioxane (3.0 mL), BrettPhos Pd G3 (34.1 mg, 0.03 mmol), BrettPhos (40.0 mg, 0.07 mmol), and CsCO3 (368.4 mg, 1.13 mmol) were added at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 7, v / v) to give tert-butyl 5-[5-cyclopropanamido-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13i) (150.0 mg, 89%) as a white solid. LCMS (ESI, m / z): [M+H] + =447.2.

[0208] Step 6: Synthesis of N-[1-methyl-2-(4-methyl-2,3-dihydro-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 13) [ka] To a solution of tert-butyl 5-[5-cyclopropanamido-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13i) (160.0 mg, 0.35 mmol) in DCM (2.0 mL) was added TFA (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 x 150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 62% B in 10 min; 254 nm) to give N-[1-methyl-2-(4-methyl-2,3-dihydro-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 13) (29.2 mg, 23%) as a white solid. LCMS (ESI, m / z): [M+H] + =347.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.43 (d, J = 7.8 Hz, 1H), 6.29 (s, 1H), 5.76 (s, 1H), 3.55 - 3.49 (m, 5H), 2.96 - 2.91 (m, 2H), 2.01 - 1.99 (m, 4H), 0.82 - 0.75 (m, 4H).

[0209] Example S14: Synthesis of N-(1-methyl-2-(6-methyl-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 14) [ka] Step 1: Synthesis of 5-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (compound 14b) [ka] To a solution of 5-bromo-6-methyl-1H-indole (compound 14a) (1.0 g, 4.76 mmol) in THF (20.0 mL) was added NaH (342.7 mg, 60%) at 0° C. under N. The resulting mixture was stirred at 0° C. under N for 1 hour. Then, SEM-Cl (1.2 g, 7.14 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. under N for 1 hour. After the reaction was completed, the reaction was quenched with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (12 / 1, v / v) to give 5-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (compound 14b) (1.2 g, 74%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =340.1.

[0210] Step 2: Synthesis of 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (compound 14d) [ka] To a solution of 5-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (Compound 14b) (500.0 mg, 1.47 mmol) in dioxane (20.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Compound 14c) (1.1 g, 4.41 mmol), KOAc (432.6 mg, 4.41 mmol), and Pd(dppf)Cl (107.5 mg, 0.15 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (12 / 1, v / v) to give 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (compound 14d) (260.0 mg, 45%) as a brown oil. LCMS (ESI, m / z): [M+H] + =388.2.

[0211] Step 3: Synthesis of 5-chloro-1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridine (compound 14f) [ka] To a solution of 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (Compound 14d) (260.0 mg, 0.67 mmol) in dioxane / HO (8.0 / 2.0 mL) was added 5-chloro-2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 14e) (196.3 mg, 0.67 mmol), KCO (463.8 mg, 3.36 mmol), and Pd(dppf)Cl (49.1 mg, 0.07 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 1, v / v) to give 5-chloro-1-methyl-2-(6-methyl- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridine (compound 14f) (150.0 mg, 52%) was obtained as a colorless oil. LCMS (ESI, m / z): [M+H] + =426.2.

[0212] Step 4: Synthesis of N-(1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 14h) [ka] To a solution of 5-chloro-1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridine (Compound 14f) (150.0 mg, 0.35 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (Compound 14g) (179.8 mg, 2.11 mmol), CsCO (344.2 mg, 1.06 mmol), BrettPhos (37.8 mg, 0.07 mmol), and BrettPhos Pd G (31.9 mg, 0.04 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give N-(1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 14h) (110.0 mg, 65%) as a white solid. LCMS (ESI, m / z): [M+H] + =475.2.

[0213] Step 5: Synthesis of N-(1-methyl-2-(6-methyl-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 14) [ka] To a solution of N-(1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 14h) (150.0 mg, 0.32 mmol) in DMF (5.0 mL) was added TBAF (1.0 mL, 0.95 mmol) and EDA (94.8 mg, 1.58 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and ethyl acetate. The resulting mixture was extracted with hexane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography using 5-100% CHCN in HO, followed by preparative HPLC under the following conditions (Column: Xselect CSH OBD column 30 x 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 35% B in 8 min; 254 nm) to give N-(1-methyl-2-(6-methyl-1H-indol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 14) (5.6 mg, 5%) as a white solid. LCMS (ESI, m / z): [M+H] + =345.2. 1 H NMR (300 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.48 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.50 (s, 1H), 7.38 - 7.36 (m, 2H), 6.44 (s, 1H), 6.39 (s, 1H), 3.54 (s, 3H), 2.19 (s, 3H), 2.05 - 1.95 (m, 1H), 0.83 - 0.76 (m, 4H).

[0214] Example S15: Synthesis of N-[1-methyl-2-(4-methyl-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15) [ka] Step 1: Synthesis of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (compound 15b) [ka] To a solution of 5-bromo-4-methyl-1H-indole (800.0 mg, 3.81 mmol) in THF (10.0 mL) was added NaH (182.8 mg, 60%) at room temperature. The resulting mixture was stirred at 0 °C for 1 h. Then, [2-(chloromethoxy)ethyl]trimethylsilane (695.1 mg, 4.17 mmol) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for another 1 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (80 / 20, v / v) to give 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (1.2 g, 92%) as a colorless oil. LCMS (ESI, m / z): [M+H] + =340.1.

[0215] Step 2: Synthesis of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (compound 15d) [ka] To a solution of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (600.0 mg, 1.76 mmol) in 1,4-dioxane (10.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (447.7 mg, 1.76 mmol), Pd(dppf)Cl2 (258.0 mg, 0.35 mmol), and KOAc (519.1 mg, 5.29 mmol). The resulting mixture was stirred at 80 °C under N2 for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (500.0 mg, crude product) as a brown solid. LCMS (ESI, m / z): [M+H] + =388.2.

[0216] Step 3: Synthesis of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (Compound 15f) [ka] To a solution of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (Compound 15d) (500.0 mg, 1.29 mmol) in 1,4-dioxane (10.0 mL) was added 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 15e) (377.5 mg, 1.29 mmol), Pd(dppf)Cl (188.9 mg, 0.26 mmol), NaCO (410.4 mg, 3.88 mmol), and HO (0.5 mL). The resulting mixture was stirred at 80 °C under N for 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (50 / 50, v / v) to give 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (150.0 mg, 23%) as a brown oil. LCMS (ESI, m / z): [M+H] + =426.2.

[0217] Step 4: Synthesis of N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15h) [ka] To a solution of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (Compound 15f) (120.0 mg, 0.28 mmol) in 1,4-dioxane (5.0 mL) was added cyclopropanecarboxamide (Compound 15g) (119.8 mg, 1.41 mmol), BrettPhos Pd G3 (51.1 mg, 0.06 mmol), BrettPhos (60.5 mg, 0.12 mmol), and Cs2CO3 (275.3 mg, 0.85 mmol). The resulting mixture was stirred at 100 °C under N2 for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / CHOH (94 / 6, v / v) to give N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15h) (130.0 mg, 2,3-c, 1,4-dimethyl-2 ... , 97%) as a brown solid. LCMS (ESI, m / z): [M+H] + =475.2.

[0218] Step 5: Synthesis of N-[1-methyl-2-(4-methyl-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15) [ka] To a solution of N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15h) (100.0 mg, 0.21 mmol) in DMF (5.0 mL) was added ethylenediamine (63.3 mg, 1.05 mmol) and TBAF (330.5 mg, 1.26 mmol). The resulting mixture was stirred at 80° C. for 16 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: YMC-Actus Triart C18 column, 30 x 250 mm, 5 μm; Mobile phase A: water (10 mmol / L FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 60% B in 8 min; 254 nm) to give N-[1-methyl-2-(4-methyl-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15) (7.1 mg, 9%) as a white solid. LCMS (ESI, m / z): [M+H] + =345.3. 1 H NMR (300 MHz, DMSO-d6): δ 11.27 (s, 1H), 10.45 (s, 1H), 8.57 (s, 1H), 8.27 - 8.15 (m, 1H), 7.43 - 7.41 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.38 (s, 1H), 3.55 (s, 3H), 2.33 (s, 3H), 2.04 - 1.99 (m, 1H), 0.89 - 0.78 (m, 4H).

[0219] Example S16: Synthesis of N-(1-methyl-2-(6-methyl-1H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 16) [ka] Step 1: Synthesis of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1H-indazole (compound 16c) [ka] To a solution of 5-chloro-2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine (compound 16a) (500.0 mg, 1.71 mmol) in dioxane / HO (8.0 / 2.0 mL) was added (6-methyl-1H-indazol-5-yl)boronic acid (compound 16b) (300.8 mg, 1.71 mmol), KCO (708.8 mg, 5.13 mmol), and Pd(PPh) (197.5 mg, 0.17 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C under N for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v). Purification by HPLC afforded 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1H-indazole (compound 16c) (260.0 mg, 51%) as a white solid. LCMS (ESI, m / z): [M+H] + =297.1.

[0220] Step 2: Synthesis of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (compound 16d) [ka] To a solution of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1H-indazole (Compound 16c) (260.0 mg, 0.88 mmol) in THF (5.0 mL), NaH (68.1 mg, 60%) was added at 0° C. under N. The resulting mixture was stirred at 0° C. for 1 hour. Then, SEM-Cl (219.1 mg, 1.31 mmol) was added to the mixture at 0° C. under N. The resulting mixture was stirred at 0° C. under N for 1 hour. After the reaction was complete, the reaction was quenched with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (compound 16d) (210.0 mg, 56%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =427.2.

[0221] Step 3: Synthesis of N-(1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 16f) [ka] To a solution of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (16d) (210.0 mg, 0.49 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (16e) (251.1 mg, 2.95 mmol), CsCO (480.7 mg, 1.48 mmol), BrettPhos (52.8 mg, 0.10 mmol), and BrettPhos Pd G (44.6 mg, 0.05 mmol) under N at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and washed with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give N-(1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 16f) (200.0 mg, 85%) as a white solid. LCMS (ESI, m / z): [M+H] + =476.2.

[0222] Step 4: Synthesis of N-(1-methyl-2-(6-methyl-1H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 16) [ka] To a solution of N-(1-methyl-2-(6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 16f) (250.0 mg, 0.53 mmol) in DMF (5.0 mL) was added TBAF (412.3 mg, 1.58 mmol) and EDA (157.7 mg, 2.63 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 16 hours. After the reaction was completed, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash column chromatography using 5-100% CHCN in HO, followed by preparative HPLC under the following conditions (Column: YMC-Actus Triart C18, 30 x 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 54% B in 10 min; 254 nm) to give N-(1-methyl-2-(6-methyl-1H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (compound 16) (40.4 mg, 22%) as a white solid. LCMS (ESI, m / z): [M+H] + =346.2. 1 H NMR (300 MHz, DMSO-d6): δ 13.13 (s, 1H), 10.50 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 6.45 (s, 1H), 3.54 (s, 3H), 2.22 (s, 3H), 2.08 - 1.98 (m, 1H), 0.84 - 0.76 (m, 4H).

[0223] Example S17: Synthesis of N-[1-methyl-2-(6-methyl-1H-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 17) [ka] Step 1: Synthesis of 5-bromo-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 17b) [ka] To a solution of 5-bromo-6-methyl-1H-1,3-benzodiazole (compound 17a) (800.0 mg, 3.79 mmol) in THF (10.0 mL) was added NaH (181.9 mg, 60%) under N at 0°C. The resulting mixture was stirred at 0°C for 1 hour. Then, [2-(chloromethoxy)ethyl]trimethylsilane (695.1 mg, 4.17 mmol) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 0°C for an additional 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (80 / 20, v / v) to give 5-bromo-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 17b) (900.0 mg, 69%) as a colorless oil. LCMS (ESI, m / z): [M+H] + =341.1.

[0224] Step 2: Synthesis of 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 17d) [ka] To a solution of 5-bromo-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 17b) (600.0 mg, 1.76 mmol) in 1,4-dioxane (10.0 mL) was added Pd(dppf)Cl (257.2 mg, 0.35 mmol), KOAc (517.6 mg, 5.27 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Compound 17c) (446.4 mg, 1.76 mmol). The resulting mixture was stirred at 80 °C under N for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 17d) (800.0 mg, crude product) as a black solid. LCMS (ESI, m / z): [M+H] + =389.2.

[0225] Step 3: Synthesis of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 17f) [ka] To a solution of 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 17d) (800.0 mg, 2.06 mmol) in 1,4-dioxane (10.0 mL) was added 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 17e) (602.5 mg, 2.06 mmol), Pd(dppf)Cl (301.4 mg, 0.41 mmol), KCO (854.0 mg, 6.18 mmol), and HO (0.5 mL). The resulting mixture was stirred at 80 °C under N for 16 h. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (65 / 35, v / v) to give 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3 -benzodiazole (compound 17f) (140.0 mg, 15%) was obtained as a brown oil. LCMS (ESI, m / z): [M+H] + =427.2.

[0226] Step 4: Synthesis of N-[1-methyl-2-(6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 17h) [ka] To a solution of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 17f) (110.0 mg, 0.26 mmol) in 1,4-dioxane (5.0 mL) was added cyclopropanecarboxamide (Compound 17g) (109.6 mg, 1.29 mmol), BrettPhos Pd G3 (46.7 mg, 0.05 mmol), BrettPhos (55.3 mg, 0.10 mmol), and Cs2CO3 (251.8 mg, 0.77 mmol). The resulting mixture was stirred at 100 °C under N2 for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / CHOH (94 / 6, v / v) to afford N-[1-methyl-2-(6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 17h) (130.0 mg, 95%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =476.2.

[0227] Step 5: Synthesis of N-(1-methyl-2-(6-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 17) [ka] To a solution of N-[1-methyl-2-(6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 17h) (100.0 mg, 0.21 mmol) in DMF (5.0 mL) was added ethylenediamine (63.2 mg, 1.05 mmol) and TBAF (329.8 mg, 1.26 mmol). The resulting mixture was stirred at 80° C. for 16 hours. After the reaction was completed, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using the following conditions (column: YMC-Ac Purification by preparative HPLC on a tus Triart C18 column, 30 x 250 mm, 5 µm; mobile phase A: water (10 mmol / L FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 60% B in 8 min; 254 nm) afforded N-[1-methyl-2-(6-methyl-1H-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 17) (7.9 mg, 10%) as a white solid. LCMS (ESI, m / z): [M+H] + = 346.3. 1 H NMR (300 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.59 (s, 1H), 8.25 - 8.20 (m, 2H), 7.58 - 7.54 (m, 2H), 6.43 (s, 1H), 3.54 (s, 3H), 2.20 (s, 3H), 2.03 - 1.97 (m, 1H), 0.89 - 0.72 (m, 4H).

[0228] Example S18: Synthesis of N-[1-methyl-2-(4-methyl-1H-indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 18) [ka] Step 1: Synthesis of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (compound 18b) [ka] To a solution of 5-bromo-4-methyl-1H-indazole (compound 18a) (500.0 mg, 2.39 mmol) in THF (10.0 mL) was added NaH (170.5 mg, 60%) under N2 at 0°C. The mixture was stirred at 0°C for 1 hour. Then, a solution of SEM-Cl (592.4 mg, 3.53 mmol) in THF (10.0 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for an additional 2 hours. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (compound 18b) (800.0 mg, 90%) as a yellow oil. LCMS (ESI): [M+H] + =341.1.

[0229] Step 2: Synthesis of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (compound 18d) [ka] To a solution of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (Compound 18b) (760.0 mg, 2.27 mmol) in dioxane (10.0 mL) was added bis(pinacolato)diboron (Compound 18c) (1.7 g, 6.80 mmol), Pd(dppf)Cl (162.9 mg, 0.23 mmol), and KOAc (655.8 mg, 6.80 mmol). The resulting mixture was stirred at 80 °C under N for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (compound 18d) (700.0 mg, 81%) as a white solid. LCMS (ESI): [M+H] + =389.2.

[0230] Step 3: Synthesis of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (compound 18f) [ka] To a solution of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (Compound 18d) (400.0 mg, 1.03 mmol) in dioxane / HO (20.0 mL / 2.0 mL) was added 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 18e) (301.4 mg, 1.03 mmol), Pd(PPh3)4 (119.1 mg, 0.13 mmol), and K3PO4 (655.3 mg, 3.09 mmol). The resulting mixture was stirred at 100 °C under N2 for 12 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (Compound 18f) (300.0 mg, 68%) as a white solid. LCMS (ESI): [M+H] + =427.2.

[0231] Step 4: Synthesis of N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 18h) [ka] To a solution of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (Compound 18f) (300.0 mg, 0.73 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (Compound 18g) (179.7 mg, 2.18 mmol), BrettPhos (75.4 mg, 0.14 mmol), BrettPhos Pd G3 (63.6 mg, 0.07 mmol), and Cs2CO3 (686.7 mg, 2.18 mmol). The resulting mixture was stirred at 100 °C under N2 for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 18h) (140.0 mg, 2,3-c, 1,4-dimethyl-2,3-dihydro-2 ... , 42%) as a red solid. LCMS (ESI): [M+H] + =476.2.

[0232] Step 5: Synthesis of N-[1-methyl-2-(4-methyl-1H-indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 18) [ka] To a solution of N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 18h) (140.0 mg, 0.29 mmol) in DMF (7.0 mL) was added ethylenediamine (88.4 mg, 1.47 mmol) and TBAF (230.8 mg, 0.88 mmol). The resulting mixture was stirred at 80° C. for 16 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v), followed by preparative HPLC to give N-[1-methyl-2-(4-methyl-1H-indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 18) (16.5 mg, 16%) as a white solid: Column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 53% B in 10 min; Detector: UV 254 nm. LCMS (ESI): [M+H] + =346.1. 1 H NMR (300 MHz, DMSO-d6): δ 13.22 (s, 1H), 10.48 (s, 1H), 8.61 (s, 1H), 8.26 - 8.21 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 3.57 (s, 3H), 2.43 (s, 3H), 2.08 - 1.97 (m, 1H), 0.82 - 0.76 (m, 4H).

[0233] Example S19: Synthesis of N-[1-methyl-2-(4-methyl-1H-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 19) [ka] Step 1: Synthesis of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 19b) [ka] To a solution of 5-bromo-4-methyl-1H-1,3-benzodiazole (compound 19a) (1.00 g, 4.73 mmol) in THF (10.0 mL) was added NaH (0.3 g, 60%) under N at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. Then, SEM-Cl (1.2 g, 7.07 mmol) was added dropwise to the mixture at 0 °C under N. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 19b) (1.0 g, 61%) as a yellow oil. LCMS (ESI, m / z): [M+H] + = 341.1.

[0234] Step 2: Synthesis of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 19d) [ka] To a mixture of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 19b) (950.0 mg, 2.78 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Compound 19c) (2.1 g, 8.34 mmol) in dioxane (10.0 mL), Pd(dppf)Cl (227.2 mg, 0.27 mmol) and KOAc (819.4 mg, 8.35 mmol) were added at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 19d) (2.0 g, crude product) as a yellow oil. LCMS (ESI, m / z): [M+H] + =389.2.

[0235] Step 3: Synthesis of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 19f) [ka] To a mixture of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 19d) (1.0 g, 2.51 mmol) and 5-chloro-2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 19e) (250.0 mg, 0.86 mmol) in dioxane / HO (10.0 / 1.0 mL) was added Pd(dppf)Cl (70.0 mg, 0.08 mmol) and KCO (354.0 mg, 2.51 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 19f) (350.0 mg, 31%) as a white solid. LCMS (ESI, m / z): [M+H] + = 427.2.

[0236] Step 4: Synthesis of N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 19h) [ka] To a mixture of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 19f) (300.0 mg, 0.70 mmol) and cyclopropanecarboxamide (Compound 19g) (239.1 mg, 2.81 mmol) in dioxane (5.0 mL), BrettPhos Pd G3 (63.6 mg, 0.07 mmol), CsCO3 (686.7 mg, 2.10 mmol), and BrettPhos (75.4 mg, 0.14 mmol) were added at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using dichloromethane / methyl alcohol (10 / 1, v / v) to give N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 19h) (220.0 mg, 65%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =476.2.

[0237] Step 5: Synthesis of N-[1-methyl-2-(4-methyl-1H-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 19) [ka] To a mixture of N-[1-methyl-2-(4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 19h) (170.0 mg, 0.36 mmol) and EDA (107.2 mg, 1.79 mmol) in DMF (2.0 mL) was added TBAF (280.3 mg, 1.07 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 hours. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using the following conditions (column: YMC-Actus Purification by preparative HPLC on a Triart C18 column, 30 x 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 19% B to 41% B in 7 min; 254 nm) afforded N-[1-methyl-2-(4-methyl-1H-1,3-benzodiazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 19) (31.4 mg, 25%) as a white solid. LCMS (ESI, m / z): [M+H] + =346.1. 1 H NMR (300 MHz, DMSO-d6): δ 12.74 - 12.60 (m, 1H), 10.49 (s, 1H), 8.61 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.51 (br, s, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.44 (s, 1H), 3.58 (s, 3H), 2.40 (s, 3H), 2.04 - 2.00 (m, 1H), 0.83 - 0.75 (m, 4H).

[0238] Example S20: Synthesis of N-[1-methyl-2-(3-methylpyridin-2-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 20) [ka] Step 1: Synthesis of 3-methyl-2-(tributylstannyl)pyridine (compound 20b) [ka] To a solution of 2-bromo-3-methylpyridine (compound 20a) (5.0 g, 29.06 mmol) in THF (125.0 mL) was added n-BuLi (4.1 mL, 64.15 mmol) dropwise at −78° C. under N2. The resulting mixture was stirred at −78° C. for 1 h. Then, tributylchlorostannane (11.3 g, 34.8 mmol) was added dropwise to the mixture at −78° C. The resulting mixture was stirred at −78° C. for another 1 h. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (80 / 20, v / v) to give 3-methyl-2-(tributylstannyl)pyridine (compound 20b). Compound 20b) (300.0 mg, 3%) was obtained as a colorless oil. LCMS (ESI): [M+H] + = 384.2.

[0239] Step 2: Synthesis of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylpyridine (compound 20d) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 20c) (200.0 mg, 0.68 mmol) in DMF (2.0 mL) was added 3-methyl-2-(tributylstannyl)pyridine (compound 20b) (522.6 mg, 1.36 mmol), CuI (13.0 mg, 0.07 mmol), LiCl (86.9 mg, 2.05 mmol), and Pd(PPh3)4 (79.0 mg, 0.07 mmol). The resulting mixture was irradiated in a microwave (MW) at 160 °C under N2 for 15 minutes. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (90 / 10, v / v) to give 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylpyridine (compound 20d) (170.0 mg, 96%) as a yellow oil. LCMS (ESI): [M+H] + = 258.1.

[0240] Step 3: Synthesis of N-[1-methyl-2-(3-methylpyridin-2-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 20) [ka] To a solution of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylpyridine (compound 20d) (210.0 mg, 0.81 mmol) in 1,4-dioxane (10.0 mL) was added BrettPhos Pd G3 (147.7 mg, 0.16 mmol), BrettPhos (174.9 mg, 0.32 mmol), CsCO3 (796.4 mg, 2.44 mmol), and cyclopropanecarboxamide (compound 20e) (104.0 mg, 1.22 mmol). The resulting mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (94 / 6, v / v) and then purified under the following conditions (Column: YMC-Actus Triart C18 column, 30 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 m Purification by preparative HPLC at 1000kJ / min; gradient: 18% B to 42% B in 8 min; 254 nm) afforded N-[1-methyl-2-(3-methylpyridin-2-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 20) (11.7 mg, 4%) as a white solid. LCMS (ESI, m / z): [M+H] + = 307.3. 1 H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.67 (s, 1H), 8.60 - 8.58 (m, 1H), 8.24 (s, 1H), 7.87 - 7.84 (m, 1H), 7.44 - 7.40 (m, 1H), 6.67 (d, J = 0.6 Hz, 1H), 3.73 (s, 3H), 2.35 (s, 3H), 2.08 - 2.00 (m, 1H), 0.85 - 0.78 (m, 4H).

[0241] Example S21: Synthesis of N-[1-methyl-2-(2-methylpyridin-3-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 21) [ka] Step 1: Synthesis of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylpyridine (compound 21b) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 21a) (200.0 mg, 0.68 mmol) in dioxane / HO (10.0 / 1.0 mL), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (179.8 mg, 0.08 mmol), Pd(dppf)Cl (10.0 mg, 0.01 mmol), and KCO (283.5 mg, 2.05 mmol) were added. The resulting mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 2, v / v) to give 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylpyridine (compound 21b) (150.0 mg, 85%) as a yellow solid. LCMS (ESI): [M+H] + =258.1.

[0242] Step 2: Synthesis of N-[1-methyl-2-(2-methylpyridin-3-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 21) [ka] To a solution of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylpyridine (compound 21b) (150.0 mg, 0.77 mmol) in dioxane (5.0 mL) was added cyclopropanecarboxamide (188.3 mg, 2.22 mmol), BrettPhos Pd G3 (66.8 mg, 0.07 mmol), BrettPhos (79.4 mg, 0.17 mmol), and Cs2CO3 (720.6 mg, 2.22 mmol). The resulting mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[1-methyl-2-(2-methylpyridin-3-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 21) (81.7 mg, 46%) as a white solid: Column: YMC-Actus Triart C18, 30 x 250 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 38% B in 8 min; Detector: UV 254 / 220 nm. LCMS (ESI): [M+H] + =307.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.64 - 8.59 (m, 2H), 8.22 (s, 1H), 7.80 - 7.76 (m, 1H), 7.41 - 7.37 (m, 1H), 6.53 (s, 1H), 3.59 (s, 3H), 2.37 (s, 3H), 2.05 - 1.95 (m, 1H), 0.82 - 0.76 (m, 4H).

[0243] Example S22: Synthesis of N-[2-(2-methoxypyridin-3-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 22) [ka] Step 1: Synthesis of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methoxypyridine (compound 22c) [ka] To a mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 22a) (300.0 mg, 1.02 mmol) and 2-methoxypyridin-3-ylboronic acid (Compound 22b) (313.7 mg, 2.05 mmol) in dioxane / HO (4.0 / 0.4 mL) was added Pd(dppf)Cl (83.7 mg, 0.10 mmol) and KCO (425.2 mg, 3.07 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 12 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) to give 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methoxypyridine (compound 22c) (230.0 mg, 82%) as a white solid. LCMS (ESI, m / z): [M+H] + =274.1.

[0244] Step 2: Synthesis of N-[2-(2-methoxypyridin-3-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 22) [ka] To a stirred mixture of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methoxypyridine (Compound 22c) (100.0 mg, 0.37 mmol) and cyclopropanecarboxamide (Compound 22d) (155.4 mg, 1.82 mmol) in dioxane (3.0 mL), CsCO (357.1 mg, 1.10 mmol), BrettPhos (39.2 mg, 0.07 mmol), and BrettPhos Pd G (33.1 mg, 0.03 mmol) were added at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: YMC-Actus Triart C18, 30 x 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 67% B in 7 min; 254 nm) to give N-[2-(2-methoxypyridin-3-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (compound 22) (79.5 mg, 67%) as a white solid. LCMS (ESI, m / z): [M+H] + =323.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.63 (s, 1H), 8.36 - 8.34 (m, 1H), 8.21 (s, 1H), 7.86 - 7.83 (m, 1H), 7.20 - 7.16 (m, 1H), 6.52 (d, J = 0.8 Hz, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 2.03 - 1.98 (m, 1H), 0.84 - 0.78 (m, 4H).

[0245] Example S23: Synthesis of cis-2-(hydroxymethyl)-N-(2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 23) [ka] Step 1: Synthesis of 6-chloro-4-iodopyridin-3-amine hydrochloride (compound 23b) [ka] A solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)carbamate (compound 23a) (5.0 g, 14.10 mmol) in HCl / 1,4-dioxane (50.0 mL, 4 mol / L) was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give 6-chloro-4-iodopyridin-3-amine hydrochloride (compound 23b) (5.0 g, crude product) as a yellow solid. LCMS (ESI, m / z): [M+H] + =254.9.

[0246] Step 2: Synthesis of 5-chloro-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (compound 23d) [ka] To a solution of 6-chloro-4-iodopyridin-3-amine hydrochloride (Compound 23b) (2.0 g, crude product) in DMF (20.0 mL) was added 1-ethynyl-2-methoxybenzene (Compound 23c) (1.3 g, 9.43 mmol), NaCO (4.2 g, 39.3 mmol), LiCl (333.2 mg, 7.86 mmol), and Pd(dppf)Cl (575.1 mg, 0.79 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (50 / 50, v / v) to give 5-chloro-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (compound 23d) (770.0 mg, 37%) as a brown solid. LCMS (ESI, m / z): [M+H] + =259.1.

[0247] Step 3: Synthesis of 5-chloro-2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (compound 23e) [ka] To a solution of 5-chloro-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (Compound 23d) (770 mg, 2.98 mmol) in THF (10.0 mL) was added NaH (371.1 mg, 60%) under N at 0° C. The resulting mixture was stirred at 0° C. under N for 1 hour. Then, CHI (2.2 g, 15.5 mmol) was added dropwise to the mixture at 0° C. under N. The resulting mixture was stirred at 0° C. for another 1 hour. After the reaction was complete, the resulting mixture was diluted with H0 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 5-chloro-2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 23e) (800.0 mg, crude product) as a brown solid. LCMS (ESI, m / z): [M+H] + =273.2.

[0248] Step 4: Synthesis of 2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-amine (compound 23g) [ka] To a solution of 5-chloro-2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 23e) (800.0 mg, crude product) in toluene (10.0 mL) was added diphenylmethanimine (Compound 23f) (1.6 g, 8.80 mmol), t-BuOK (987.5 mg, 8.80 mmol), Xantphos (339.5 mg, 0.59 mmol), and Pd(dba) (268.6 mg, 0.29 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (87 / 13, v / v) to give 2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-amine (compound 23g) (240.0 mg, 15%) as a brown solid. LCMS (ESI, m / z): [M+H] + =254.1.

[0249] Step 5: Synthesis of (cis)-2-((2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)carbamoyl)cyclopropane-1-carboxylate (compound 23i) [ka] To a solution of 2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-amine (Compound 23g) (240.0 mg, 0.95 mmol) in DMF (5.0 mL) was added cis-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (Compound 23h) (136.6 mg, 0.95 mmol), DIEA (612.3 mg, 4.74 mmol), and HATU (432.3 mg, 1.14 mmol) at 0 °C under N 2 . The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 99, v / v) to give (cis)-2-((2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)carbamoyl)methyl cyclopropane-1-carboxylate (Compound 23i) (190.0 mg, 53%) as a brown solid. LCMS (ESI, m / z): [M+H] + =380.2.

[0250] Step 6: cis-2-(hydroxymethyl)-N-(2-(2-methoxyphenyl) Synthesis of (1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 23) [ka] To a solution of (cis)-2-((2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)carbamoyl)methyl cyclopropane-1-carboxylate (Compound 23i) (170.0 mg, 0.45 mmol) in THF / CHOH (5.0 / 1.0 mL) was added NaBH (169.5 mg, 4.48 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified under the following conditions (column: XBridge Prep OBD II). Purification by preparative HPLC on a C18 column, 19 x 250 mm, 5 um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH (preparative); flow rate: 25 mL / min; gradient: 54% B to 70% B in 7 min; 254 nm gave cis-2-(hydroxymethyl)-N-(2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 23) (5.3 mg, 3%) as a white solid. LCMS (ESI, m / z): [M+H] + =352.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 7.56 - 7.50 (m, 1H), 7.39 - 7.36 (m, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.13 - 7.08 (m, 1H), 6.42 (d, J = 0.6 Hz, 1H), 4.48 - 4.45 (m, 1H), 3.82 (s, 3H), 3.69 - 3.55 (m, 5H), 2.10 - 2.07 (m, 1H), 1.50 - 1.34 (m, 1H), 0.98 - 0.90 (m, 2H).

[0251] Example S24: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 24) [ka] Step 1: 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methyl-1 Synthesis of H-pyrrolo[2,3-c]pyridine (compound 24c) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 24a) (500.0 mg, 1.70 mmol) in 1,4-dioxane / HO (36.0 / 3.6 mL) was added KCO (708.7 mg, 5.12 mmol), 3-methoxy-2-methylphenylboronic acid (compound 24b) (425.5 mg, 2.56 mmol), and Pd(dppf)Cl (250.1 mg, 0.34 mmol) under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using ether / ethyl acetate (87 / 13, v / v) to give 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (compound 24c) (380.0 mg, 77%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =287.1.

[0252] Step 2: Synthesis of 3-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-2-methylphenol (compound 24d) [ka] To a solution of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 24c) (380.0 mg, 1.32 mmol) in CHCl (5.0 mL) was added BBr (1616.2 mg, 6.45 mmol) under N at 0 °C. The resulting mixture was stirred at 0 °C for 2.5 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using ether / ethyl acetate (85 / 15, v / v) to give 3-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-2-methylphenol (Compound 24d) (380.0 mg, 99%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =273.1.

[0253] Step 3: Synthesis of (1S,2S)-2-fluoro-N-(2-(3-hydroxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 24) [ka] To a solution of 3-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-2-methylphenol (Compound 24d) (200.0 mg, 0.73 mmol) in dioxane (10.0 mL), CsCO (716.8 mg, 2.20 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 24e) (378.0 mg, 3.66 mmol), BrettPhos (157.4 mg, 0.29 mmol), and BrettPhos Pd G (132.9 mg, 0.14 mmol) were added at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (80 / 20, v / v), followed by preparative HPLC under the following conditions (Column: Xselect CSH OBD column 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 38% B in 8 min; 220 nm) to give (1S,2S)-2-fluoro-N-(2-(3-hydroxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 24) (10.7 mg, 4%) as a white solid. LCMS (ESI, m / z): [M+H] + = 340.1. 1 H NMR (300 MHz, DMSO-d): δ 10.46 (s, 1H), 9.57 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 7.11 - 7.03 (m, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 6.33 (s, 1H), 4.95 - 4.71 (m, 1H), 3.48 (s, 3H), 2.17 - 2.08 (m, 1H), 1.87 (s, 3H), 1.61 - 1.54 (m, 1H), 1.11 - 1.02 (m, 1H).

[0254] Example S25: Synthesis of (1S,2S)-2-fluoro-N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 25) [ka] Step 1: Synthesis of 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 25c) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 25a) (300.0 mg, 1.03 mmol) in 1,4-dioxane / HO (8.0 mL / 2.0 mL) was added 2-methoxy-6-methylphenylboronic acid (compound 25b) (204.3 mg, 1.23 mmol), KCO (425.3 mg, 3.08 mmol), and Pd(dppf)Cl (75.1 mg, 0.10 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using petroleum ether / ethyl acetate (1 / 1, v / v) to give 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 25c) (90.0 mg, 30%) as a brown oil. LCMS (ESI, m / z): [M+H] + =287.1.

[0255] Step 2: Synthesis of (1S,2S)-2-fluoro-N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 25) [ka] To a solution of 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 25c) (60.0 mg, 0.21 mmol) in 1,4-dioxane (6.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 25d) (107.9 mg, 1.05 mmol), BrettPhos (22.5 mg, 0.04 mmol), CsCO (204.5 mg, 0.63 mmol), and BrettPhos Pd G (19.0 mg, 0.02 mmol) at room temperature under N. The reaction mixture was stirred at 120 °C under N for 1.5 hours in a microwave oven. After the reaction was complete, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by the following conditions (column: XBridge Prep OBD Purification by preparative HPLC on a C18 column, 30 x 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 70% B in 7 min; 254 nm) afforded (1S,2S)-2-fluoro-N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 25) (10.3 mg, 13%) as a white solid. LCMS (ESI, m / z): [M+H] + =354.2. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.41 - 7.37 (m, 1H), 7.02 - 6.98 (m, 2H), 6.36 (s, 1H), 4.99 - 4.81 (m, 1H), 3.70 (s, 3H), 3.48 (s, 3H), 2.25 - 2.19 (m, 1H), 2.06 (s, 3H), 1.68 - 1.61 (m, 1H), 1.15 - 1.10 (m, 1H).

[0256] Example S26: Synthesis of (1S,2S)-2-fluoro-N-[2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 26) [ka] Step 1: Synthesis of 5-chloro-2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 26c) [ka] A mixture of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 26a) (500.0 mg, 1.71 mmol), 5-fluoro-2-methoxyphenylboronic acid (compound 26b) (348.6 mg, 2.05 mmol), KCO (708.8 mg, 5.13 mmol), and Pd(dppf)Cl (125.1 mg, 0.17 mmol) in dioxane (10.0 mL) and HO (2.0 mL) was stirred at 100 °C for 16 h under N. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (94 / 6, v / v) to give 5-chloro-2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 26c) (483.5 mg, 97%) as a white solid. LCMS (ESI, m / z): [M+H] + = 291.1.

[0257] Step 2: Synthesis of (1S,2S)-2-fluoro-N-[2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 26) [ka] A mixture of 5-chloro-2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 26c) (150.0 mg, 0.52 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (compound 26d) (63.8 mg, 0.62 mmol), CsCO (213.9 mg, 1.55 mmol), BrettPhos (55.4 mg, 0.10 mmol), and BrettPhos Pd G (46.8 mg, 0.05 mmol) in dioxane (5.0 mL) was irradiated with microwave radiation at 100 °C for 2 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / CHOH (94 / 6, v / v) and then by preparative HPLC under the following conditions (Column: YMC-Actus Triart C18, 30 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B in 10 min; 254 nm) to give (1S,2S)-2-fluoro-N-[2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 26) (10.4 mg, 5%) as a white solid. LCMS (ESI, m / z): [M+H] + = 358.1. 1 H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.62 (s, 1H), 8.21 (s, 1H), 7.44 - 7.33 (m, 1H), 7.29 - 7.20 (m, 2H), 6.49 (s, 1H), 5.04 - 4.76 (m, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 2.28 - 2.15 (m, 1H), 1.71 - 1.58 (m, 1H), 1.15 - 1.03 (m, 1H).

[0258] Example S27: Synthesis of (1S,2S)-2-fluoro-N-[2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 27) [ka] Step 1: Synthesis of 5-chloro-2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 27c) [ka] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 27a) (300.0 mg, 1.03 mmol) in 1,4-dioxane / HO (5.0 / 1.0 mL) was added 2-fluoro-6-methoxyphenylboronic acid (compound 27b) (209.2 mg, 1.23 mmol), KCO (425.3 mg, 3.08 mmol), and Pd(dppf)Cl (75.05 mg, 0.10 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 3 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (52 / 48, v / v) to give 5-chloro-2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 27c) (100.0 mg, 33%) as a white solid. LCMS (ESI, m / z): [M+H] + =291.0.

[0259] Step 2: Synthesis of (1S,2S)-2-fluoro-N-[2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 27) [ka] To a solution of 5-chloro-2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 27c) (150.0 mg, 0.52 mmol) in 1,4-dioxane (5.0 mL), (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 27d) (265.9 mg, 2.58 mmol), CsCO (504.3 mg, 1.55 mmol), BrettPhos (55.4 mg, 0.10 mmol), and BrettPhos Pd G (46.77 mg, 0.05 mmol) were added at room temperature under N. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (34 / 66, v / v), followed by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 63% B in 7 min; 254 nm) to give (1S,2S)-2-fluoro-N-[2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 27) (22.5 mg, 12%) as a white solid. LCMS (ESI, m / z): [M+H] + =358.2. 1 H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.64 (s, 1H), 8.22 (s, 1H), 7.58 - 7.51 (m, 1H), 7.32 - 7.00 (m, 2H), 6.51 (s, 1H), 5.01 - 4.81 (m, 1H), 3.81 (s, 3H), 3.59 (s, 3H), 2.25 - 2.18 (m, 1H), 1.71 - 1.63 (m, 1H), 1.11 - 1.05 (m, 1H).

[0260] Example S28: Synthesis of (1S,2S)-2-fluoro-N-(2-(6-methoxy-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide formate (Compound 28) [ka] Step 1: Synthesis of 5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (compound 28b) [ka] To a solution of 5-bromo-6-methoxy-1H-benzo[d]imidazole (750 mg, 3.30 mmol) in THF (30.0 mL) was added NaH (396.3 mg, 60%) at 0 °C under N. The resulting mixture was stirred at 0 °C for 1 h under N. Then, SEM-Cl (826.0 mg, 4.96 mmol) was added dropwise to the mixture at 0 °C under N. The resulting mixture was stirred at 0 °C for another 1 h. After the reaction was complete, the reaction mixture was quenched with H0 at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / MeOH (12 / 1, v / v). Preparation gave 5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.0 g, 84%) as a brown oil. LCMS (ESI, m / z): [M+H] + =357.1.

[0261] Step 2: Synthesis of 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (compound 28d) [ka] To a solution of 5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (Compound 28b) (300.0 mg, 0.84 mmol) in dioxane (10.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Compound 28c) (639.6 mg, 2.52 mmol), KOAc (247.2 mg, 2.52 mmol), and Pd(dppf)Cl (61.4 mg, 0.80 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / MeOH (10 / 1, v / v) to give 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (compound 28d) (320.0 mg, 94%) as a brown oil. LCMS (ESI, m / z): [M+H] + =405.2.

[0262] Step 3: Synthesis of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (compound 28f) [ka] To a solution of 6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (Compound 28d) (260.0 mg, 0.64 mmol) in dioxane / HO (16.0 / 4.0 mL) was added 5-chloro-2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 28e) (188.1 mg, 0.64 mmol), KCO (266.6 mg, 1.93 mmol), and Pd(dppf)Cl (47.0 mg, 0.06 mmol) was added at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / MeOH (10 / 1, v / v) to give 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (compound 28f) (250.0 mg, 87%) as a brown solid. LCMS (ESI, m / z): [M+H] + =443.2.

[0263] Step 4: Synthesis of (1S,2S)-2-fluoro-N-(2-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 28h) [ka] To a solution of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (Compound 28f) (400.0 mg, 0.90 mmol) in dioxane (20.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 28g) (465.4 mg, 4.51 mmol), CsCO (882.5 mg, 2.71 mmol), BrettPhos (96.9 mg, 0.18 mmol), and BrettPhos Pd G (81.8 mg, 0.09 mmol) at room temperature under N. The final reaction mixture was irradiated with microwave radiation under N at 120 °C for 1.5 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / MeOH (10 / 1, v / v) to afford (1S,2S)-2-fluoro-N-(2-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 28h) (60.0 mg, 13%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =510.2.

[0264] Step 5: Synthesis of (1S,2S)-2-fluoro-N-(2-(6-methoxy-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide formate (compound 28) [ka] To a solution of (1S,2S)-2-fluoro-N-(2-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 28h) (60.0 mg, 0.12 mmol) in DCM (3.0 mL) was added TFA (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in ACN (3.0 mL) and NH.sub.3·HO (3.0 mL). The resulting mixture was stirred at room temperature for an additional 16 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (Column: Xselect CSH OBD column 30 x 150 mm, 5 um; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% to 14% in 7 min; 254 nm) to give (1S,2S)-2-fluoro-N-(2-(6-methoxy-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide formate (Compound 28) (2.9 mg, 5%) as a white solid. LCMS (ESI, m / z): [M+H] + =380.3. 1 H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 10.53 (s, 1H), 8.59 (s, 1H), 8.22 - 8.17 (m, 3H), 7.56 (s, 1H), 7.30 (s, 1H), 6.46 (s, 1H), 5.01 - 4.80 (m, 1H), 3.83 (s, 3H), 3.60 (s, 3H), 2.24 - 2.17 (m, 1H), 1.70 - 1.60 (m, 1H). 1.18 - 1.09 (m, 1H).

[0265] Example S29: Synthesis of (1S,2S)-2-fluoro-N-[2-(4-methoxy-1H-1,3-benzodiazol-5-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 29) [ka] Step 1: Synthesis of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (compound 29c) [ka] To a solution of 4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 29a) (300.3 mg, 0.74 mmol) in 1,4-dioxane / HO (10.0 mL / 2.0 mL) was added 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 29b) (181.0 mg, 0.62 mmol), KCO (256.6 mg, 1.86 mmol), and Pd(dppf)Cl (45.3 mg, 0.06 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (3 / 2, v / v) to give 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 29c) (170 0.0 mg, 62%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =443.2.

[0266] Step 2: Synthesis of (1S,2S)-2-fluoro-N-[2-(4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 29e) [ka] To a solution of 5-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 29c) (180.0 mg, 0.41 mmol) in 1,4-dioxane (15.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 29d) (209.4 mg, 1.34 mmol), BrettPhos (43.6 mg, 0.08 mmol), CsCO (397.1 mg, 1.22 mmol), and BrettPhos Pd G (36.8 mg, 0.04 mmol) under N at room temperature. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl2 / MeOH (5 / 1, v / v) to give (1S,2S)-2-fluoro-N-[2-(4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 29e) (60.0 mg, 16%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =510.2.

[0267] Step 3: Synthesis of (1S,2S)-2-fluoro-N-[2-(4-methoxy-1H-1,3-benzodiazol-5-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 29) [ka] To a solution of (1S,2S)-2-fluoro-N-[2-(4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazol-5-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (Compound 29e) (181.0 mg, 0.36 mmol) in CHCl (8.0 mL) was added TFA (8.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH3CN (8.0 mL) and NH3·H2O (8.0 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30 x 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 35% B in 9 min; 254 nm) to give (1S,2S)-2-fluoro-N-[2-(4-methoxy-1H-1,3-benzodiazol-5-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropane-1-carboxamide (compound 29) (14.0 mg, 10%) as a white solid. LCMS (ESI, m / z): [M+H] + =380.2. 1 H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 10.50 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.29 - 7.16 (m, 2H), 6.41 (s, 1H), 4.98 - 4.82 (m, 1H), 4.32 (s, 3H), 3.72 (s, 3H), 2.33 - 2.19 (m, 1H), 1.71 - 1.59 (m, 1H), 1.16 - 1.10 (m, 1H).

[0268] Example S30: Synthesis of (1S,2S)-2-fluoro-N-(2-(7-methoxy-1H-indazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 30) [ka] Step 1: Synthesis of 6-bromo-3-methyl-2-nitrophenol (compound 30b) [ka] To a solution of 2-bromo-5-methylphenol (compound 30a) (20.0 g, 106.9 mmol) in CHCl (80.0 mL) was added HSO (7.4 mL, 75.55 mmol) under N at 0 °C. Then, HNO (8.0 mL, 126.85 mmol) was added dropwise to the mixture under N at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with CHCl. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) to give 6-bromo-3-methyl-2-nitrophenol (compound 30b) (6.5 g, 26%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =232.0.

[0269] Step 2: Synthesis of 1-bromo-2-methoxy-4-methyl-3-nitrobenzene (compound 30c) [ka] To a solution of 6-bromo-3-methyl-2-nitrophenol (compound 30b) (6.5 g, 28.01 mmol) in DMF (20.0 mL) were added KCO (11.6 g, 84.04 mmol) and CHCl (6.0 g, 42.02 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) to give 1-bromo-2-methoxy-4-methyl-3-nitrobenzene (compound 30c) (6.1 g, 88%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =246.0.

[0270] Step 3: Synthesis of 3-bromo-2-methoxy-6-methylaniline (compound 30d) [ka] To a solution of 1-bromo-2-methoxy-4-methyl-3-nitrobenzene (compound 30c) (1.5 g, 0.84 mmol) in MeOH / HO (16.0 / 4.0 mL) was added NH4Cl (1.6 g, 30.48 mmol) at room temperature. Then, Fe (1.7 g, 30.48 mmol) was added to the mixture at 80 °C. The resulting mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give 3-bromo-2-methoxy-6-methylaniline (compound 30d) (1.0 g, 75%) as a brown oil. LCMS (ESI, m / z): [M+H] + =216.0.

[0271] Step 4: Synthesis of 6-bromo-7-methoxy-1H-indazole (compound 30e) [ka] To a solution of 3-bromo-2-methoxy-6-methylaniline (compound 30d) (1.4 g, 6.48 mmol) in AcOH (30.0 mL) was added tert-butyl nitrate (t-BuONO, 0.73 g, 7.09 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give 6-bromo-7-methoxy-1H-indazole (compound 30e) (1.0 g, 67%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =227.0.

[0272] Step 5: Synthesis of 6-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (compound 30f) [ka] To a solution of 6-bromo-7-methoxy-1H-indazole (compound 30e) (1.0 g, 4.40 mmol) in THF (30.0 mL) was added NaH (528.4 mg, 60%) at 0° C. under N. The resulting mixture was stirred at 0° C. under N for 1 hour. SEM-Cl (1.1 g, 6.61 mmol) was then added dropwise to the mixture at 0° C. under N. The resulting mixture was stirred at 0° C. under N for another 1 hour. After the reaction was complete, the reaction mixture was quenched with H0 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give 6-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (compound 30f) (1.4 g, 88%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =357.1.

[0273] Step 6: Synthesis of 7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Compound 30h) [ka] To a solution of 6-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Compound 30f) (1.4 g, 3.92 mmol) in dioxane (20.0 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Compound 30g) (3.0 g, 11.75 mmol), KOAc (1.2 g, 11.75 mmol), and Pd(dppf)Cl (0.3 g, 0.39 mmol) were added at room temperature under N. The resulting mixture was stirred at 80 °C under N for 16 hours. After the reaction was complete, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using CHOH / HO (85 / 15, v / v) to give 7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (compound 30h) (350.0 mg, 22%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =405.2.

[0274] Step 7: Synthesis of 6-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Compound 30j) [ka] To a solution of 7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Compound 30h) (300.0 mg, 0.74 mmol) in dioxane / HO (10.0 / 2.0 mL) was added 5-chloro-2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 30i) (217.0 mg, 0.74 mmol), KCO (307.6 mg, 2.23 mmol), and Pd(dppf)Cl (54.3 mg, 0.07 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to give 6-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Compound 30j) (200.0 m g, 60%) as a yellow oil. LCMS (ESI, m / z): [M+H] + =443.2.

[0275] Step 8: Synthesis of (1S,2S)-2-fluoro-N-(2-(7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 301) [ka] To a solution of 6-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (Compound 30j) (130.0 mg, 0.29 mmol) in dioxane (10.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 30k) (151.3 mg, 1.47 mmol), CsCO (286.8 mg, 0.88 mmol), BrettPhos (31.5 mg, 0.06 mmol), and BrettPhos Pd G (26.6 mg, 0.03 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C under N for 4 h. After the reaction was completed, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using CHCl / MeOH (10 / 1, v / v) to give (1S,2S)-2-fluoro-N-(2-(7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 30l) (110.0 mg, 73%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =510.2.

[0276] Step 9: Synthesis of (1S,2S)-2-fluoro-N-(2-(7-methoxy-1H-indazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 30) [ka] To a solution of (1S,2S)-2-fluoro-N-(2-(7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 301) (200.0 mg, 0.39 mmol) in DCM (3.0 mL) was added TFA (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. To the residue in ACN (3.0 mL) was added NH3·H2O (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 16 hours. After the reaction was complete, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (Column: Xselect CSH OBD column 30 x 150 mm, 5 um; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% to 18% in 8 min; 254 nm) to give (1S,2S)-2-fluoro-N-(2-(7-methoxy-1H-indazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 30) (12.6 mg, 8%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + =380.2. 1 H NMR (300 MHz, DMSO-d6): δ 13.53 (s, 1H), 10.56 (s, 1H), 8.66 (s, 1H), 8.24 - 8.22 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 5.05 - 4.78 (m, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 2.27 - 2.17 (m, 1H), 1.73 - 1.59 (m, 1H), 1.18 - 1.11 (m, 1H).

[0277] Example S31: Synthesis of (1S,2S)—N-[2-(2,3-dihydro-1H-indol-4-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]-2-fluorocyclopropane-1-carboxamide (Compound 31) [ka] Step 1: Synthesis of tert-butyl 4-bromo-2,3-dihydroindole-1-carboxylate (compound 31b) [ka] To a solution of 4-bromo-2,3-dihydro-1H-indole (compound 31a) (2.0 g, 10.10 mmol) in CHCl (30.0 mL) was added TEA (3.1 g, 30.29 mmol) and di-tert-butyl dicarbonate (3.3 g, 15.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (30 / 70, v / v) to give tert-butyl 4-bromo-2,3-dihydroindole-1-carboxylate (compound 31b) (2.7 g, 90%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =298.0.

[0278] Step 2: Synthesis of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroindole-1-carboxylate (compound 31c) [ka] To a solution of tert-butyl 4-bromo-2,3-dihydroindole-1-carboxylate (Compound 31b) (2.7 g, 9.06 mmol) in 1,4-dioxane (30.0 mL) was added bis(pinacolato)diboron (6.9 g, 27.17 mmol), KOAc (2.7 g, 27.17 mmol), and Pd(dppf)Cl (0.7 g, 0.91 mmol). The resulting mixture was stirred at 80 °C under N for 16 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (5 / 95, v / v) to give tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroindole-1-carboxylate (compound 31c) (2.0 g, 63%) as a white solid. LCMS (ESI, m / z): [M+H] + =346.2.

[0279] Step 3: Synthesis of tert-butyl 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydroindole-1-carboxylate (Compound 31e) [ka] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroindole-1-carboxylate (Compound 31c) (400.0 mg, 1.16 mmol) in 1,4-dioxane / HO (15.0 mL / 2.0 mL) was added 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 31d) (338.9 mg, 1.16 mmol), KCO (480.4 mg, 3.48 mmol), and Pd(dppf)Cl (84.8 mg, 0.12 mmol). The resulting mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (70 / 30, v / v) to give tert-butyl 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydroindole-1-carboxylate (Compound 31e) (360.0 mg, 81%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =384.1.

[0280] Step 4: Synthesis of tert-butyl 4-[5-[(1S,2S)-2-fluorocyclopropanamido]-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydroindole-1-carboxylate (Compound 31g) [ka] To a solution of tert-butyl 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydroindole-1-carboxylate (Compound 31e) (330.0 mg, 0.86 mmol) in 1,4-dioxane (10.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 31f) (265.9 mg, 2.58 mmol), CsCO (840.3 mg, 2.58 mmol), BrettPhos (92.3 mg, 0.17 mmol), and BrettPhos Pd G (77.9 mg, 0.09 mmol). The resulting mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (20 / 80, v / v) to give tert-butyl 4-[5-[(1S,2S)-2-fluorocyclopropanamido]-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydroindole-1-carboxylate (Compound 31g) (250.0 mg, 64%) as a yellow solid. LCMS (ESI, m / z): [M+H] + =451.2.

[0281] Step 5: (1S,2S)—N-[2-(2,3-dihydro-1H-indol-4-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]-2-fluorocyclopropane Synthesis of propane-1-carboxamide (compound 31) [ka] To a solution of tert-butyl 4-[5-[(1S,2S)-2-fluorocyclopropanamido]-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydroindole-1-carboxylate (Compound 31g) (200.0 mg, 0.44 mmol) in DCM (5.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the mixture was adjusted to 7 with aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (Column: YMC-Actus Triart C18 column, 30 x 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 57% B in 10 min; 254 nm) to give (1S,2S)—N-[2-(2,3-dihydro-1H-indol-4-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]-2-fluorocyclopropane-1-carboxamide (Compound 31) (14.0 mg, 9%) as a white solid. LCMS (ESI, m / z): [M+H] + = 351.2. 1 H NMR (300 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.60 (s, 1H), 8.20 (s, 1H), 7.10 - 7.05 (m, 1H), 6.64 - 6.60 (m, 2H), 6.50 (s, 1H), 5.75 (s, 1H), 5.03 - 4.78 (m, 1H), 3.72 (s, 3H), 3.47 - 3.41 (m, 2H), 2.93 - 2.88 (m, 2H), 2.23 - 2.18 (m, 1H), 1.70 - 1.59 (m, 1H), 1.17 - 1.10 (m, 1H).

[0282] Example S32: Synthesis of (1S,2S)-2-fluoro-N-(2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 32) [ka] Step 1: Synthesis of 2-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound 32c) [ka] To a solution of 3-bromo-2-(methoxy-d)pyridine (Compound 32a) (1.0 g, 5.23 mmol) in 1,4-dioxane (20.0 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Compound 32b) (2.7 g, 10.5 mmol), KOAc (1.5 g, 15.7 mmol), and Pd(dppf)Cl (383.0 mg, 0.52 mmol) were added at room temperature under N. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (80 / 20, v / v) to give 2-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound 32c) (1.2 g, 96%) as a brown oil. LCMS (ESI, m / z): [M+H] + =239.2.

[0283] Step 2: Synthesis of 5-chloro-2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (compound 32e) [ka] 5-chloro-2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine (compound To a solution of 32d) (600.0 mg, 2.05 mmol) in 1,4-dioxane / HO (10.0 / 2.0 mL), 2-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound 32c) (488.4 mg, 3.17 mmol), KCO (850.5 mg, 6.15 mmol), and Pd(dppf)Cl (150.1 mg, 0.21 mmol) were added at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (74 / 26, v / v) to give 5-chloro-2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (compound 32e) (490.0 mg, 86%) as a pale yellow solid. LCMS (ESI, m / z): [M+H] + =277.1.

[0284] Step 3: Synthesis of (1S,2S)-2-fluoro-N-(2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (compound 32) [ka] To a solution of 5-chloro-2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 32e) (190.0 mg, 0.69 mmol) in 1,4-dioxane (10.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (Compound 32f) (353.9 mg, 3.43 mmol), CsCO (671.1 mg, 2.06 mmol), BrettPhos (73.1 mg, 0.14 mmol), and BrettPhos Pd G (62.2 mg, 0.07 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was complete, the resulting mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (1 / 99, v / v) and then by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 65% B in 7 min; 254 nm) to give (1S,2S)-2-fluoro-N-(2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 32) (17.9 mg, 7%) as a white solid. LCMS (ESI, m / z): [M+H] + =344.2. 1 H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.64 (s, 1H), 8.35 - 8.33 (m, 1H), 8.22 (s, 1H), 7.86 - 7.83 (m, 1H), 7.19 - 7.16 (m, 1H), 6.53 (d, J = 0.4 Hz, 1H), 5.00 - 4.80 (m, 1H), 3.64 (s, 3H), 2.22 - 2.19 (m, 1H), 1.69 - 1.63 (m, 1H), 1.20 - 1.05 (m, 1) H).

[0285] Example S33: Synthesis of (1R,2R)-2-fluoro-N-(2-(2-(methoxy-d3)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyrid...

Claims

[Claim 1] The invention described in the specification.

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