5- and 6-azaindole compounds for inhibiting Bcr-Abl tyrosine kinase

Abstract

The present disclosure relates to compounds and compositions for inhibiting Bcr-Abl tyrosine kinase, methods for preparing the compounds and compositions, and the use of the compounds and compositions in treating various cancers such as chronic myeloid leukemia (CML).

Description

[0001] This application is a divisional application of a patent application filed on October 4, 2021, with application number 202180080488.1 and titled “5- and 6-azaindole compounds for inhibiting Bcr-Abl tyrosine kinase”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 087,763, filed on October 5, 2020, and U.S. Provisional Application No. 63 / 224,236, filed on July 21, 2021, the disclosure of each of which is incorporated herein by reference in its entirety. Technical Field

[0004] Provided herein are compounds and compositions for inhibiting Bcr-Abl tyrosine kinase, methods for preparing the compounds and compositions, and their use in treating various cancers, such as chronic myeloid leukemia (CML). Background Art

[0005] A cytogenetic abnormality known as the Philadelphia chromosome is highly associated with the development of many hematological malignancies, including most chronic myeloid leukemias (CML) and a subset of acute lymphoblastic leukemias (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 an oncogenic fusion gene product, Bcr-Abl. The resulting fusion protein is both overexpressed and possesses constitutive kinase-promoting activity, which then drives the activation of numerous intracellular signaling cascades to induce the uncontrolled cell growth, division, and survival associated with oncogenic transformation. Therefore, therapeutic intervention with Bcr-Abl tyrosine kinase inhibitors represents the cornerstone of the current treatment paradigm for patients with Philadelphia-positive tumor conditions.

[0006] Imatinib (STI-571), a small molecule Bcr-Abl tyrosine kinase inhibitor (Bcr-AblTKI), was developed in the early 1990s as a highly effective treatment for CML and is still used as a first-line treatment for CML today. However, in more aggressive cases of CML, patients often relapse due to the development of resistance. The main mechanism of this resistance stems from a variety of on-target genetic alterations that drive abnormal overexpression of Bcr-Abl fusions or, more commonly, introduce amino acid mutations within the Abl kinase domain that reduce imatinib's binding affinity for the active site, thereby significantly reducing its inhibitory activity. These alterations can arise randomly and represent subpopulations within the initial tumor cell population, or arise under the selective pressure of inhibitor treatment. A major on-target Bcr-Abl resistance mutation stems from a point mutation that introduces an isoleucine residue instead of a threonine (T315I) at position 315 (also known as the "gatekeeper" position) within the Abl kinase domain. This mutant form of BCR-Abl is significantly resistant to all second-generation Bcr-AblTKIs (Nilotinib, Dasatinib, Bosutinib, Radotinib) except imatinib. Currently, there is only one treatment option for patients with the T315I mutation—the third-line Bcr-Abl TKI Ponatinib. Although effective in treating T315I CML patients, Ponatinib has poor selectivity for Bcr-Abl compared to many other protein kinases. As a result, Ponatinib has been reported to induce significant dose-limiting toxicities, which then limit its ability to effectively engage the target to achieve clinical efficacy.

[0007] In addition to on-target and off-target resistance, intolerance to Bcr-Abl TKIs also presents a major clinical challenge. Over 50% of patients with Ph+ leukemia require dose modifications due to adverse events. In fact, approximately 30% of patients are forced to undergo dose reductions within the first six months of treatment. These drug-related side effects appear early in the course of treatment, and while manageable in most cases, toxicity can still occur, significantly impacting patient quality of life and leading to decreased adherence. Consequently, 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 result in potentially debilitating side effects. Specifically, potent inhibition of VEGFR, PDGFR, c-Kit, and / or c-Src family members can lead to dose-limiting side effects in patients. To address these side effects, dose reductions, dose interruptions, and even dose discontinuations are often necessary during treatment, ultimately resulting in suboptimal therapeutic efficacy.

[0008] Therefore, there remains a substantial unmet medical need for Bcr-Abl TKIs with improved selectivity in Philadelphia-positive disease to improve tolerability and enhanced potency against extensive resistance mechanisms. Summary of the Invention

[0009] Provided herein are compounds and compositions that selectively inhibit Bcr-Abl tyrosine kinase and are useful in treating disorders mediated by Bcr-Abl tyrosine kinase.

[0010] In one aspect, provided herein is a compound of formula (I),

[0011]

[0012] or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein:

[0013] X is NR 3’ or CR 3 ,

[0014] Y is NR 2 or CR 4 ,

[0015] When X is NR 3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a5 Double bonds;

[0016] R 0 For the group

[0017] m is an integer from 0 to 3;

[0018] 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 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 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 moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0019] R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0020] R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN;

[0021] R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl or -CN;

[0022] R 4 is -H, C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0023] R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0024] R 6 -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 to 8-membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4 to 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 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0025] Each R 7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0026] Each R 8 is independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0027] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0028] 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,

[0029] wherein n is an integer from 0 to 2; and

[0030] Each R 10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0031] In another aspect, provided herein is a compound of formula (I),

[0032]

[0033]

[0034] or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein:

[0035] X is NR 3’ or CR 3 ,

[0036] Y is NR 2 or CR 4 ,

[0037] When X is NR 3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a 5 Double bonds;

[0038] R 0 For the group

[0039] m is an integer from 0 to 3;

[0040] 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 1 wherein the alkyl, alkylene, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0041] R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0042] R3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN;

[0043] R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl or -CN;

[0044] R 4 is -H, C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0045] R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0046] R 6 -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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0047] Each R 7are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0048] Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0049] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0050] 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,

[0051] wherein n is an integer from 0 to 2; and

[0052] Each R 10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0053] In some embodiments, the compound of formula (I) is a compound of formula (IA):

[0054]

[0055] In some embodiments, the compound of Formula (I) is a compound of Formula (IAi) or Formula (IA-ii):

[0056]

[0057] in

[0058] m is an integer of 0 or 2;

[0059] Each R 1are 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 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0060] R 2 is -H, -CH3, CD3, -CHF2 or -CH2CH3;

[0061] R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN;

[0062] R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl or -CN;

[0063] R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen;

[0064] R 5 C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0065]

[0066]

[0067] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0068] Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0069] Each R 8 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0070] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0071] Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and

[0072] Each R 10 It is 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 1-6 deuterium atoms.

[0073] 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 wherein R 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with H or C1-C3 alkyl. In other embodiments that may be combined with any of the preceding embodiments, R5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0074]

[0075] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 In yet other embodiments that may be combined with any of the preceding embodiments, R 2 is -CH3, CD3 or CH2CH3; R 3 is -H, -F, -CH3 or -CN; R 3 ' is -H or -CH3; and R 4 In yet another embodiment 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 independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0076] In 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):

[0077]

[0078]

[0079] in

[0080] m is an integer 0 or 1;

[0081] R 1 -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH;

[0082] R 2 is -CH3, CD3 or -CH2CH3;

[0083] R 3 is -H, -F, -CH3 or -CN;

[0084] R 3’ is -H or -CH3;

[0085] R 4is -H, -F or -CH3;

[0086] R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0087]

[0088] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 group substitution;

[0089] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with H or C1-C3 alkyl;

[0090] Each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and

[0091] Each R 10 is independently -H, -CH 3 , -CD 3 or -CH 2 CH 3 , wherein said -CH 3 or said -CH 2 CH 3 is optionally substituted with hydroxyl and / or -OCH 3 . In 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):

[0092]

[0093] in

[0094] m is an integer 0 or 1;

[0095] R 1 is -F;

[0096] R 2 is -CH3;

[0097] R 3 is -H or -CH3;

[0098] R 3’ is -H or -CH3;

[0099] R 4 is -CH3;

[0100] R 5is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of:

[0101]

[0102] wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 group substitution;

[0103] Each R 9 independently -F or -OR 10 ,and

[0104] Each R 10 are independently -H or -CH3.

[0105] In other embodiments of this aspect, the compound of formula (I) is a compound of formula (IB):

[0106]

[0107] In some embodiments of the aforementioned embodiments, the compound of Formula (I) is a compound of Formula (IBi) or Formula (IB-ii):

[0108]

[0109] in

[0110] R 2 is -H, -CH3, CD3, -CHF2 or -CH2CH3;

[0111] R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN;

[0112] R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl or -CN;

[0113] R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen;

[0114] R 5 C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0115]

[0116] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9group substitution;

[0117] R 6 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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0118] Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0119] Each R 8 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0120] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0121] Each R9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and

[0122] Each R 10 independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3 or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy and / or C1-C3 alkoxy.

[0123] 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 where R 6 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein 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 other embodiments that may be combined with any of the preceding embodiments, R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0124] wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 In yet 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, -CH3, -CD3, -CF2H or -CF3. In other embodiments that may be combined with any of the preceding embodiments, R 2 is -H or -CH3; R 3 -H; R 3 ' is -H; and R 4 It is H or -CH3.

[0125] In some embodiments that may be combined with any of the preceding embodiments, the compound of Formula (I) is a compound of Formula (IBi) or Formula (IB-ii):

[0126]

[0127] in

[0128] R 2 is -H or -CH3;

[0129] R 3 is -H;

[0130] R 3 'for -H;

[0131] R 4 is -H or -CH3;

[0132] R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0133]

[0134] wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 group substitution;

[0135] R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ ;

[0136] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0137] Each R 9 are independently -F, -OR 10 , -CH3, and

[0138] Each R 10 is independently -H, -CH3, -CD3, -CF2H or -CF3.

[0139] Also provided herein is a compound selected from the group consisting of:

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] or a pharmaceutically acceptable salt, solvate, hydrate or co-crystal thereof, or a mixture of any of the foregoing.

[0154] 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 cocrystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0155] In 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 cocrystal thereof, or a mixture of any of the foregoing substances, or a pharmaceutical composition comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances.

[0156] In 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, comprising administering to the human a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal 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 cocrystal thereof, or a mixture of any of the foregoing.

[0157] In some embodiments of this aspect, the leukemia is a refractory leukemia. In certain embodiments of the aforementioned embodiments, the refractory leukemia is associated with a mutation in the Bcr-Abl tyrosine kinase gene that results 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 further embodiments of the aforementioned embodiments, the refractory leukemia is associated with a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I. In other embodiments that may be combined with any of the preceding embodiments of this aspect, the method further comprises administering one or more pharmaceutical agents comprising an anti-microtubule therapeutic agent, 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 irradiation.

[0158] This application also includes the following embodiments.

[0159] 1. A compound of formula (I):

[0160]

[0161] or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein:

[0162] X is NR 3’ or CR 3 ,

[0163] Y is NR 2 or CR 4 ,

[0164] When X is NR 3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a5 Double bonds;

[0165] R 0 For the group

[0166] m is an integer from 0 to 3;

[0167] 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 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 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 moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0168] R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0169] R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN;

[0170] R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl or -CN;

[0171] R 4 is -H, C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0172] R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0173] R 6 -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 to 8-membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4 to 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 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0174] Each R 7 is independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0175] Each R 8 is independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0176] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0177] 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,

[0178] wherein n is an integer from 0 to 2; and

[0179] Each R 10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0180] 2. A compound of formula (I):

[0181]

[0182] or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein:

[0183] X is NR 3’ or CR 3 ,

[0184] Y is NR 2 or CR 4 ,

[0185] When X is NR3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a 5 Double bonds;

[0186] R 0 For the group

[0187] m is an integer from 0 to 3;

[0188] 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 1 wherein the alkyl, alkylene, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0189] R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0190] R 3is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN;

[0191] R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl or -CN;

[0192] R 4 is -H, C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0193] R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0194] R 6 -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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0195] Each R 7 is independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0196] Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0197] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0198] 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,

[0199] wherein n is an integer from 0 to 2; and

[0200] Each R 10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0201] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of formula (I) is a compound of formula (IA):

[0202]

[0203] 4. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (IAi) or Formula (IA-ii):

[0204]

[0205] in

[0206] m is an integer of 0 or 2;

[0207] 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 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0208] R 2 is -H, -CH3, CD3, -CHF2 or -CH2CH3;

[0209] R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN;

[0210] R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl or -CN;

[0211] R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen;

[0212] R 5 C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0213]

[0214]

[0215] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0216] Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0217] Each R 8 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0218] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0219] Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and

[0220] Each R 10 It is 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 1-6 deuterium atoms.

[0221] 5. The compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0222] Each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH; and

[0223] where R 1 Each pair of R 7’ and R 8’Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with -H or C1-C3 alkyl.

[0224] 6. A compound as described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances, wherein

[0225] R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0226]

[0227] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution.

[0228] 7. The compound of any one of embodiments 1 to 6, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0229] R 2 is -CH3, -CD3 or -CH2CH3;

[0230] R 3 is -H, -F, -CH3 or -CN;

[0231] R 3’ is -H or -CH3; and

[0232] R 4 is -H, -F or -CH3.

[0233] 8. A compound as described in any one of embodiments 1 to 7, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0234] Each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and

[0235] Each R 10 independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0236] 9. The compound of any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (IAi) or Formula (IA-ii):

[0237]

[0238] in

[0239] m is an integer 0 or 1;

[0240] R 1 -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH;

[0241] R 2 is -CH3, -CD3 or -CH2CH3;

[0242] R 3 is -H, -F, -CH3 or -CN;

[0243] R 3’ is -H or -CH3;

[0244] R 4 is -H, -F or -CH3;

[0245] R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0246]

[0247] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 group substitution;

[0248] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with -H or C1-C3 alkyl;

[0249] Each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and

[0250] Each R 10independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0251] 10. The compound of any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (IAi) or Formula (IA-ii):

[0252]

[0253] in

[0254] m is an integer 0 or 1;

[0255] R 1 is -F;

[0256] R 2 is -CH3;

[0257] R 3 is -H or -CH3;

[0258] R 3’ is -H or -CH3;

[0259] R 4 is -CH3;

[0260] R 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of:

[0261]

[0262] wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 group substitution;

[0263] Each R 9 independently -F or -OR 10 ,and

[0264] Each R 10 are independently -H or -CH3.

[0265] 11. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (IB):

[0266]

[0267] 12. The compound of any one of embodiments 1, 2, and 11, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (IBi) or Formula (IB-ii):

[0268]

[0269] in

[0270] R 2 is -H, -CH3, CD3, -CHF2 or -CH2CH3;

[0271] R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN;

[0272] R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl or -CN;

[0273] R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen;

[0274] R 5 C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0275]

[0276] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0277] R 6 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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0278] Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0279] Each R 8 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0280] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0281] Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and

[0282] Each R 10 independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3 or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy and / or C1-C3 alkoxy.

[0283] 13. The compound of any one of embodiments 1 to 2 and 11 to 12, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0284] R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ ;and

[0285] where R 6 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O and S, and wherein 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.

[0286] 14. The compound of any one of embodiments 1 to 2 and 11 to 13, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0287] R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0288]

[0289] wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution.

[0290] 15. The compound of any one of embodiments 1 to 2 and 11 to 14, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0291] Each R 9 are independently -F, -OR 10 or -CH3, and

[0292] Each R 10 is independently -H, -CH3, -CD3, -CF2H or -CF3.

[0293] 16. A compound as described in any one of embodiments 1 to 2 and 11 to 15, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein

[0294] R 2 is -H or -CH3;

[0295] R 3 is -H;

[0296] R3’ is -H; and

[0297] R 4 It is -H or -CH3.

[0298] 17. The compound of any one of Embodiments 1 to 2 and 11 to 16, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (IBi) or Formula (IB-ii):

[0299]

[0300] in

[0301] R 2 is -H or -CH3;

[0302] R 3 is -H;

[0303] R 3’ is -H;

[0304] R 4 is -H or -CH3;

[0305] R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of: wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 group substitution;

[0306] R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ ;

[0307] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0308] Each R 9 are independently -F, -OR 10 or -CH3, and

[0309] Each R 10 is independently -H, -CH3, -CD3, -CF2H or -CF3.

[0310] 18. A compound selected from the group consisting of:

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322] or a pharmaceutically acceptable salt, solvate, hydrate or co-crystal thereof, or a mixture of any of the foregoing.

[0323] 19. A compound selected from the group consisting of:

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] or a pharmaceutically acceptable salt, solvate, hydrate or co-crystal thereof, or a mixture of any of the foregoing.

[0337] 20. A pharmaceutical composition comprising a compound as described in any one of embodiments 1 to 19, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0338] 21. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell to an effective amount of a compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 20.

[0339] 22. 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, comprising administering to the human a compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition of embodiment 20.

[0340] 23. The method of embodiment 22, wherein the leukemia is a refractory leukemia.

[0341] 24. The method of embodiment 23, wherein the refractory leukemia is associated with a mutation in the Bcr-Abl tyrosine kinase gene that results 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.

[0342] 25. The method of embodiment 24, wherein the refractory leukemia is associated with a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

[0343] 26. The method of embodiment 23, wherein the human with refractory leukemia has one or more 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.

[0344] 27. The method of embodiment 26, wherein the human suffering from refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

[0345] 28. The method of any one of embodiments 21 to 27, further comprising administering one or more pharmaceutical agents comprising an anti-microtubule therapeutic agent, 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 irradiation. DETAILED DESCRIPTION

[0346] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0347] I. Definition

[0348] As used herein, the following definitions shall apply unless otherwise stated. In addition, if any term or symbol used herein is not defined as described below, it shall have the ordinary meaning in the art.

[0349] As used herein, the term "excipient" means an inert or inactive substance that can be used to produce a drug or pharmaceutical agent, such as a tablet containing a compound of the present disclosure as an active ingredient. The term excipient can include a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, chewable tablet material, sweetener or flavoring agent, suspending agent / gelling agent or wet granulation agent. 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 / encapsulation aids include, for example, calcium carbonate, glucose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, crosslinked sodium carboxymethyl cellulose, gellan gum, Sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, glucose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending agents / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, glucose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0350] The terms "individual," "subject," and "patient" refer to mammals and include humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some embodiments, the patient is a human.

[0351] 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.

[0352] "Pharmaceutically acceptable" means safe, non-toxic, and suitable for in vivo or human administration.

[0353] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon radical (e.g., C1-C6 means 1 to 6 carbons) with a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. 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.

[0354] The term "cycloalkyl," "carbocyclic," or "carbocycle" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices. As used herein, "cycloalkyl," "carbocyclic," or "carbocycle" is also intended to refer to bicyclic, polycyclic, and spirocyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norbornene, spirocyclic C 5-12 Alkanes, etc. In some embodiments, "cycloalkyl" encompasses 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 can be aromatic, provided that the polycyclic cycloalkyl is bound to the parent structure via a non-aromatic carbon. For example, 1,2,3,4-tetrahydronaphthalene-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl, while 1,2,3,4-tetrahydronaphthalene-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl.

[0355] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain hydrocarbon radical consisting of the specified number of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms 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 where the alkyl fluoride is attached to the rest of the molecule. "Heteroalkyl" may contain up to three unsaturated units and also includes monohalogenated and polyhalogenated variants, or combinations thereof. Examples include -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(CH3)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.

[0356] The term "heterocycloalkyl", "heterocyclic" or "heterocycle" refers to a cycloalkyl group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) containing 1-5 heteroatoms selected from the group consisting of N, O and S as ring atoms, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Unless otherwise indicated, a "heterocycloalkyl", "heterocyclic" or "heterocycle" ring can be a monocyclic, bicyclic, bridged or fused ring system, spirocyclic or polycyclic ring system. Non-limiting examples of "heterocycloalkyl," "heterocyclic," or "heterocyclic" rings 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, and tropane. A "heterocycloalkyl," "heterocyclic," or "heterocyclic" group can be attached to the rest of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkyl” includes 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 6- to 10-membered heterocycloalkyl, 7- to 10-membered heterocycloalkyl, 8- to 10-membered heterocycloalkyl, 9- to 10-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 4- to 9-membered heterocycloalkyl, 5- to 9-membered heterocycloalkyl, 6- to 9-membered heterocycloalkyl, 7- to 9-membered heterocycloalkyl, 8- to 9-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-membered heterocycloalkyl, 3- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 5-membered heterocycloalkyl, or 3- to 4-membered heterocycloalkyl. In other embodiments, "heterocycloalkyl" can 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" encompasses C3-C9 heterocycloalkyl, C3-C8 heterocycloalkyl, C3-C7 heterocycloalkyl, C3-C6 heterocycloalkyl, C3-C5 heterocycloalkyl, C3-C4 heterocycloalkyl, C4-C9 heterocycloalkyl, C4-C8 heterocycloalkyl, C4-C7 heterocycloalkyl, C4-C6 heterocycloalkyl, C4-C5 heterocycloalkyl, C5-C9 heterocycloalkyl, C5-C8 heterocycloalkyl, C5-C7 heterocycloalkyl, C5-C6 heterocycloalkyl, C6-C9 heterocycloalkyl, C6-C8 heterocycloalkyl, C6-C7 heterocycloalkyl, C7-C9 heterocycloalkyl, C7-C8 heterocycloalkyl, or C8-C9 heterocycloalkyl. It will be appreciated that a "heterocycloalkyl" group as described in terms of the number of ring atoms may also be described in terms of the number of carbon atoms in the ring.For example, a piperazinyl ring can be described as a C4 heterocycloalkyl ring or a 6-membered heterocycloalkyl ring; an azetidinyl or oxetanyl ring can each be described as a C3 heterocycloalkyl ring or a 4-membered heterocycloalkyl ring.

[0357] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group will have 10 or fewer carbon atoms.

[0358] The term "heteroalkylene" by itself or as part of another substituent means a saturated or unsaturated or polyunsaturated divalent radical derived from a heteroalkyl group, as exemplified by -CH2-CH2-S-CH2CH2-, -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH═CH-, -CH2-CH═C(H)CH2-O-CH2-, and -S-CH2-C≡C-. For heteroalkylene, heteroatoms can also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0359] The term "heterocycloalkylene" by itself or as part of another substituent means a saturated or unsaturated or polyunsaturated divalent radical derived from heterocycloalkyl. For heterocycloalkylene, heteroatoms may also occupy either or both chain termini.

[0360] The terms "alkoxy" and "alkylamino" are used in their conventional sense and refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom or an amino group, respectively.

[0361] The term "heterocycloalkoxy" means a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described.

[0362] Unless otherwise indicated, the term "halo" or "halogen," by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C4 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0363] The term "haloalkyl-OH" refers to a haloalkyl group as described above that is also substituted with one or more hydroxyl groups. The term "haloalkyl-OH" is intended to include haloalkyl groups substituted with one hydroxyl group, as well as haloalkyl groups substituted with multiple hydroxyl groups. For example, the term "haloalkyl-OH" includes -CH(F)OH, -CH2CFHCH2OH, -CH(OH)CF3, and the like.

[0364] The term "alkyl-OH" refers to an alkyl group substituted with one or more hydroxyl groups. The term "alkyl-OH" is intended to include alkyl groups substituted with one hydroxyl group, as well as alkyl groups substituted with multiple hydroxyl groups. For example, the term "alkyl-OH" includes -CH2OH, -CH(OH)CH3, -CH2CH2OH, -C(CH3)2OH, etc.

[0365] The term "alkyl-CN" refers to an alkyl group substituted with one or more cyano groups. The term "alkyl-CN" is intended to include alkyl groups substituted with one cyano group, as well as alkyl groups substituted with multiple cyano groups. For example, the term "alkyl-CN" includes -CH2CN, -CH2CH2CN, -CH(CN)CH3, etc.

[0366] Unless otherwise indicated, the term "aryl" means a polyunsaturated, typically aromatic hydrocarbon radical which may be a single ring or multiple rings (up to three rings) fused together. In some embodiments, "aryl" includes 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 the polycyclic aryl are aromatic (e.g., naphthyl). In other embodiments, the polycyclic aryl may include a non-aromatic ring fused to the aromatic ring, provided that the polycyclic aryl is bound to the parent structure via atoms in the aromatic ring. Thus, in some embodiments, 1,2,3,4-tetrahydronaphthalene-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalene-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered not to be an aryl group. Similarly, in some embodiments, 1,2,3,4-tetrahydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered not to be an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein, regardless of the point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl). In some embodiments, aryl is phenyl or naphthyl. In certain embodiments, aryl is phenyl.

[0367] The term "heteroaryl" refers to an aromatic group (or ring) containing 1 to 5 heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Where valence permits, the heteroaryl group can be attached to the rest of the molecule via carbon or heteroatoms. In some embodiments, both rings of the polycyclic heteroaryl are aromatic. In other embodiments, the polycyclic heteroaryl may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl is bound to the parent structure via atoms in the aromatic ring. For example, in some embodiments, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl.

[0368] 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, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. In some embodiments, the term "heteroaryl" encompasses a 5- to 10-membered heteroaryl, a 6- to 10-membered heteroaryl, a 7- to 10-membered heteroaryl, an 8- to 10-membered heteroaryl, a 9- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 6- to 9-membered heteroaryl, a 7- to 9-membered heteroaryl, an 8- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 6- to 8-membered heteroaryl, a 7- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, a 6- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl.

[0369] In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") will include both substituted and unsubstituted forms of the indicated groups. The term "substituted" means that a specified group or portion carries 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, etc. The term "unsubstituted" means that a specified group does not carry a substituent. Where the term "substituted" is used to describe a structural system, substitution is intended to occur at any valence-allowed position on the system. When a group or portion carries more than one substituent, it is understood that the substituents may be the same or different from each other. In some embodiments, the substituted group or moiety carries one to five substituents. In some embodiments, the substituted group or moiety carries one substituent. In some embodiments, the substituted group or moiety carries two substituents. In some embodiments, the substituted group or moiety carries three substituents. In some embodiments, the substituted group or moiety carries four substituents. In some embodiments, the substituted group or moiety carries five substituents.

[0370] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples of instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes embodiments where the group or moiety is substituted and embodiments where the group or moiety is not substituted.

[0371] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0372] As used herein, the term "chiral" refers to molecules that have the property that their mirror image counterparts are non-superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image counterparts.

[0373] 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.

[0374] As used herein, a wavy line that intersects a bond in a chemical structure Indicates the point of attachment of an atom in a chemical structure to which a wavy bond connects to the rest of the molecule or to the rest of a molecular fragment.

[0375] As used herein, a group in brackets (e.g., X a ) followed by a subscript integer range (for example, (X a ) 0-1 ) means that the group can have the number of occurrences specified by the integer range. For example, (X a ) 0-1 Indicator group X a It may not exist or may appear once.

[0376] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated under high-resolution analytical procedures such as electrophoresis and chromatography.

[0377] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0378] The stereochemical definitions and conventions used herein generally follow those of 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 centers or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of this disclosure. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the optical rotation of a compound for plane polarized light, where (-) or l means that the compound is left-handed. Compounds with the (+) or d prefix are right-handed. For a given chemical structure, these stereoisomers are identical, except that they are mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or processes where stereoselectivity or stereospecificity is not yet present. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that are not optically active.

[0379] 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 proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0380] As used herein, the term "solvate" refers to an associate 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 unsolvated forms as well as solvated forms (including hydrated forms). In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure.

[0381] As used herein, the term "co-crystal" refers to a solid that is a crystalline, single-phase material composed of two or more different molecular or ionic compounds, typically in stoichiometric ratios, that are neither solvates nor simple salts. A co-crystal is composed of two or more components that form a unique crystal structure with unique properties. A co-crystal is generally characterized by a crystal structure that is typically held together by free, reversible, non-covalent interactions. As used herein, a co-crystal refers to a compound of the present disclosure and at least one other component that forms a crystal structure in a defined stoichiometric ratio.

[0382] As used herein, the term "protecting group" refers to a substituent that is typically used to block or protect a specific functional group on a compound. For example, an "amino protecting group" is a substituent attached to an amino group to block or protect the amino functionality in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a hydroxy substituent that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a carboxyl substituent that blocks or protects the carboxyl functionality. Common carboxyl protecting groups include benzenesulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrosulfinyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, etc. For a general description of protecting groups and their uses, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4th ed., Wiley-Interscience, New York, 2006.

[0383] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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 salts, and the like. 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-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hyrobacillin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. 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, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like; and 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts and the like; and salts of organic acids such as glucuronic acid or galacturonic acid, and the like (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0384] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a 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 for the purposes of this disclosure, these salts are equivalent to the parent form of the compound.

[0385] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (eg, individual enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0386] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also includes isotopically labeled variants of the present disclosure that are identical to those described herein, but in fact one or more atoms are replaced by an atom having an atomic mass or mass number different from the predominant atomic mass or mass number that the atom is typically found in nature. All isotopes of any particular atom or element specified are considered within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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 I. Certain isotopically labeled compounds of the present disclosure (e.g., 3 H or 14 C-labeled ones) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are useful because of their ease of preparation and detectability. Further use of heavier isotopes such as deuterium (i.e., 2 F) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life and reduced dosage requirements) and thus may be preferred in some circumstances. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0387] "Treatment" of a patient's disease refers to suppressing the disease or preventing the development of the disease; or improving or causing the disease to regress. As used herein, "treatment" is a method for obtaining a beneficial or desired result (including clinical results). For the purposes 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 caused by a disease or condition, alleviating the degree of a disease or condition, stabilizing a disease or condition (e.g., preventing or delaying the worsening of a disease or condition), delaying the occurrence or recurrence of a disease or condition, delaying or slowing the progress of a disease or condition, improving the disease or condition state, providing relief (partial or complete relief) of the disease or condition, reducing the dosage of one or more other drugs required for treating the disease or condition, enhancing the effect of another drug for treating the disease or condition, delaying the progress of the disease or condition, improving the quality of life, and / or prolonging the patient's survival. "Treatment" also includes the alleviation of the pathological results of a disease or condition. The method of this disclosure contemplates any one or more of these aspects of treatment.

[0388] To "prevent" or "prevent" a disease in a patient means to prevent the development of the disease in a patient who is susceptible to the disease or who is not yet showing symptoms of the disease.

[0389] The phrase "therapeutically effective amount" means an amount of a compound of the present disclosure that is used to: (i) treat or prevent a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0390] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0391] It should be understood that some features of the disclosure described in the context of a separate embodiment for the sake of clarity may also be provided in combination in a single embodiment. On the contrary, the various features of the present invention described in the context of a single embodiment for the sake of brevity may also be provided individually or in any suitable sub-combination. All combinations of embodiments belonging to the chemical groups represented by the variables are specifically encompassed by the present invention and disclosed herein, as if each combination were individually and clearly disclosed, to the extent that such combinations comprise compounds that are stable compounds (i.e., compounds that can be separated, characterized, and tested for their biological activity). In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically encompassed by the present invention and disclosed herein, as if each sub-combination of the chemical groups were individually and clearly disclosed herein.

[0392] II.Compounds

[0393] In one aspect, provided herein is a compound of formula (I),

[0394]

[0395]

[0396] or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein:

[0397] X is NR 3’ or CR 3 ,

[0398] Y is NR 2 or CR 4 ,

[0399] When X is NR 3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a 5 Double bonds;

[0400] R 0 For the group

[0401] m is an integer from 0 to 3;

[0402] 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 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR7’ 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 moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0403] R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0404] R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN;

[0405] R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl or -CN;

[0406] R 4 is -H, C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0407] R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0408] R 6 -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)-NR7’ R 8’ , C1-C2 alkylene-(C3-C6 cycloalkylene)-(C0-C2 alkylene)-OH, C1-C2 alkylene-(4 to 8-membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4 to 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 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0409] Each R 7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0410] Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0411] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0412] 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,

[0413] wherein n is an integer from 0 to 2; and

[0414] Each R 10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0415] In one aspect, there is provided a compound of formula (I)

[0416]

[0417] or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing, wherein:

[0418] X is NR 3’ or CR 3 ,

[0419] Y is NR 2 or CR 4 ,

[0420] When X is NR 3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a 5 Double bonds;

[0421] R 0 For the group

[0422] m is an integer from 0 to 3;

[0423] 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)-NR7’ 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 moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0424] R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0425] R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN;

[0426] R 3’ is -H, C1-C3 alkyl, -C3-C6 cycloalkyl or -CN;

[0427] R 4 is -H, C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms;

[0428] R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0429] R 6 -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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0430] Each R 7 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0431] Each R 8 are independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl;

[0432] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0433] 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,

[0434] wherein n is an integer from 0 to 2; and

[0435] Each R10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

[0436] In some embodiments of this aspect, R 0 for In which R 0 for In some embodiments of the present invention, 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 the present invention, R 0 for

[0437] In some embodiments, the compound of formula (I) is a compound of formula (IA) or formula (IB):

[0438]

[0439] 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-(4 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 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 1wherein the alkyl, alkylene, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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.

[0440] 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 1 wherein the alkyl, alkylene, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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 In some embodiments, each R 1 are independently C1-C3 alkyl, C1-C3 alkylene-NR 7 R 8 、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 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 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-NR7 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 8 or C1-C2 alkylene-(C4-C6 heterocycloalkylene)-(C0-C2 alkylene)-NR 7’ R 8’ 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. In some embodiments, each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, wherein R 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein 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 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH, wherein R 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring 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 1In some embodiments, each R 1 are independently C1-C3 alkylene-NR 7’ R 8’ In certain embodiments, each R 1 R is independently optionally substituted -C1-C2 alkylene-N-morpholinyl or optionally substituted -C1-C2 alkylene-N-piperazinyl. 1 are independently optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted or optionally substituted In certain embodiments, each R 1 are independently optionally substituted Optionally substituted Optionally substituted or optionally substituted In some embodiments, each R 1 Independently

[0441] In certain embodiments, each R 1 Independently In certain other embodiments, each R 1 Independently In still other embodiments, each R 1 Independently 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 -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3 or -CH(CN)CH2CH3. In certain other embodiments, each R 1 are independently -CH2OH or -CH2CH2OH.

[0442] In some embodiments of this aspect, X is CR 3 and Y is NR 2 Where X is CR 3 and Y is NR 2 In some embodiments, R 2is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted by 1-3 fluorine atoms and / or 1-6 deuterium atoms, and R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN.

[0443] In some embodiments, R 2 is -H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein 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, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 2 Is -H or C3-C6 cycloalkyl. In some embodiments, R 2 is a C1-C3 alkyl group or a C3-C6 cycloalkyl group, wherein the C1-C3 alkyl group 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 group, wherein the C1-C3 alkyl group is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 2 is -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, wherein said -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2 is optionally substituted by 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R 2 is a C3-C6 cycloalkyl group. 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0444] In some embodiments, R 2 Is -H, -CH3, CD3, -CHF2 or -CH2CH3. In some embodiments, R 2 is -CH3, -CD3, -CHF2 or -CH2CH3. In some embodiments, R 2 is -H, -CD3, -CHF2 or -CH2CH3. In some embodiments, R 2 is -H, -CH3, -CHF2 or -CH2CH3. In some embodiments, R 2 is -H, -CH3, -CD3 or -CH2CH3. In some embodiments, R 2 is -H, -CH3, -CD3 or -CHF2. In some embodiments, R 2is -CH3, -CD3 or -CHF2. In some embodiments, R 2 is -CH3 or -CH2CH3. In some embodiments, R 2 It is -H or -CH3.

[0445] In some embodiments, R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN. In some embodiments, R 3 Is -H, C1-C3 alkyl, C3-C6 cycloalkyl or halogen. In some embodiments, R 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, C3-C6 cycloalkyl, halogen or -CN. In some embodiments, R 3 is C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN. In some embodiments, R 3 is -H, C1-C3 alkyl, C3-C6 cycloalkyl, halogen or -CN. In some embodiments, R 3 Is -H, -F, -CH3 or -CN. In some embodiments, R 3 is -H, -F or -CH3. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is -H or -F. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is -H. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is -CN.

[0446] In some embodiments, R 2 is -CH3, -CD3 or -CH2CH3, and R3 Is -H, -F, -CH3 or -CN. In some embodiments, R 2 is -CH3, and R 3 Is -H, -F, -CH3 or -CN. In some embodiments, R 2 is -CD3, and R 3 Is -H, -F, -CH3 or -CN. In some embodiments, R 2 is -CH2CH3, and R 3 Is -H, -F, -CH3 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 In some embodiments, R 2 is -CH3, -CD3 or -CH2CH3, and R 3 In some embodiments, R 2 is -CH3, -CD3 or -CH2CH3, and R 3 In some embodiments, R 2 is -CH3, -CD3 or -CH2CH3, and R 3 Is -H, -F, -CH3 or -CN. In some embodiments, R 2 is -CH3, and R 3 In some embodiments, R 2 is -CH3, and R 3 is -H. In some embodiments, R 2 is -CH3, and R 3 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.

[0447] In other embodiments of this aspect, X is NR 3’ And Y is CR 4 Where 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, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms.

[0448] 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, C3-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’ In some embodiments, R 3 ' is -H or C3-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 C3-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’ In some embodiments, R 3 ' is C3-cycloalkyl. In some embodiments, R 3 ' is -CN.

[0449] In some embodiments, R 4 is -H or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 4 In some embodiments, R 4 is 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 4is a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. 4 is -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, wherein said -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2 is optionally substituted by 1-3 fluorine atoms and / or 1-6 deuterium atoms. In certain embodiments, R 4 is CH3. In some embodiments, R 4 In certain embodiments, R 4 In certain other embodiments, R 4 In some embodiments, R 4 is -H, -F or -CH3. In some embodiments, R 4 Is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen. In some embodiments, R 4 Is -H, -CH3, -CD3, -CHF2 or -CH2CH3. In some embodiments, R 4 Is -H, -CH3, -CD3, -CHF2 or halogen. In some embodiments, R 4 is -H, -CH3, -CD3, -CH2CH3 or halogen. In some embodiments, R 4 is -H, -CH3, -CHF2, -CH2CH3 or halogen. In some embodiments, R 4 is -H, -CD3, -CHF2, -CH2CH3 or halogen. In some embodiments, R 4 is -CH3, -CD3, -CHF2, -CH2CH3 or halogen. In some embodiments, R 4 In some embodiments, R 4 is -CH3 or -CH2CH3. In some embodiments, R 4 It is -CH3, -CD3 or -CHF2.

[0450] In some embodiments, R 3 ' is -H or -CH3, and R 4 is -H, -F or -CH3. In some embodiments, R 3 ' is -H, and R 4 is -H, -F or -CH3. In some embodiments, R 3 ' is -CH3, and R 4 is -H, -F or -CH3. 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 In some embodiments, R 3 ' is -H or -CH3, and R 4 In certain embodiments, R 3’ is -H, and R 4 In certain embodiments, R 3 ' is -H, and R 4 In certain embodiments, R 3 ' is -H, and R 4 In certain embodiments, R 3 ' is -CH3, and R 4 In certain embodiments, R 3 ' is -CH3, and R 4 In certain other embodiments, R 3’ is -CH3, and R 4 is -CH3.

[0451] In some embodiments, R 5 C6-C 14 aryl or 5 to 10 membered heteroaryl, wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 In some embodiments, R 5 C6-C 14 Aryl, wherein the C6-C 14 The aryl group is optionally substituted with 1 to 5 R 9 In some embodiments, R 5 is phenyl, wherein the phenyl group is optionally substituted by 1-5 R 9 In some embodiments, R 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is optionally substituted by 1-5 R 9 In some embodiments, R 5 is a 5- to 10-membered heteroaryl group selected from the group consisting of:

[0452] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9In some embodiments, R 5 is a 5- to 10-membered heteroaryl group selected from the group consisting of: in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 In some embodiments, R 5 is a 5- to 10-membered heteroaryl group selected from the group consisting of:

[0453] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 In some embodiments, R 5 is a 5- to 10-membered heteroaryl group selected from the group consisting of: wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 In some embodiments, R 5 is a 5- to 10-membered heteroaryl group selected from the group consisting of: wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution.

[0454] In some embodiments, R 5 is a 5- to 10-membered heteroaryl group selected from the group consisting of:

[0455] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 In some embodiments, R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0456]

[0457] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 In some embodiments, R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of: wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution.

[0458] In some embodiments, R 6 -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 to 8-membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4 to 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 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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.

[0459] In some embodiments, R 6 -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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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.

[0460] In some embodiments, R 6 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 to 8-membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 , C1-C2 alkylene-(4 to 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 6wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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 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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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 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 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 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 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 C1-C6 alkylene-NR 7 R 8 、C1-C6 alkylene-NR 7’ R 8’ , C-C6 alkylene-OH or C1-C6 alkylene-CN. In some embodiments, R 6 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- to 8-membered heterocycloalkylene)-(C0-C2 alkylene)-NR7 R 8 , C1-C2 alkylene-(4- to 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 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’ , where R 6 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein 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 certain other embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R8’ , where R 6 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein 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 In certain embodiments, R 6 is -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2. In certain other embodiments, R 6 In some embodiments, R 6 C1-C3 alkylene-NR 7’ R 8’ In certain embodiments, each R 6 R is independently optionally substituted -C1-C2 alkylene-N-morpholinyl or optionally substituted -C1-C2 alkylene-N-piperazinyl. 6 are independently optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted or optionally substituted In certain embodiments, each R 6 are independently optionally substituted Optionally substituted Optionally substituted or optionally substituted In some embodiments, each R 6 Independently

[0461] In certain embodiments, each R 6 Independently In certain other embodiments, each R 6 Independently In still other embodiments, each R 6 Independently

[0462] In some embodiments, each R 7R is independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl. 7 R 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 In certain embodiments, each R 7 is independently -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2. In some embodiments, each R 7 is independently C3-C6 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 C2-C3 haloalkyl, wherein each halogen atom of each C2-C3 haloalkyl is independently -F, -Cl or -Br. 7 is independently C2-C3 alkylene-CN. In certain embodiments, each R 7 is 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 7are independently -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3 or -CH(OH)CH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH(OCH3)CH3, -CH(CH2OH)CH3, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2, -CH2CH(NH2)CH3 or -CH(NH2)CH2 CH3, -CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH3, -CH(NHCH3)CH3, -CH(CH2NH2CH3, -CH2CH2SH, -CH(SH)CH3, -CH2CH 2CH2SH, -CH2CH(SH)CH3 or -CH(SH)CH2CH3, -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, -CH(SCH3)CH3 or -CH(CH2SH)CH3.

[0463] In some embodiments, each R 8 R is independently -H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-CN or C1-C6 heteroalkyl. 8 R 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 In certain embodiments, each R 8 is independently -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2. In some embodiments, each R 8 is independently C3-C6 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 C2-C3 haloalkyl, wherein each halogen atom of each C2-C3 haloalkyl is independently -F, -Cl or -Br. 8 is independently C2-C3 alkylene-CN. In certain embodiments, each R 8is 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)CH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH(OCH3)CH3, -CH(CH2OH)CH3, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2, -CH2CH(NH2)CH3 or -CH(NH2)CH2 CH3, -CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH3, -CH(NHCH3)CH3, -CH(CH2NH2CH3, -CH2CH2SH, -CH(SH)CH3, -CH2CH 2CH2SH, -CH2CH(SH)CH3 or -CH(SH)CH2CH3, -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, -CH(SCH3)CH3 or -CH(CH2SH)CH3.

[0464] In some embodiments, each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein 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 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with -H or C1-C3 alkyl. In some embodiments, each pair of R 7’ and R 8’Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein 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 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with -H or C1-C3 alkyl.

[0465] 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, wherein 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 , -CH3 or -CN. In some embodiments, each R 9 are independently -F, -OR 10 Or -CH3. In some embodiments, each R 9 independently -F or -OR 10 In certain embodiments, each R 9 is independently -F, -OH, -OCH3 or -OCD3.

[0466] In some embodiments, each R 10 R is independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1-6 deuterium atoms. 10R is 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 1-6 deuterium atoms. 10 is independently -H, -CH3, -CD3, -CH2CH3 or cyclopropyl, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3. 10 is independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3. 10 is independently -H, -CH3, -CD3, -CF2H or -CF3. In some embodiments, each R 10 are independently -H or -CH3.

[0467] In some embodiments, the compound of Formula (I) is a compound of Formula (IA), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing:

[0468]

[0469] In some embodiments, the compound of Formula (I) or Formula (IA) is a compound of Formula (IAi) or (IA-ii):

[0470]

[0471]

[0472] in

[0473] m is an integer of 0 or 2;

[0474] 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 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0475] R 2 is -H, -CH3, CD3, -CHF2 or -CH2CH3;

[0476] R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN;

[0477] R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl or -CN;

[0478] R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen;

[0479] R 5 C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0480]

[0481]

[0482] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0483] Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0484] Each R 8is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0485] Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0486] Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and

[0487] Each R 10 It is 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 1-6 deuterium atoms.

[0488] In some embodiments, each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH; and wherein R 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with H or C1-C3 alkyl.

[0489] In some embodiments, R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of: in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution.

[0490] In some embodiments, R 2 is -CH3, CD3 or -CH2CH3; R 3is -H, -F, -CH3 or -CN; R 3’ is -H or -CH3; and R 4 is -H, -F or -CH3.

[0491] In some embodiments, each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and each R 10 independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0492] 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; 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 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0493] in indicates a single bond or a double bond, and wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution; each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with H or C1-C3 alkyl; each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and each R 10 independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

[0494] 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; R1 -F; R 2 -CH3; R 3 is -H or -CH3; R 3’ is -H or -CH3; R 4 -CH3; R 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of: wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 Group substitution; each R 9 independently -F or -OR 10 , and each R 10 are independently -H or -CH3.

[0495] In some embodiments, the compound of formula (I) is a compound of formula (IB), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing:

[0496]

[0497] In some embodiments, the compound of Formula (I) or Formula (IB) is a compound of Formula (IBi) or (IB-ii):

[0498]

[0499] in

[0500] R 2 is -H, -CH3, CD3, -CHF2 or -CH2CH3;

[0501] R 3 is -H, C1-C3 alkyl, C3-cycloalkyl, halogen or -CN;

[0502] R 3’ is -H, C1-C3 alkyl, C3-cycloalkyl or -CN;

[0503] R 4 is -H, -CH3, -CD3, -CHF2, -CH2CH3 or halogen;

[0504] R 5 C6-C 14 aryl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of:

[0505]

[0506]

[0507] in indicates a single bond or a double bond, and wherein the C6-C 14 Aryl or said 5 to 10 membered heteroaryl is optionally substituted by 1 to 5 R 9 group substitution;

[0508] R 6 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’ , where R 6 wherein the alkyl, alkylene, cycloalkyl, cycloalkylene and heterocycloalkylene moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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;

[0509] Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0510] Each R 8 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl;

[0511] Each pair of R 7’ and R 8’Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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;

[0512] Each R 9 are independently halogen, -OR 10 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and

[0513] Each R 10 independently -H, C1-C3 alkyl, -CD3, -CF2H, -CF3 or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy and / or C1-C3 alkoxy.

[0514] In some embodiments, R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ ; and where R 6 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O and S, and wherein 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.

[0515] In some embodiments, R 5 is phenyl or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is selected from the group consisting of: wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution.

[0516] In some embodiments, each R 9 are independently -F, -OR 10 , -CH3, and each R 10 is independently -H, -CH3, -CD3, -CF2H or -CF3.

[0517] In some embodiments, R 2 is -H or -CH3; R 3 -H; R 3’ is -H; and R 4It is H or -CH3.

[0518] 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; R 3 -H; R 3 ' is -H; R 4 is -H or -CH3; R 5 is phenyl or a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from: wherein the phenyl group or the 5- to 10-membered heteroaryl group is optionally substituted by 1-3 R 9 Group substitution; R 6 is C1-C3 alkyl or C1-C3 alkylene-NR 7’ R 8’ ; Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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 -F, -OR 10 , -CH3, and each R 10 is independently -H, -CH3, -CD3, -CF2H or -CF3.

[0519] In some embodiments, a compound selected from the compounds in Table 1 is provided, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing.

[0520] Table 1

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538] Although certain compounds described in Table 1 exist as specific stereoisomers and / or in non-stereochemical forms, it should be understood that any or all non-stereochemical forms and any or all stereochemical forms, including any enantiomeric or diastereomeric forms, as well as any tautomeric or other forms, of any compound in Table 1 are described herein. In some embodiments, the compound described herein is selected from Compounds 1-147.

[0539] The present disclosure also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. The present disclosure also includes any or all stereochemical forms of the compounds described, including any enantiomers or diastereoisomers, and any tautomers or other forms, such as N-oxides, solvates, hydrates or isotopomers. The present disclosure also includes cocrystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to include all possible stereoisomers of the compound described. In addition, in the case of describing a specific stereochemical form, it should be understood that the present invention also includes other stereochemical forms. The present invention also includes all forms of the compound, such as crystalline forms or non-crystalline forms of the compound. Compositions comprising compounds of the present invention are also contemplated, such as compositions of substantially pure compounds (including their specific stereochemical forms). Compositions comprising mixtures of compounds of the present invention at any ratio are also included in the present invention, including mixtures of two or more stereochemical forms of the compounds of the present invention at any ratio, thereby including racemic, non-racemic, enantiomer-enriched and proportionate mixtures of the compound.

[0540] In the description herein, it should be understood that each description, variation, embodiment or aspect of a section can be combined with each description, variation, embodiment or aspect of other sections, just as if each combination of descriptions were explicitly listed separately. For example, the descriptions provided herein for R of formula (I) 0 Each description, variation, embodiment or aspect may be combined with 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 10 Each description, variation, embodiment or aspect combination of formula (I) is as if each combination is clearly listed separately. It should also be understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, are equally applicable to other chemical formulas described in detail herein and are described in the same manner as if each description, variation, embodiment or aspect were separately listed for all chemical formulas. For example, all descriptions, variations, embodiments or aspects of formula (I), where applicable, are equally applicable to any one of formulas (IA), (IAi), (IB), (IBi) and (IB-ii) described in detail herein, and are described in the same manner as if each description, variation, embodiment or aspect were separately listed for all chemical formulas.

[0541] III. General Synthesis Methods

[0542] The compounds of the present disclosure can be prepared by a number of methods, as generally described below and more specifically described in the examples below (such as the schemes provided in the examples below). In the following method descriptions, when used in the depicted chemical formulas, the symbols should be understood to represent those groups mentioned above in connection with the chemical formulas herein.

[0543] The intermediate described in the following preparation may contain many nitrogen, hydroxyl and acid protecting groups, such as esters. The variable protecting group can be the same or different at each occurrence, depending on the specific reaction conditions and the specific transformation to be carried out. Protection and deprotection conditions are well known to the technician and are described in the literature. See, for example, Greene and Wuts, Protective Groups in Organic Synthesis, (T.Greene and P.Wuts, eds., 2nd edition, 1991).

[0544] For the sake of clarity, certain stereochemical centers are not specified and certain substituents have been eliminated in the following schemes, and it is not intended to limit the teaching of the schemes in any way. In addition, individual isomers, enantiomers and diastereomers can be separated or resolved by one of ordinary skill in the art at any convenient time point in the synthesis of the compounds of the invention by methods such as selective crystallization techniques or chiral chromatography (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).

[0545] The compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing substances, can be prepared by a variety of procedures known in the art, some of which are described in the examples below. The specific synthesis steps of each described route can be combined in different ways to prepare compounds of the present disclosure or salts thereof. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, grinding and crystallization. Reagents and raw materials can be easily obtained by those of ordinary skill in the art. Other reagents and raw materials can be made by standard organic and heterocyclic chemistry techniques similar to those for the synthesis of compounds of similar known structures, as well as by the procedures (including any novel procedures) described in the following examples.

[0546] The 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 、R 6 , and m are as defined for Formula (I) or any applicable variations thereof as 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; 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.

[0547] Scheme A - Part I

[0548]

[0549] Scheme A - Part II.

[0550]

[0551] Scheme A - Part III.

[0552]

[0553] Compounds of (IAi) can be prepared according to the general synthetic schemes shown in parts I-III of Scheme A. In part I of Scheme A, a 6-azaindole compound of formula Aia (wherein LG 1 is a leaving group (such as chlorine or bromine)), the nitrogen of the imidazole group is protected by a protecting group P 1 (eg, protected by a Boc-group or a SEM-group) to give a compound of formula Aib. 2 (such as iodine) is added to the protected compound of formula Aib, which is R 5 The obtained compound of general formula Aic is further reacted to introduce a substituent R into the 6-azaindole nucleus as needed. 2 ' and R 3 , to produce an intermediate compound of formula Aih. As shown in Scheme A, R 2 'With the same R as described herein 2 Same definition, except R 2 is hydrogen, in which case R 2 ' is a protecting group P 1 Similarly, the substituent R 3 ” has the same 3 Same definition, except R 3 "Excluding hydrogen. LG 3 and LG 4 is a leaving group such as chloro, bromo or iodine.

[0554] In Part II of Scheme A, R 5 The addition of an aryl or heteroaryl moiety to a compound of formula Aih is replaced by LG 2 The position occupied by the other intermediate compounds of the general formula Ail. 5 The installation of the moiety can be achieved, for example, by two routes as shown above. In the first route, the compound of formula Aih is reacted with a suitable boronic acid derivative containing the desired R 5 Aik group, where R A and R Bare independently selected from halogen, OH and O-(C1-C6 alkyl), or R A and R B Together with the boron atom to which they are attached, they form a 5-10 membered heterocyclic ring to give an intermediate compound of formula Ail. In the second route, the compound of formula Aih is directly reacted with a boronic acid or a derivative thereof, wherein R c is a suitable leaving group (such as O-C1-C3 alkyl, or another boronic acid or derivative thereof, i.e. in a diboron compound) to obtain a 6-azaindolyl-borate compound of formula Aii. The obtained borate compound is further reacted with a compound containing R 5 The substrate (Aij) is reacted to obtain a compound of formula Ail.

[0555] In Scheme A, part III, a compound of formula Ail is reacted with an appropriate cyclopropanecarboxamide of formula Aim to provide a compound of formula IAi.

[0556] Scheme B - Part I

[0557]

[0558] Scheme B - Part II.

[0559]

[0560] Scheme B - Part III.

[0561]

[0562] Similar to Scheme A, Scheme B describes the preparation of compounds of formula (IA-ii) having a 5-azaindole nucleus. Compounds of (IA-ii) can be prepared according to the general synthetic scheme shown in parts I-III of Scheme B. In part I of Scheme B, a 5-azaindole compound of formula A-ii-a (wherein LG 1 is a leaving group (such as chlorine or bromine)), the nitrogen of the imidazole group is protected by a protecting group P 1 (e.g., protected by a Boc-group or a SEM-group) to give a compound of formula A-ii-b. 2 (such as iodine) is added to the protected compound of general formula A-ii-b, which is R 5 The obtained compound of general formula A-ii-c is further reacted to introduce a substituent R into the 5-azaindole nucleus as needed. 4 ' and R 3 '", to produce the intermediate compound of formula A-ii-h. As shown in Scheme B, the substituent R 3 '" has the same 3Same definition, except R 3 '" is hydrogen, in which case R 3 '" is a protecting group P 1 Similarly, R 4 'With the same R as described herein 4 Same definition, except R 4 'Excluding hydrogen. LG 3 and LG 4 is a leaving group such as chloro, bromo or iodine.

[0563] In part II of Scheme B, R 5 The addition of an aryl or heteroaryl moiety to a compound of formula A-ii-h is carried out by LG 2 The position occupied by R is obtained to obtain other intermediate compounds of the general formula A-ii-1. 5 The installation of the moiety can be achieved, for example, by two routes as shown above. In the first route, a compound of formula A-ii-h is reacted with a suitable boronic acid derivative containing the desired R 5 Group A-ii-k, 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 Together with the boron atom to which they are attached, a 5-10 membered heterocyclic ring is formed to give an intermediate compound of formula A-ii-1. In the second route, the compound of formula A-ii-h is directly reacted with a boronic acid or a derivative thereof, wherein R c is a suitable leaving group (such as O-C1-C3 alkyl, or another boronic acid or its derivative, i.e. in a diboron compound) to obtain a 5-azaindolyl-borate compound of formula A-ii-i. The obtained borate compound is further reacted with a 5-azaindolyl-borate compound containing R 5 ) to react with a substrate (A-ii-j) to obtain a compound of formula A-ii-l.

[0564] In Scheme B, part III, a compound of formula A-ii-1 is reacted with an appropriate cyclopropanecarboxamide of formula A-ii-m to provide a compound of formula IA-ii.

[0565] Compounds of formula (IB) can also be prepared according to the general synthetic schemes shown in Scheme C and Scheme D. In Scheme C, a 6-azaindolyl compound of formula Ail obtained from Scheme A (Part I and Part II) is reacted with a suitable urea compound of formula Bim to give a compound of formula IBi. In Scheme D, a 5-azaindolyl compound of formula A-ii-l obtained from Scheme B (Part I and Part II) is reacted with a suitable urea compound of formula B-ii-m to give a compound of formula IB-ii.

[0566] Plan C

[0567]

[0568] Plan D

[0569]

[0570] Alternatively, the addition of cyclopropylcarboxamido or urea moieties as described in Scheme A (Part III), Scheme B (Part III), Scheme C and Scheme D can be substituted with the methods described in Scheme E, Scheme F, Scheme G and Scheme H, respectively.

[0571] Plan E

[0572]

[0573] In Scheme E, the intermediate compound of formula Ail is aminated (such as with diphenylformimine) to give a compound of formula Ain. The resulting compound of formula Ain is then reacted with cyclopropanecarboxylic acid or its derivative Aio (wherein LG 5 The compound of formula (IAi) is reacted with a cyclopropanecarboxylic acid or a derivative thereof (wherein LG is alkyl) to give the desired compound of formula (IAi). Similarly, in Scheme F, the intermediate compound of formula A-ii-1 is aminated (such as with diphenylformimine) to give a compound of formula A-ii-n. The compound of formula A-ii-n is then reacted with cyclopropanecarboxylic acid or a derivative thereof (wherein LG is alkyl) to give the desired compound of formula (IAi). 5 It may be -OH, Cl-, -O-C1-C6 alkyl, etc.) to react to obtain the desired compound of formula (IA-ii).

[0574] Plan F

[0575]

[0576] Compounds of formula (IB) can also be prepared from compounds of formula Ain and A-ii-n as described in Scheme G and Scheme H. In Scheme G, compounds of formula Ain are reacted with carboxylic acid derivatives (e.g., phenylcarbonyl chloride and R-containing 6 The free amine Bio is reacted in successive steps to give urea compounds of the general formula IBi. Similarly, in Scheme H, compounds of the general formula A-ii-n are reacted with carboxylic acid derivatives and R-containing 6 The free amines B-ii-o are reacted in successive steps to give the desired urea compounds of the general formula IB-ii.

[0577] Plan G

[0578]

[0579] Plan H

[0580]

[0581] Schemes I and J below describe alternatives for preparing 5-azaindole 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 (eg, iodine)) and an R-containing 3 and R 5 In Scheme J, a 4-aminopyridine compound of formula A-ii-p is reacted with an R-containing compound of formula A-ii-q. 4 and R 5 The acetylene compound is reacted to provide an intermediate compound of formula A-ii-r.

[0582] Plan I

[0583]

[0584] Plan J

[0585]

[0586] Prior to coupling, the intermediate compounds of formula Air and formula A-ii-r may be further reacted, for example, to attach or remove any protecting groups or to introduce substituents R 2 or R 3 , to obtain the final cyclopropylcarboxamido compounds of formula (IAi) and (IA-ii) or the ureido compounds of formula (IBi) and (IB-ii) as shown in Schemes A to H.

[0587] IV. Pharmaceutical Compositions and Formulations

[0588] Any of the compounds described herein can be formulated into a pharmaceutically acceptable composition.

[0589] Pharmaceutical compositions of any of the compounds detailed herein are encompassed by the present disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed 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. In one aspect, a pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical composition can be in a form suitable for oral, buccal, parenteral, intranasal, topical, or rectal administration, or in a form suitable for administration by inhalation.

[0590] The compounds as detailed herein can be in purified form in one aspect, and compositions comprising the compounds in purified form are detailed herein. Compositions comprising the compounds as detailed herein or their pharmaceutically acceptable salts, solvates, hydrates or co-crystals, or mixtures of any of the foregoing are provided, such as compositions of substantially pure compounds. In some embodiments, the compositions containing the compounds as detailed herein or their pharmaceutically acceptable salts, solvates, hydrates or co-crystals, or mixtures of any of the foregoing are in substantially pure form. In one variation, "substantially pure" refers to a composition containing no more than 35% impurities, wherein impurities represent compounds other than the compound or its salt that constitutes the majority of the composition. For example, a composition of substantially pure compounds selected from the compounds of Table 1 refers to a composition containing no more than 35% impurities, wherein impurities represent compounds other than the compounds of Table 1. In one variation, a composition of substantially pure compounds or their pharmaceutically acceptable salts, solvates, hydrates or co-crystals, or mixtures of any of the foregoing is provided, wherein the composition contains no more than 25% impurities. 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, wherein the composition contains no more than 20% impurities. 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, wherein the composition contains no more than 10% impurities. 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, wherein the composition contains no more than 5% impurities. 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, wherein the composition contains no more than 3% impurities. In yet 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, wherein the composition contains no more than 1% impurities. 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, wherein the composition contains no more than 0.5% impurities. In other variations, a composition of a substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurities, which can be different stereochemical forms of the compound. For example, but not limited to, 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.

[0591] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions containing substantially pure forms of the compounds are provided. In another variation, the disclosure includes pharmaceutical compositions comprising the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are applicable to any compound or form thereof described in detail herein. In some embodiments, the compounds and compositions as provided herein are sterile. Sterilization methods known in the art may be applicable to any compound or form thereof and compositions thereof as described in detail herein.

[0592] The compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. The compounds or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, can be formulated with a suitable carrier to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, lozenges, troches, gums, dispersions, suppositories, ointments, poultices (catharsis), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays 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.

[0593] The compounds described in detail herein, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing substances, can be used to prepare formulations, such as pharmaceutical formulations, by combining the one or more compounds, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing substances with a pharmaceutically acceptable carrier. Depending on the treatment form of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. In addition, the pharmaceutical formulation may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coatings, or antioxidants for regulating osmotic pressure. The formulations comprising the compounds may also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th edition (2000), which is incorporated herein by reference.

[0594] The compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, can be administered to an individual in the form of generally acceptable oral compositions such as tablets, coated tablets, and gel capsules in hard or soft shells, emulsions or suspensions. Examples of carriers that can be used to prepare such compositions are lactose, corn starch or its derivatives, talc, stearates or their salts, and the like. Acceptable carriers for soft shell gel capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and the like. In addition, the pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for regulating osmotic pressure, buffers, coating agents, or antioxidants.

[0595] Any compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances can be formulated into a tablet in any dosage form, for example, a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances can be formulated into a 10 mg tablet.

[0596] 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 a 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 drug. In some embodiments, the composition is used in the methods described herein. In some embodiments, the composition is used in the treatment of a disease or condition described herein.

[0597] Also described are compositions prepared for the co-administration of a compound provided herein and one or more other pharmaceutical agents. Co-administration can be performed simultaneously or in any order. Provided herein is a compound that can be formulated for co-administration with the one or more other pharmaceutical agents in the same dosage form (e.g., single tablet or single intravenous injection) or in a separate dosage form (e.g., two separate tablets, two separate intravenous injections, or a tablet and an intravenous injection). In addition, co-administration can be, for example, 1) delivered simultaneously by the same route of delivery (e.g., tablet or intravenous injection), 2) delivered sequentially by the same route of delivery or different routes of delivery on the same day, or 3) delivered by the same route of delivery or different routes of delivery on different days.

[0598] V. How to use

[0599] The compounds and compositions described in detail herein, such as pharmaceutical compositions containing a compound of formula (I) as provided herein or any variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances and a pharmaceutically acceptable carrier or excipient, can be used in the administration and treatment methods as provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods in which the compound or composition is applied to cells for screening purposes and / or for quality control assays.

[0600] On the one hand, there is provided herein a method for inhibiting the enzymatic activity of Bcr-Abl tyrosine kinase, comprising contacting an effective amount of a compound or composition provided herein with a Bcr-Abl tyrosine kinase. In some embodiments, there is provided herein a method for inhibiting the Bcr-Abl tyrosine kinase in a cell, comprising administering an effective amount of a compound or composition of the present disclosure to the cell. In some embodiments, there is provided herein a method for inhibiting the Bcr-Abl tyrosine kinase in an individual in need, comprising administering an effective amount of a compound or composition of the present invention to the individual. In some variations, provided herein is a method for inhibiting the Bcr-Abl tyrosine kinase in an individual in need, comprising administering an effective amount of a compound or composition of the present invention to the individual. In some variations, provided herein is a compound that selectively inhibits Bcr-Abl tyrosine kinase. Therefore, in some embodiments, provided herein is a method for selectively inhibiting Bcr-Abl tyrosine kinase compared to other tyrosine kinases, wherein the other tyrosine kinases include but are not limited to c-KIT, FGFR, PDGFR, SRC, CSFR1 or VEGFR.

[0601] The compounds and compositions described herein can be used in methods of treating diseases or conditions mediated by Bcr-Abl tyrosine kinase activity. In some embodiments, the compound or composition is administered according to the dosages described herein.

[0602] In some embodiments, provided herein is a method for treating a disease or condition mediated by Bcr-Abl tyrosine kinase activity, comprising administering an effective amount of a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances to an individual in need of treatment. In some embodiments, the disease or condition is a cancer mediated by Bcr-Abl tyrosine kinase activity. In some embodiments, the disease or condition is chronic myeloid leukemia (CML), acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). In some embodiments, the disease or condition is cancer, such as 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.

[0603] In certain embodiments, the leukemia is chronic myeloid leukemia. Chronic myeloid leukemia may be characterized by a state of disease progression, such as that determined by blast cells. In further 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.

[0604] In some embodiments, the disease or condition mediated by Bcr-Abl tyrosine kinase activity is refractory or tolerant to first-line treatment, second-line treatment and / or third-line treatment. In certain embodiments, the condition mediated by Bcr-Abl tyrosine kinase activity is refractory or tolerant to treatment with one or more Bcr-Abl tyrosine kinase inhibitors, which are selected from the group consisting of imatinib, nilotinib, dasatinib, bafetinib, bosutinib, radotinib, asciminib and ponatinib. First-line treatment as described herein includes the use of imatinib; second-line treatment and third-line treatment as 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.

[0605] Drug-resistant subtypes of diseases or conditions 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 where a disease or condition mediated by Bcr-Abl tyrosine kinase activity is refractory to treatment, the disease or condition is characterized as being associated with one or more Bcr-Abl-dependent resistance mechanisms. Bcr-Abl-dependent resistance mechanisms include, but are not limited to, one or more point mutations that produce amino acid substitutions at the following positions within 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 refractory disease or condition mediated by the Bcr-Abl tyrosine kinase is associated with one or more specific point mutations in the Bcr-Abl tyrosine kinase gene that result 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 refractory disease or condition mediated by Bcr-Abl tyrosine kinase is associated with a mutation that produces a T315I substitution. In a further embodiment, the refractory disease or condition mediated by Bcr-Abl tyrosine kinase is associated with a T315I mutation at the start of treatment and an I315M mutation after ponatinib. In other embodiments, the refractory disease or condition mediated by Bcr-Abl tyrosine kinase is associated with one or more mutations (M244V, G250E, Q252H, Y253H / F, E255K / V) that cause amino acid substitutions within the P-loop.

[0606] In some embodiments, a method of treating cancer in an individual in need is provided, comprising administering to the individual an effective amount of a compound of formula (I) as described herein or any variant thereof. In some embodiments, the cancer is a 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, chronic myeloid leukemia (CML), Philadelphia positive acute lymphoblastic leukemia (Ph+ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia is refractory. In certain embodiments, the leukemia is chronic myeloid leukemia. In further embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia. In other embodiments, chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia is refractory due to an associated T315I mutation. In certain embodiments of the foregoing embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia associated with a T315I mutation.

[0607] On the one hand, there is provided herein a method for treating cancer in an individual in need thereof, wherein the regulation of Bcr-Abl tyrosine kinase activity suppresses or improves the pathology and / or symptoms of cancer, the method comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, there is provided herein a method for treating cancer, wherein the regulation of Bcr-Abl tyrosine kinase activity suppresses the pathology and / or symptoms of cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, there is provided herein a method for treating cancer, wherein the regulation of Bcr-Abl tyrosine kinase activity improves the pathology and / or symptoms of cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein.

[0608] In another aspect, there is provided herein a method for preventing cancer, wherein regulation of Bcr-Abl tyrosine kinase activity prevents the pathology and / or symptoms of cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In another aspect, there is provided herein a method for delaying the onset and / or development of a cancer mediated by Bcr-Abl tyrosine kinase activity in an individual (such as a human) at risk of developing cancer. It will be understood that, in the absence of an individual developing cancer, delaying development can encompass prevention.

[0609] On the one hand, there is provided herein a method for delaying the onset and / or development of cancer in an individual in need thereof, comprising administering a therapeutically effective amount of a compound or composition provided herein to the individual. 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, chronic myeloid leukemia (CML), Philadelphia positive acute lymphoblastic leukemia (Ph+ALL), acute myeloid leukemia (AML) or mixed phenotype acute leukemia is refractory. In certain embodiments, the leukemia is chronic myeloid leukemia. In a further embodiment, chronic myeloid leukemia is refractory chronic myeloid leukemia.In other embodiments, chronic myeloid leukemia (CML), Philadelphia positive acute lymphoblastic leukemia (Ph+ALL), acute myeloid leukemia (AML) or mixed phenotype acute leukemia are refractory due to the related T315I mutation.In other embodiments, chronic myeloid leukemia is the refractory chronic myeloid leukemia related to the T315I mutation.On the one hand, there is provided herein a method for delaying the onset and / or development of chronic myeloid leukemia in an individual in need, comprising administering a compound or composition herein provided to the individual for treatment of an effective amount.On the one hand, there is provided herein a method for delaying the onset and / or development of refractory 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, comprising administering a compound or composition herein provided to the individual for treatment of an effective amount. In one aspect, provided herein is a method of delaying the onset and / or progression 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 an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein.

[0610] In one aspect, provided herein are compounds of formula (I) or any variant thereof, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, for use in therapy. In some embodiments, provided herein are compounds of formula (I) or any variant thereof, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, or pharmaceutical compositions comprising such compounds, for use in the treatment of cancer. In some embodiments, provided herein are compounds of formula (I) or any variant thereof, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, or pharmaceutical compositions comprising such compounds, 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. In some embodiments, a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances, or a pharmaceutical composition comprising such a compound is provided for use in the treatment of chronic myeloid leukemia (CML). In some embodiments, a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances, or a pharmaceutical composition comprising such a compound is provided 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, provided is a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal 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.

[0611] In another embodiment, provided herein is a compound of formula (I) or any variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal 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 variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal 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 used to treat chronic myeloid leukemia. In some embodiments, the medicament is used to treat 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 used to treat refractory chronic myeloid leukemia. In other embodiments, the agent is used to treat 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. In some embodiments, the agent is used to treat refractory chronic myeloid leukemia associated with the T315I mutation.

[0612] In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate, dog, cat, rabbit, or rodent. In some embodiments, the subject is a primate. In some embodiments, the subject is a human. In some embodiments, the human is at least about or about any of 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 less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.

[0613] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering irradiation. 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., doxorubicin), 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., aximinib), MEK1 / 2 inhibitors (e.g., trametinib, binimetinib), AKT inhibitors (e.g., ipatasertib), PI3K inhibitors (e.g., apelisib) and irradiation.

[0614] VI. Dosage and Administration Methods

[0615] The dosage 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 (such as a human) may vary depending on the specific compound or salt thereof, the method of administration, and the specific cancer being treated (e.g., the type and stage of the 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.

[0616] The compounds provided herein, or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof, or mixtures of any of the foregoing, can be administered to a subject via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal administration.

[0617] On the one hand, the effective amount of the compound can be a dosage of about 0.01 to about 100 mg / kg. The effective amount or dosage of the compound of the present disclosure can be determined by conventional methods, such as modeling, dose escalation or clinical trials, considering conventional factors, such as the mode or approach of administration or drug delivery, the pharmacokinetics of the reagent, the severity and course of the disease to be treated, the health status, condition and body weight of the subject. Exemplary dosage is in the range of about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0618] In one aspect, any of the methods provided herein can comprise administering to a subject a pharmaceutical composition containing an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.

[0619] Provided herein are compounds or compositions that can be administered to an individual for the required time or duration according to an effective dosing regimen, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, and in some variations, for the lifetime of a sustainable individual. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be continuously administered to an individual (e.g., at least once a day) over a period of time. The frequency of administration can also be less than once a day, for example, approximately once a week. The frequency of administration can exceed once a day, for example, twice or three times a day. The frequency of administration can also be intermittent, including "drug holidays" (e.g., once a day for 7 days, followed by no administration for 7 days, repeated for any 14-day period, such as about 2 months, about 4 months, about 6 months, or longer). Any frequency of administration can be used with any compound described herein and any dosage described herein.

[0620] VII. Products and Kits

[0621] The present disclosure further provides an article 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 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, and the like. The article can be further sterilized and / or sealed.

[0622] The present disclosure also provides a kit for implementing the method of the present disclosure, which includes one or more compounds as described herein or a composition comprising a compound as described herein. The kit can adopt any compound disclosed herein. In one variation, the kit adopts a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a mixture of any of the foregoing substances. The kit can be used for any one or more purposes as described herein, and therefore can contain instructions for treating any disease as described herein, such as for treating 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 refractory chronic myeloid leukemia. In certain embodiments of the foregoing embodiments, the cancer is refractory chronic myeloid leukemia associated with T315I mutation.

[0623] The kit optionally further comprises a container comprising one or more additional pharmaceutical agents, and the kit further comprises, on or in the package insert, instructions for treating the subject with an effective amount of the one or more additional pharmaceutical agents.

[0624] The kit typically includes suitable packaging. The kit may include one or more containers comprising any compound described herein. Each component (if more than one component) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container.

[0625] The kit can be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or subunit dosage. For example, a kit can be provided containing a sufficient dose of a compound disclosed herein and / or another pharmaceutically active compound that can be used for the diseases detailed herein to provide effective treatment to an individual over a long period of time, such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or any period of time longer. The kit can also include multiple unit doses of the compound and instructions for use and be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0626] The kit may optionally include a set of instructions, typically written instructions, but electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable, which relate to the use of the components of the disclosed methods. The instructions included with the kit typically include information about the components and their administration to an individual.

[0627] Example

[0628] It will be understood that the present disclosure is made by way of example only and that those skilled in the art may make various changes in the combination and arrangement of parts without departing from the spirit and scope of the present disclosure.

[0629] Synthesis Example

[0630] The chemical reactions in the described examples can be readily adapted to prepare many other compounds disclosed herein, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure can be successfully performed by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art in addition to those described, or by routine modifications to reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be considered to have applicability to the preparation of other compounds of the present disclosure.

[0631] Abbreviations used in the examples include the following: ACN: acetonitrile; Brettphos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; dppf: 1,1'-diphenylferrocenyl-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-diazoniumbicyclo[2.2.2]octanebis(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, azabenzotriazole tetramethyluronium hexafluorophosphate; LCMS: liquid chromatography-mass spectrometry; LDA: lithium diisopropylamide; LiHMDS: lithium hexamethyldisilazane; 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.

[0632] Example S1: Synthesis of N-(2-(2-hydroxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 1)

[0633]

[0634] Step 1: Synthesis of tert-butyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Compound 1b)

[0635]

[0636] 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 completed, 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 in vacuo. The residue was purified by flash column chromatography with 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.

[0637] Step 2: Synthesis of tert-butyl 5-chloro-2-iodopyrrolo[2,3-c]pyridine-1-carboxylate (Compound 1c)

[0638]

[0639] 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. A solution of iodine (3.0 g, 11.82 mmol) in THF (10.0 mL) was then added dropwise at -78 ° C. The mixture was stirred at -78 ° C under N2 for 4 hours. After the reaction was completed, the reactant 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 in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1 v / v) to give tert-butyl 5-chloro-2-iodopyrrolo[2,3-c]pyridine-1-carboxylate (Compound 1c) (1.0 g, 13%) as a white solid. LCMS (ESI): [M+H] + =379.0.

[0640] Step 3: Synthesis of 5-chloro-2-iodo-1H-pyrrolo[2,3-c]pyridine (Compound 1d)

[0641]

[0642] To a stirred solution of 5-chloro-2-iodo-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (Compound 1c) (1.0 g, 2.61 mmol) in CH2Cl2 (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 in vacuo. The residue was purified by flash column chromatography with 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.

[0643] Step 4: Synthesis of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (Compound 1e)

[0644]

[0645] At 0 ° C, NaH (167.8 mg, 60%) was added 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). The mixture was stirred under N2 at 0 ° C for 2 hours. Then a solution of CH3I (70.8 mg, 0.44 mmol) in THF (5.0 mL) was added dropwise to the mixture. The mixture was stirred under N2 at 0 ° C for 2 hours. After the reaction was completed, 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 in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 2 v / v) to give 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 1e) (800.0 mg, 79%) as a white solid. LCMS(ESI):[M+H] + =292.9.

[0646] Step 5: Synthesis of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]phenol (Compound 1g)

[0647]

[0648] 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 H2O (1.0 mL) was added 2-hydroxyphenylboronic acid (compound 1f) (113.7 mg, 0.82 mmol), Pd(dppf)Cl2 (100.6 mg, 0.13 mmol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred under N2 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 with 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.

[0649] Step 6: Synthesis of N-[2-(2-hydroxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 1)

[0650]

[0651] 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 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 in vacuo. The residue was purified by preparative HPLC using the following conditions: column: YMC-Actus Triart C18, 30x250 mm, 5 μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 50 mL / min; gradient: from 43% B to 64% B in 7 minutes; detector, UV 254 nm, 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. LCMS (ESI): [M+H] + =308.0. 1H NMR (300MHz, DMSO-d6): δ10.47(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).

[0652] Example S2: Synthesis of N-(2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 2)

[0653]

[0654] Step 1: Synthesis of 5-chloro-2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 2b)

[0655]

[0656] 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 H2O (1.0 mL) was added 2-methoxyphenylboronic acid (124.9 mg, 0.82 mol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 ° C under N2 for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 2 v / v) to give 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.

[0657] Step 2: Synthesis of N-[2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 2)

[0658]

[0659] 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) was added 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). The resulting mixture was stirred at 100 ° C for 4 hours. After the reaction was complete, the resulting mixture was diluted with H2O 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 in vacuo. The residue was purified by preparative HPLC using the following conditions: column: YMC-Actus Triart C18, 30x250 mm, 5um; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 17% B to 40% B in 7 minutes; detector, UV 254 / 220 nm to obtain N-[2-(2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 2) (63.2 mg, 32%) as a white solid. LCMS (ESI): [M+H] + =322.1. 1 H NMR (300MHz, DMSO-d6): δ10.52(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=8.4Hz,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).

[0660] Example S3: Synthesis of N-[2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 3)

[0661]

[0662] Step 1: Synthesis of 5-chloro-2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 3c)

[0663]

[0664] 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 / H2O (5.0 / 0.5 mL) was added Pd(dppf)Cl2 (55.8 mg, 0.06 mmol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 ° C under N2 for 12 hours. After completion of the reaction, the reactant 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 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.

[0665] Step 2: Synthesis of N-[2-(2-ethoxyphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 3)

[0666]

[0667] 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 hours. After completion of the reaction, 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 30x150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 40% B to 62% B in 8 minutes; 254 nm; RT1: 7.47 minutes) 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 (300MHz, DMSO-d6): δ10.47(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),7.1 1-7.06(m,1H),6.41(d,J=0.6Hz,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).

[0668] Example S4: Synthesis of N-[2-[2-(2-hydroxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 4)

[0669]

[0670] Step 1: Synthesis of [2-(2-bromophenoxy)ethoxy](tert-butyl)dimethylsilane (Compound 4c)

[0671]

[0672] At room temperature under N2, to a mixture of 2-bromophenol (compound 4a) (5.0g, 28.90mmol) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (compound 4b) (7.6g, 43.32mmol) in THF (100.0mL) was added PPh3(11.3g, 43.35mmol). Then at 0°C under N2, DIAD (8.7g, 43.37mmol) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 2 hours. After the 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 (10 / 1, v / v) to obtain [2-(2-bromophenoxy)ethoxy](tert-butyl)dimethylsilane (compound 4c) (8.0g, 83%) as a yellow solid.

[0673] Step 2: Synthesis of tert-butyldimethyl[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy]silane (Compound 4e)

[0674]

[0675] 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'-bis(1,3,2-dioxaborolane) (compound 4d) (2.3 g, 9.05 mmol) in dioxane (10.0 mL) was added Pd(dppf)Cl2 (0.2 g, 0.30 mmol) and KOAc (0.9 g, 9.05 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction 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 flash column chromatography with 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.

[0676] Step 3: Synthesis of 2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-5-chloro-1-methylpyrrolo[2,3-c]pyridine (Compound 4g)

[0677]

[0678] 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-dioxaborolane-2-yl)phenoxy]ethoxy]silane (compound 4e) (1.1 g, 3.07 mmol) in dioxane / H2O (10.0 / 1.0 mL) was added Pd(dppf)Cl2 (75.0 mg, 0.10 mmol) and K2CO3 (425.2 mg, 3.07 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reactant 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 flash column chromatography with 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.

[0679] Step 4: Synthesis of N-[2-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]phenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 4i)

[0680]

[0681] 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) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reactant 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 flash column chromatography with 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.

[0682] Step 5: Synthesis of N-[2-[2-(2-hydroxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 4)

[0683]

[0684] 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 in vacuo. The residue was purified by preparative HPLC using the following conditions (column: Xselect CSH OBD column 30x150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 22% B to 48% B in 9 minutes; 220 nm; RT1: 8.03) to give 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 (300MHz, DMSO-d6): δ10.47(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=0.6Hz,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).

[0685] Example S5: Synthesis of N-(2-(2-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 5)

[0686]

[0687] Step 1: Synthesis of 1-bromo-2-(2-methoxyethoxy)benzene (Compound 5c)

[0688]

[0689] At 0 DEG C under N2, to a mixture of 2-bromophenol (compound 5a) (2.0g, 11.56mmol) and PPh3(4.5g, 17.34mmol), 2-methoxyethanol (compound 5b) (1.3g, 17.34mmol) in THF, DIAD (3.5g, 17.35mmol) was added. At room temperature under N2, the resulting mixture was stirred for 2 hours. After the reaction was complete, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (4 / 1, v / v) to obtain 1-bromo-2-(2-methoxyethoxy)benzene (compound 5c) (2.3g, 86%) as a yellow oil.

[0690] Step 2: Synthesis of 2-[2-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 5e)

[0691]

[0692] 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'-bis(1,3,2-dioxaborolane) (compound 5d) (3.6 g, 14.29 mmol) in dioxane (20.0 mL) was added Pd(dppf)Cl2 (348.2 mg, 0.47 mmol) and KOAc (1.4 g, 14.26 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reactant 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 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.

[0693] Step 3: Synthesis of 5-chloro-2-[2-(2-methoxyethoxy)phenyl]-1-methylpyrrolo[2,3-c]pyridine (Compound 5g)

[0694]

[0695] 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 / H2O (4 / 0.4 mL) was added Pd(dppf)Cl2 (55.8 mg, 0.06 mmol) and K2CO3 (283.5 mg, 2.05 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction 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 flash column chromatography with 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.

[0696] Step 4: Synthesis of N-(2-(2-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (Compound 5)

[0697]

[0698] 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) 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. The resulting mixture was stirred at 100°C under N2 for 16 hours. After completion of the reaction, the reactant 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 30x150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 35% B to 57% B in 8 minutes; 254 nm; RT1: 7.3 minutes) 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 (400MHz, DMSO-d6): δ10.47(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=8.0Hz,1H),7.12-7. 08(m,1H),6.43(d,J=0.4Hz,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).

[0699] Example S6: Synthesis of N-[2-(2-cyanophenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 6)

[0700]

[0701] Step 1: Synthesis of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]benzonitrile (Compound 6b)

[0702]

[0703] To a solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 6a) (200.0 mg, 0.68 mmol) in dioxane / H2O ((10.0 / 1.0 mL)) was added 2-cyanophenylboronic acid (120.7 mg, 0.82 mmol), Pd(dppf)Cl2 (100.6 mg, 0.17 mmol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80°C under N2 for 16 hours. 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 (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.

[0704] Step 2: Synthesis of N-[2-(2-cyanophenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 6)

[0705]

[0706] 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 hours. After completion of the reaction, 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: 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: from 35% B to 48% B in 7 minutes. Detector, UV 254 / 220 nm, to obtain N-[2-(2-cyanophenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 6) (28.6 mg, 22%) as a white solid. LCMS (ESI): [M+H] + =317.0. 1 H NMR (300MHz, DMSO-d6): δ10.57(s,1H),8.72(s,1H),8.26(s,1H),8.07(d,J=7.8Hz,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).

[0707] Example S7: Synthesis of N-[2-(3-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 7)

[0708]

[0709] Step 1: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 7c)

[0710]

[0711] At room temperature under N2, to a solution of 5-chloro-2-iodo-1-methylpyrrolo-[2,3-c]pyridine (compound 7a) (200.0 mg, 0.68 mmol) in dioxane (10.0 mL) and H2O (1.0 mL) was added 3-methoxy-2-methylphenylboronic acid (compound 7b) (136.2 mg, 0.82 mmol), Pd (dppf) Cl2 (100.0 mg, 0.13 mmol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 ° C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (97 / 3, v / v) to obtain 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.

[0712] Step 2: Synthesis of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylphenol (Compound 7d)

[0713]

[0714] 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 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 in vacuo 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.

[0715] Step 3: Synthesis of N-[2-(3-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 7)

[0716]

[0717] 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) was added 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 Cs2CO3 (465.9 mg, 1.43 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 3 hours. After completion of the reaction, 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 in vacuo. The residue was purified by preparative HPLC using the following conditions (column: Xselect CSHOBD column 30x150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 5% B to 30% B in 8 minutes; 220 nm) to obtain 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 (300MHz, DMSO-d6): δ10.48(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=0.6Hz,1H),3.55(s,3H),2.05-1.97(m,1H),1.94(s,3H),0.84-0.78(m,4H).

[0718] Example S8: Synthesis of N-[2-(4-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 8)

[0719]

[0720] Step 1: Synthesis of 4-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylphenol (Compound 8c)

[0721]

[0722] 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 / H2O (2.0 / 0.2 mL) was added Pd(dppf)Cl2 (100.0 mg, 0.13 mmol) and K2CO3 (283.5 mg, 2.05 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, 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 in vacuo. 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.

[0723] Step 2: Synthesis of N-[2-(4-hydroxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 8)

[0724]

[0725] 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) was added CsCO (304.6 mg, 0.93 mmol), Brettphos (33.4 mg, 0.06 mmol) and BrettPhos Pd G (28.2 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, 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 in vacuo. The residue was purified by preparative HPLC using the following conditions: column: YMC-Actus Triart C18, 20x250 mm, 5 μm, 12 nm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 28% B to 48% B in 8 minutes; 254 / 220 nm; to obtain 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. LCMS (ESI, m / z): [M+H] + =322.1. 1 H NMR (300MHz, DMSO-d6): δ10.47(s,1H),9.67(s,1H),8.56(s,1H),8.17(s,1H),7.12(d,J=8.1Hz,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).

[0726] Example S9: Synthesis of N-[2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 9)

[0727]

[0728] Step 1: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 9b)

[0729]

[0730] 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) was added 3-methoxy-2-methylphenylboronic acid (136.9 mg, 0.82 mmol), Pd(dppf)Cl2 (50.3 mg, 0.68 mmol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 ° 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 with 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.

[0731] Step 2: Synthesis of N-[2-(3-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 9)

[0732]

[0733] 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) was added 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). The resulting mixture was stirred at 100 ° C for 4 hours. After completion of the reaction, 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: 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: from 16% B to 25% B in 7 minutes. Detector, UV 254 / 220 nm, to obtain 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. LCMS (ESI): [M+H] +=336.2. 1 H NMR (400MHz, DMSO-d6): δ10.51(s,1H),8.61(s,1H),8.21(s,1H),7.34-7.30(m,1H),7.12(d,J=8.0Hz,1 H), 6.93 (d, J = 7.2Hz, 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).

[0734] Example S10: Synthesis of N-[2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 10)

[0735]

[0736] Step 1: Synthesis of 5-chloro-2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 10b)

[0737]

[0738] To a stirred solution of 5-chloro-2-iodo-1-methylpyrrolo[2,3-c]pyridine (compound 10a) (200.0 mg, 0.68 mmol) in dioxane (10.0 mL) and H2O (1.0 mL) was added 4-methoxy-2-methylphenylboronic acid (136.9 mg, 0.81 mmol) and K2CO3 (283.5 mg, 2.05 mmol). The resulting mixture was stirred at 80 ° C under N2 for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 2 v / v) to give 5-chloro-2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (compound 10b) (190.0 mg, 97%) as a white solid. LCMS (ESI): [M+H] + =287.1.

[0739] Step 2: Synthesis of N-[2-(4-methoxy-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 10)

[0740]

[0741] 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 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 in vacuo. The residue was purified by preparative HPLC using 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: from 29% B to 55% B in 10 minutes; detector, UV 254 nm, 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. LCMS (ESI): [M+H] + =336.2. 1 H NMR (300MHz, DMSO-d6): δ10.49(s,1H),8.58(s,1H),8.18(s,1H),7.25(d,J=8.4Hz,1H),6.97(d,J=2.1Hz,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).

[0742] Example S11: Synthesis of N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 11)

[0743]

[0744] Step 1: Synthesis of 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 11c)

[0745]

[0746] 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 / H2O (2.0 / 0.2 mL) was added Pd(dppf)Cl2 (100.0 mg, 0.13 mmol) and K2CO3 (283.0 mg, 2.05 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ° C for 2 hours. After completion of the reaction, 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 in vacuo. 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.

[0747] Step 2: Synthesis of N-[2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 11)

[0748]

[0749] 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 Cs2CO3 (170.4 mg, 0.52 mmol), Brettphos (18.7 mg, 0.03 mmol) and BrettPhos Pd G3 (15.8 mg, 0.02 mmol). The resulting mixture was stirred at 100 ° C under N2 for 16 hours. After completion of the reaction, 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 in vacuo. The residue was purified by preparative HPLC using the following conditions: column: YMC-Actus Triart C18, 30x250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 46% B to 60% B in 8 minutes; 254 nm; to obtain 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. LCMS (ESI, m / z): [M+H] + =336.1. 1 H NMR (300MHz, DMSO-d6): δ10.47(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).

[0750] Example S12: Synthesis of N-[2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 12)

[0751]

[0752] Step 1: Synthesis of 5-chloro-2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 12c)

[0753]

[0754] 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 the reaction was completed, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 2, v / v) to obtain 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.

[0755] Step 2: Synthesis of N-[2-(5-fluoro-2-methylphenyl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 12)

[0756]

[0757] 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 hours. After completion of the reaction, 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 in vacuo. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (10 / 1, v / v) and then by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30x250 mm, 5um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 49% B to 79% B in 7 minutes; 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 (400MHz, DMSO-d6): δ10.50(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).

[0758] 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)

[0759]

[0760] Step 1: Synthesis of 5-bromo-4-methyl-2,3-dihydro-1H-indole (Compound 13b)

[0761]

[0762] At 0 ° C under N2, NaBH3CN (1.0 g, 16.72 mmol) was added to a solution of 5-bromo-4-methyl-1H-indole (compound 13a) (880.0 mg, 4.18 mmol) in HOAc (15.0 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the pH value of the mixture was adjusted to 9 with NaOH (aqueous solution). 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 phase flash chromatography with 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.

[0763] Step 2: Synthesis of tert-butyl 5-bromo-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13c)

[0764]

[0765] At room temperature, DMAP (460.8 mg, 3.72 mmol) was added to a mixture of 5-bromo-4-methyl-2,3-dihydro-1H-indole (800.0 mg, 3.77 mmol) and Boc2O (2.5 g, 11.32 mmol) in DCM (20.0 mL). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with CH2Cl2. 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 with petroleum ether / EtOAc (8 / 1, v / v) to give 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.

[0766] 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)

[0767]

[0768] 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)Cl2 (173.4 mg, 0.23 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ° C for 16 hours. After completion of the reaction, the reaction 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 flash column chromatography with 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.

[0769] 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)

[0770]

[0771] 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-dioxaborolane-2-yl)-2,3-dihydroindole-1-carboxylate (442.1 mg, 1.21 mmol) in dioxane / H2O (5.0 / 0.5 mL) was added Pd(PPh3)4 (118.5 mg, 0.10 mmol) and K2CO3 (425.2 mg, 3.07 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, the 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 flash column chromatography with 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.

[0772] Step 5: Synthesis of tert-butyl 5-[5-cyclopropionylamino-1-methylpyrrolo[2,3-c]pyridin-2-yl]-4-methyl-2,3-dihydroindole-1-carboxylate (Compound 13i)

[0773]

[0774] 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) was added Brettphos Pd G3 (34.1 mg, 0.03 mmol), BrettPhos (40.0 mg, 0.07 mmol) and Cs2CO3 (368.4 mg, 1.13 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, 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 flash column chromatography with 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.

[0775] 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)

[0776]

[0777] 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 complete, the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 32% B to 62% B in 10 minutes; 254 nm) to obtain 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 (300MHz, DMSO-d6): δ10.45(s,1H),8.54(s,1H),8.16(s,1H),6.88(d,J=7.8Hz,1H),6.43(d,J=7.8Hz, 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).

[0778] 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)

[0779]

[0780] Step 1: Synthesis of 5-bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (Compound 14b)

[0781]

[0782] At 0 ° C under N2, NaH (342.7 mg, 60%) was added to a solution of 5-bromo-6-methyl-1H-indole (compound 14a) (1.0 g, 4.76 mmol) in THF (20.0 mL). The resulting mixture was stirred at 0 ° C under N2 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 N2 for 1 hour at 0 ° C. After the reaction was completed, the reactant 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 with petroleum ether / ethyl acetate (12 / 1, v / v) to obtain 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.

[0783] 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)

[0784]

[0785] 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'-bis(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 N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, 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 flash column chromatography with 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.

[0786] 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)

[0787]

[0788] 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 / H2O (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), K2CO3 (463.8 mg, 3.36 mmol) and Pd(dppf)Cl2 (49.1 mg, 0.07 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 2 hours. After completion of the reaction, 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 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%) as a colorless oil. LCMS (ESI, m / z): [M+H] + =426.2.

[0789] 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)

[0790]

[0791] 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), Cs2CO3 (344.2 mg, 1.06 mmol), Brettphos (37.8 mg, 0.07 mmol) and BrettPhos Pd G3 (31.9 mg, 0.04 mmol) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. After completion of the reaction, 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 flash column chromatography with 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.

[0792] 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)

[0793]

[0794] 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 hours. After completion of the reaction, 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 reverse phase flash column chromatography using 5-100% CH3CN in H2O, and then by preparative HPLC using the following conditions (column: Xselect CSH OBD column, 30×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 10% B to 35% B in 8 minutes; 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 (300MHz, DMSO-d6): δ11.16(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).

[0795] Example S15: Synthesis of N-[1-methyl-2-(4-methyl-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15)

[0796]

[0797] Step 1: Synthesis of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indole (Compound 15b)

[0798]

[0799] At room temperature, NaH (182.8 mg, 60%) was added to a solution of 5-bromo-4-methyl-1H-indole (800.0 mg, 3.81 mmol) in THF (10.0 mL). The resulting mixture was stirred at 0 ° C for 1 hour. [2-(chloromethoxy)ethyl]trimethylsilane (695.1 mg, 4.17 mmol) was then added dropwise to the mixture at 0 ° C. The resulting mixture was stirred for another 1 hour at 0 ° C. After the reaction was completed, 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 in vacuo. The residue was purified by flash column chromatography with 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.

[0800] 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)

[0801]

[0802] 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'-bis(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 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 in vacuo 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) as a brown solid. LCMS (ESI, m / z): [M+H] + =388.2.

[0803] 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)

[0804]

[0805] 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)Cl2 (188.9 mg, 0.26 mmol), Na2CO3 (410.4 mg, 3.88 mmol) and H2O (0.5 mL). The resulting mixture was stirred at 80°C under N2 for 16 hours. After completion of the reaction, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography with 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.

[0806] 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)

[0807]

[0808] 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 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 combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (94 / 6, v / v) to afford 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, 97%) as a brown solid. LCMS (ESI, m / z): [M+H] + =475.2.

[0809] Step 5: Synthesis of N-[1-methyl-2-(4-methyl-1H-indol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 15)

[0810]

[0811] 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 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 in vacuo. The residue was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30 x 250 mm, 5 μm; mobile phase A: water (10 mmol / LFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 60% B in 8 minutes; 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 (300MHz, DMSO-d6): δ11.27(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=8.1Hz,1H ),7.04(d,J=8.4Hz,1H),6.56(d,J=8.1Hz,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).

[0812] 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)

[0813]

[0814] Step 1: Synthesis of 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-6-methyl-1H-indazole (Compound 16c)

[0815]

[0816] 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 / H2O (8.0 / 2.0 mL) was added (6-methyl-1H-indazole-5-yl)boronic acid (compound 16b) (300.8 mg, 1.71 mmol), K2CO3 (708.8 mg, 5.13 mmol) and Pd(PPh3)4 (197.5 mg, 0.17 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ° C under N2 for 2 hours. After completion of the reaction, 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 flash column chromatography with 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-1H-indazole (Compound 16c) (260.0 mg, 51%) as a white solid. LCMS (ESI, m / z): [M+H] + =297.1.

[0817] 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)

[0818]

[0819] 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) was added NaH (68.1 mg, 60%) at 0°C under N2. The resulting mixture was stirred at 0°C for 1 hour. SEM-Cl (219.1 mg, 1.31 mmol) was then added to the mixture at 0°C under N2. The resulting mixture was stirred at 0°C under N2 for 1 hour. After completion of the reaction, the reactant was quenched 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 flash column chromatography with 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.

[0820] 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)

[0821]

[0822] 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 (compound 16d) (210.0 mg, 0.49 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (compound 16e) (251.1 mg, 2.95 mmol), Cs2CO3 (480.7 mg, 1.48 mmol), Brettphos (52.8 mg, 0.10 mmol) and BrettPhos Pd G3 (44.6 mg, 0.05 mmol) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. After completion of the reaction, 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 flash column chromatography with 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.

[0823] 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)

[0824]

[0825] 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 completion of the reaction, 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 reverse phase flash column chromatography using 5-100% CH3CN in H2O and then by preparative HPLC using 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: from 24% B to 54% B in 10 minutes; 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 (300MHz, DMSO-d6): δ13.13(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).

[0826] 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)

[0827]

[0828] Step 1: Synthesis of 5-bromo-6-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 17b)

[0829]

[0830] At 0 ° C under N2, NaH (181.9 mg, 60%) was added 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). 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 for another 2 hours at 0 ° C. After the reaction was completed, 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 in vacuo. The residue was purified by flash column chromatography with 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.

[0831] 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)

[0832]

[0833] 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)Cl2 (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'-bis(1,3,2-dioxaborolane) (Compound 17c) (446.4 mg, 1.76 mmol). The resulting mixture was stirred at 80°C under N2 for 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 in vacuo 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) as a black solid. LCMS (ESI, m / z): [M+H] + =389.2.

[0834] 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)

[0835]

[0836] 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)Cl2 (301.4 mg, 0.41 mmol), K2CO3 (854.0 mg, 6.18 mmol), and H2O (0.5 mL). The resulting mixture was stirred at 80°C under N2 for 16 hours. After completion of the reaction, the resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography using 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%) as a brown oil. LCMS (ESI, m / z): [M+H] + =427.2.

[0837] 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)

[0838]

[0839] 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 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 combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with CH2Cl2 / CH3OH (94 / 6, v / v) to give 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.

[0840] 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)

[0841]

[0842] 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 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 in vacuo. The residue was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30x250 mm, 5um; mobile phase A: water (10 mmol / LFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 60% B in 8 minutes; 254 nm) to give 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 (300MHz, DMSO-d6): δ10.46(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).

[0843] Example S18: Synthesis of N-[1-methyl-2-(4-methyl-1H-indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 18)

[0844]

[0845] Step 1: Synthesis of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]indazole (Compound 18b)

[0846]

[0847] At 0 DEG C under N2, NaH (170.5 mg, 60%) was added to a solution of 5-bromo-4-methyl-1H-indazole (compound 18a) (500.0 mg, 2.39 mmol) in THF (10.0 mL). The mixture was stirred at 0 DEG 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 DEG C. The mixture was stirred for another 2 hours at 0 DEG C. After the reaction was completed, the reactant 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 in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1 v / v) to obtain 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.

[0848] 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)

[0849]

[0850] 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)Cl2 (162.9 mg, 0.23 mmol) and KOAc (655.8 mg, 6.80 mmol). The resulting mixture was stirred at 80°C under N2 for 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 in vacuo. The residue was purified by flash column chromatography with 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.

[0851] 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)

[0852]

[0853] 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 / H2O (20.0 / 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 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 in vacuo. The residue was purified by flash column chromatography with 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.

[0854] 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)

[0855]

[0856] 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), BrettPhosPd 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 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 in vacuo. The residue was purified by flash column chromatography with 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, 42%) as a red solid. LCMS (ESI): [M+H] + =476.2.

[0857] Step 5: Synthesis of N-[1-methyl-2-(4-methyl-1H-indazol-5-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 18)

[0858]

[0859] 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 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 in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then by preparative HPLC using the following conditions: column: YMC-Actus Triart C18, 30x150 mm, 5um; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 23% B to 53% B in 10 minutes; detector, UV 254 nm, 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. LCMS (ESI): [M+H] + =346.1. 1 H NMR (300MHz, DMSO-d6): δ13.22(s,1H),10.48(s,1H),8.61(s,1H),8.26-8.21(m,2H),7.49(d,J=8.4Hz, 1H), 7.30 (d, J = 8.7Hz, 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).

[0860] 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)

[0861]

[0862] Step 1: Synthesis of 5-bromo-4-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,3-benzodiazole (Compound 19b)

[0863]

[0864] At 0 ° C under N2, NaH (0.3 g, 60%) was added 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). The resulting mixture was stirred at 0 ° C for 1 hour. Then at 0 ° C under N2, SEM-Cl (1.2 g, 7.07 mmol) was added dropwise to the mixture. 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 with petroleum ether / ethyl acetate (2 / 1, v / v) to obtain 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.

[0865] 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)

[0866]

[0867] 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'-bis(1,3,2-dioxaborolane) (Compound 19c) (2.1 g, 8.34 mmol) in dioxane (10.0 mL) was added Pd(dppf)Cl2 (227.2 mg, 0.27 mmol) and KOAc (819.4 mg, 8.35 mmol) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction 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 flash column chromatography with 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) as a yellow oil. LCMS (ESI, m / z): [M+H] + =389.2.

[0868] 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)

[0869]

[0870] 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 / H2O (10.0 / 1.0 mL) was added Pd(dppf)Cl2 (70.0 mg, 0.08 mmol) and K2CO3 (354.0 mg, 2.51 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction 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 flash column chromatography with 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.

[0871] 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)

[0872]

[0873] 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) was added BrettPhosPd G3 (63.6 mg, 0.07 mmol), Cs2CO3 (686.7 mg, 2.10 mmol) and BrettPhos (75.4 mg, 0.14 mmol) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction 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 flash column chromatography with 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.

[0874] 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)

[0875]

[0876] 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 reactant 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: YMC-Actus Triart C18, 30x150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 19% B to 41% B in 7 minutes; 254 nm) to give 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 HNMR (300MHz, DMSO-d6): δ12.74-12.60(m,1H),10.49(s,1H),8.61(s,1H),8.32(s,1H),8.21(s,1H),7.51(b r,s,1H),7.17(d,J=8.1Hz,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).

[0877] Example S20: Synthesis of N-[1-methyl-2-(3-methylpyridin-2-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 20)

[0878]

[0879] Step 1: Synthesis of 3-methyl-2-(tributylstannyl)pyridine (Compound 20b)

[0880]

[0881] At -78 ° C under N2, n-BuLi (4.1 mL, 64.15 mmol) was added dropwise to a solution of 2-bromo-3-methylpyridine (compound 20a) (5.0 g, 29.06 mmol) in THF (125.0 mL). The resulting mixture was stirred at -78 ° C for 1 hour. Tributyltin chloride (11.3 g, 34.8 mmol) was then added dropwise to the mixture at -78 ° C. The resulting mixture was stirred for another 1 hour at -78 ° C. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to obtain 3-methyl-2-(tributylstannyl)pyridine (compound 20b) (300.0 mg, 3%) as a colorless oil. LCMS(ESI):[M+H] + =384.2.

[0882] Step 2: Synthesis of 2-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-3-methylpyridine (Compound 20d)

[0883]

[0884] 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). Under N2, the resulting mixture was irradiated with microwaves (MW) at 160°C for 15 minutes. 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 in vacuo. 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.

[0885] Step 3: Synthesis of N-[1-methyl-2-(3-methylpyridin-2-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 20)

[0886]

[0887] 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), Cs2CO3 (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 completion of the reaction, 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 in vacuo. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (94 / 6, v / v) and then by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30x250 mm, 5um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 18% B to 42% B in 8 minutes; 254 nm) to give 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 (300MHz, DMSO-d6): δ10.52(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=0.6Hz,1H),3.73(s,3H),2.35(s,3H),2.08-2.00(m,1H),0.85-0.78(m,4H).

[0888] Example S21: Synthesis of N-[1-methyl-2-(2-methylpyridin-3-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 21)

[0889]

[0890] Step 1: Synthesis of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methylpyridine (Compound 21b)

[0891]

[0892] 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) was added 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). The resulting 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 with 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.

[0893] Step 2: Synthesis of N-[1-methyl-2-(2-methylpyridin-3-yl)pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 21)

[0894]

[0895] 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 completion of the reaction, 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: YMC-Actus Triart C18, 30x250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 27% B to 38% B in 8 minutes; detector, UV 254 / 220 nm to obtain 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. LCMS (ESI): [M+H] + =307.2. 1 H NMR (300MHz, DMSO-d6): δ10.52(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).

[0896] Example S22: Synthesis of N-[2-(2-methoxypyridin-3-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 22)

[0897]

[0898] Step 1: Synthesis of 3-[5-chloro-1-methylpyrrolo[2,3-c]pyridin-2-yl]-2-methoxypyridine (Compound 22c)

[0899]

[0900] 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 / H2O (4.0 / 0.4 mL) was added Pd(dppf)Cl2 (83.7 mg, 0.10 mmol) and K2CO3 (425.2 mg, 3.07 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ° C for 12 hours. After completion of the reaction, 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 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.

[0901] Step 2: Synthesis of N-[2-(2-methoxypyridin-3-yl)-1-methylpyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide (Compound 22)

[0902]

[0903] 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) was added CsCO (357.1 mg, 1.10 mmol), BrettPhos (39.2 mg, 0.07 mmol) and BrettPhos Pd G (33.1 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, 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: YMC-Actus Triart C18, 30×250 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 37% B to 67% B in 7 minutes; 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 (300MHz, DMSO-d6): δ10.49(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=0.8Hz,1H),3.92(s,3H),3.64(s,3H),2.03-1.98(m,1H),0.84-0.78(m,4H).

[0904] 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)

[0905]

[0906] Step 1: Synthesis of 6-chloro-4-iodopyridin-3-amine hydrochloride (Compound 23b)

[0907]

[0908] 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.

[0909] Step 2: Synthesis of 5-chloro-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (Compound 23d)

[0910]

[0911] 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 N2. The resulting mixture was stirred at 100 ° C for 16 hours. After the reaction was completed, 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 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.

[0912] Step 3: Synthesis of 5-chloro-2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 23e)

[0913]

[0914] At 0 ° C under N2, NaH (371.1 mg, 60%) was added 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). The resulting mixture was stirred at 0 ° C under N2 for 1 hour. Then at 0 ° C under N2, CH3I (2.2 g, 15.5 mmol) was added dropwise to the mixture. The resulting mixture was stirred at 0 ° C for another 1 hour. After the reaction was completed, 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 to obtain 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.

[0915] Step 4: Synthesis of 2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-amine (Compound 23g)

[0916]

[0917] 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 benzhydrylamine (compound 23f) (1.6 g, 8.80 mmol), t-BuOK (987.5 mg, 8.80 mmol), XantPhos (339.5 mg, 0.59 mmol) and Pd2(dba)3 (268.6 mg, 0.29 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, 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 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.

[0918] Step 5: Synthesis of (cis)-methyl 2-((2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)carbamoyl)cyclopropane-1-carboxylate (Compound 23i)

[0919]

[0920] 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 N2. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, 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 flash column chromatography with petroleum ether / ethyl acetate (1 / 99, v / v) to give (cis)-methyl 2-((2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)carbamoyl)cyclopropane-1-carboxylate (Compound 23i) (190.0 mg, 53%) as a brown solid. LCMS (ESI, m / z): [M+H] + =380.2.

[0921] Step 6: Synthesis of cis-2-(hydroxymethyl)-N-(2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane-1-carboxamide (Compound 23)

[0922]

[0923] To a solution of methyl (cis)-2-((2-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)carbamoyl)cyclopropane-1-carboxylate (Compound 23i) (170.0 mg, 0.45 mmol) in THF / CH3OH (5.0 / 1.0 mL) was added NaBH4 (169.5 mg, 4.48 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: XBridgePrep OBD C18 column, 19×250 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: MeOH-preparative; flow rate: 25 mL / min; gradient: 54% B to 70% B in 7 minutes; 254 nm) to afford 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 (300MHz, DMSO-d6): δ10.40(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=8.1Hz,1H),7.13-7.08( m,1H),6.42(d,J=0.6Hz,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).

[0924] Example S24: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 24)

[0925]

[0926] Step 1: Synthesis of 5-chloro-2-(3-methoxy-2-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Compound 24c)

[0927]

[0928] 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 / H2O (36.0 / 3.6 mL) was added K2CO3 (708.7 mg, 5.12 mmol), 3-methoxy-2-methylphenylboronic acid (compound 24b) (425.5 mg, 2.56 mmol) and Pd(dppf)Cl2 (250.1 mg, 0.34 mmol) under N2. The resulting mixture was stirred at 80 ° C for 16 hours. After completion of the reaction, 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 in vacuo. 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.

[0929] Step 2: Synthesis of 3-(5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-2-methylphenol (Compound 24d)

[0930]

[0931] 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 CH2Cl2 (5.0 mL) was added BBr3 (1616.2 mg, 6.45 mmol) at 0°C under N2. The resulting mixture was stirred at 0°C for 2.5 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 in vacuo. The residue was purified by flash column chromatography with 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.

[0932] 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)

[0933]

[0934] 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) was added 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) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, 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 in vacuo. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate (80 / 20, v / v) and then by preparative HPLC using the following conditions (column: Xselect CSH OBD column 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 20% B to 38% B in 8 minutes; 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 HNMR (300MHz, DMSO-d6): δ10.46(s,1H),9.57(s,1H),8.53(s,1H),8.14(s,1H),7.11-7.03(m,1H),6.87(d,J=8.1Hz,1H),6.71(d, J=7.5Hz,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).

[0935] 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)

[0936]

[0937] Step 1: Synthesis of 5-chloro-2-(2-methoxy-6-methylphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 25c)

[0938]

[0939] 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 / H2O (8.0 mL / 2.0 mL) was added 2-methoxy-6-methylphenylboronic acid (compound 25b) (204.3 mg, 1.23 mmol), K2CO3 (425.3 mg, 3.08 mmol) and Pd(dppf)Cl2 (75.1 mg, 0.10 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ° C for 16 hours. After completion of the reaction, 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 in vacuo. The residue was purified by flash column 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.

[0940] 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)

[0941]

[0942] 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), Cs2CO3 (204.5 mg, 0.63 mmol) and BrettPhos Pd G3 (19.0 mg, 0.02 mmol) at room temperature under N2. The reaction mixture was stirred at 120 ° C. in a microwave for 1.5 hours. After completion of the reaction, 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 in vacuo. The residue was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 40% B to 70% B in 7 minutes; 254 nm) to give (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. 1 HNMR (400MHz, DMSO-d6): δ10.50(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).

[0943] 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)

[0944]

[0945] Step 1: Synthesis of 5-chloro-2-(5-fluoro-2-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 26c)

[0946]

[0947] 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 H0 (2.0 mL) was stirred at 100 ° C. under N for 16 hours. 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 in vacuo. 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.

[0948] 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)

[0949]

[0950] 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), Cs2CO3 (213.9 mg, 1.55 mmol), BrettPhos (55.4 mg, 0.10 mmol) and BrettPhos Pd G3 (46.8 mg, 0.05 mmol) in dioxane (5.0 mL) was irradiated with microwave irradiation at 100 ° C for 2 hours. After completion of the reaction, 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 in vacuo. The residue was purified by flash column chromatography using CH2Cl2 / CH3OH (94 / 6, v / v) and then by preparative HPLC using 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: from 25% B to 55% B in 10 minutes; 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 (300MHz, DMSO-d6): δ10.52(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).

[0951] 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)

[0952]

[0953] Step 1: Synthesis of 5-chloro-2-(2-fluoro-6-methoxyphenyl)-1-methylpyrrolo[2,3-c]pyridine (Compound 27c)

[0954]

[0955] 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 / H2O (5.0 / 1.0 mL) was added 2-fluoro-6-methoxyphenylboronic acid (compound 27b) (209.2 mg, 1.23 mmol), K2CO3 (425.3 mg, 3.08 mmol) and Pd(dppf)Cl2 (75.05 mg, 0.10 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ° C for 3 hours. After completion of the reaction, 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 flash column chromatography with 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.

[0956] 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)

[0957]

[0958] 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) was added (1S, 2S)-2-fluorocyclopropane-1-carboxamide (compound 27d) (265.9 mg, 2.58 mmol), Cs2CO3 (504.3 mg, 1.55 mmol), BrettPhos (55.4 mg, 0.10 mmol) and Brettphos Pd G3 (46.77 mg, 0.05 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ° C for 4 hours. After completion of the reaction, 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 flash column chromatography with petroleum ether / ethyl acetate (34 / 66, v / v) and then by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30×250 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 45% B to 63% B in 7 minutes; 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 (400MHz, DMSO-d6): δ10.54(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).

[0959] 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)

[0960]

[0961] Step 1: Synthesis of 5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (Compound 28b)

[0962]

[0963] 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 N2. The resulting mixture was stirred under N2 for 1 hour at 0°C. SEM-Cl (826.0 mg, 4.96 mmol) was then added dropwise to the mixture at 0°C under N2. The resulting mixture was stirred for another 1 hour at 0°C. After completion of the reaction, the reaction mixture was quenched with H2O 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 CH2Cl2 / MeOH (12 / 1, v / v) to give 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.

[0964] 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)

[0965]

[0966] 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'-bis(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 N2. The resulting mixture was stirred at 80°C for 16 hours. After completion of the reaction, 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 flash column chromatography with CH2Cl2 / 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.

[0967] 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...

Claims

1. A compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X is NR 3’ or CR 3 , Y is NR 2 or CR 4 , When X is NR 3’ When Y is CR 4 , Y has to CR 5 double bond, and X has to CR 5 single bond; or when X is CR 3 When Y is NR 2 , Y has to CR 5 single bond, and X has a 5 Double bonds; 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 to 8 membered heterocycloalkylene)-(C0-C2 alkylene)-NR 7 R 8 、C1-C2 alkylene-(4 to 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 moieties are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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 1-3 fluorine atoms and / or 1-6 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 1-3 fluorine atoms and / or 1-6 deuterium atoms; R 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is optionally substituted by 1-5 R 9 group substitution; 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; Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 3- to 8-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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, wherein n is an integer from 0 to 2; and Each R 10 independently -H, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl is optionally substituted with hydroxy, C1-C3 alkoxy and / or 1 to 6 deuterium atoms.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (IAi) or formula (IA-ii): in 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’ , where R 1 wherein the alkyl, alkylene, cycloalkylene and heterocycloalkylene are optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and wherein 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 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of: in indicates a single bond or a double bond, and wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-5 R 9 group substitution; Each R 7 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl; Each R 8 is independently -H, C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkyl-CN or C2-C3 heteroalkyl; Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N, O, and S, and wherein 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 , C1-C3 alkyl, -CF2H, -CF3, C3-C6 cycloalkyl or -CN, and Each R 10 It is 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 1-6 deuterium atoms.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Each R 1 are independently -F, C1-C3 alkylene-NR 7’ R 8’ or C1-C3 alkylene-OH; and where R 1 Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, they independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with -H or C1-C3 alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of: wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 Group substitution.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH3, -CD3 or -CH2CH3; R 3 is -H, -F, -CH3 or -CN; R 3’ is -H or -CH3; and R 4 is -H, -F or -CH3.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and Each R 10 independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (IAi) or formula (IA-ii): in m is an integer 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 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of: wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 group substitution; Each pair of R 7’ and R 8’ Together with the nitrogen atom to which they are attached, independently form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains 1-2 additional heteroatoms selected from the group consisting of N and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted with -H or C1-C3 alkyl; Each R 9 are independently -F, -Cl, -OR 10 , -CH3 or -CN, and Each R 10 independently -H, -CH3, -CD3 or -CH2CH3, wherein said -CH3 or said -CH2CH3 is optionally substituted with hydroxyl and / or -OCH3.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (IAi) or formula (IA-ii): in m is an integer 0 or 1; R 1 is -F; R 2 is -CH3; R 3 is -H or -CH3; R 3’ is -H or -CH3; R 4 is -CH3; R 5 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is selected from the group consisting of: wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-3 R 9 group substitution; Each R 9 independently -F or -OR 10 ,and Each R 10 is independently -H, -CH3 or -CD3.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Each R 9 are independently -F, -OR 10 or -CH3, and Each R 10 is independently -H, -CH3, -CD3, -CF2H or -CF3.

10. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia in a human in need thereof.

12. The use according to claim 11, wherein the leukemia is refractory leukemia.

13. The use of claim 12, wherein the human suffering from refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene that result 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.

14. The use according to claim 13, wherein the human suffering from refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

15. The use of claim 11, further comprising administering one or more pharmaceutical agents.

16. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound according to claim 16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

18. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

19. Use of a compound according to claim 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia in a human in need thereof.

20. The use according to claim 19, wherein the leukemia is refractory leukemia.

21. The use of claim 20, wherein the human suffering from refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene that result 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.

22. The use of claim 21, wherein the human suffering from refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

23. The use of claim 19, further comprising administering one or more pharmaceutical agents.

24. A pharmaceutical composition comprising the compound of claim 18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

25. Use of a compound according to claim 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia in a human in need thereof.

26. The use according to claim 25, wherein the leukemia is refractory leukemia.

27. The use of claim 26, wherein the human suffering from refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene that result 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.

28. The use of claim 27, wherein the human suffering from refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

29. The use of claim 25, further comprising administering one or more pharmaceutical agents.

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is -H or -CH3; R 3 is -H; R 3’ is -H; and R 4 It is -H or -CH3.

31. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

32. Use of a compound according to claim 31 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia in a human in need thereof.

33. The use according to claim 32, wherein the leukemia is refractory leukemia.

34. The use of claim 33, wherein the human suffering from refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene that result 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.

35. The use of claim 34, wherein the human suffering from refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

36. The use of claim 32, further comprising administering one or more pharmaceutical agents.

37. A pharmaceutical composition comprising the compound of claim 31, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

38. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

39. Use of a compound according to claim 38, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed phenotype acute leukemia in a human in need thereof.

40. The use according to claim 39, wherein the leukemia is refractory leukemia.

41. The use of claim 40, wherein the human suffering from refractory leukemia has one or more mutations in the Bcr-Abl tyrosine kinase gene that result 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.

42. The use of claim 41, wherein the human suffering from refractory leukemia has a mutation in the Bcr-Abl tyrosine kinase gene that results in a specific amino acid substitution, T315I.

43. The use of claim 39, further comprising administering one or more pharmaceutical agents.

44. A pharmaceutical composition comprising the compound of claim 38, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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