5- and 6-azaindole compounds for inhibition of BCR-ABL tyrosine kinases for use in the treatment of cancer

Abstract

The present disclosure relates to compounds and compositions for inhibition of Bcr-Abl tyrosine kinases, methods of preparing said compounds and compositions, and their use in the treatment of various cancers, such as chronic myeloid leukemia (CML).

Description

5- AND 6-AZAINDOLE COMPOUNDS FOR INHIBITION OF BCR-ABL TYROSINE KINASES CROSS REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims priority benefit to U.S. Provisional Application No. 63 / 708,221, filed October 16, 2024, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes. FIELD OF THE INVENTION

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

[0003] The cytogenetic abnormality known as the Philadelphia chromosome is highly associated with the occurrence of a number of hematological malignancies, including a majority of chronic myeloid leukemias (CML) and a subset of acute lymphoblastic leukemias (Ph+ ALL). The Philadelphia chromosome is a product of a translocation between the breakpoint cluster region (BCR) gene on chromosome 22 and the Abelson (ABL) tyrosine kinase gene on chromosome 9, resulting in the oncogenic fusion gene product Bcr-Abl. The resultant fusion protein is both overexpressed and harbors constitutive kinase activity that then drives the activation of a number of intracellular signaling cascades to induce the uncontrolled cell growth, division and survival associated with oncogenic transformation. Accordingly, therapeutic intervention employing inhibitors of the Bcr-Abl tyrosine kinase represents a cornerstone of the current treatment paradigm for patients with Philadelphia- positive neoplastic disorders.

[0004] Imatinib (STI-571), a small molecule Bcr-Abl tyrosine kinase inhibitor (Bcr-Abl TKI), was developed as a highly effective treatment for CML in the early 1990s and is still employed today as a first line treatment for CML. However, in more aggressive cases of CML, patients often relapse due to the emergence of resistance. The primary mechanism of this resistance derives from a variety of on-target genetic alterations that drives either aberrant overexpression of the Bcr-Abl fusion or, more commonly, introduce amino acid mutations within the Abl kinase domain that reduce imatinib’s binding affinity for the activesite thereby markedly reducing its inhibitory activity. These alterations can either appear stochastically and represent a sub-population within the initial tumor cell population or arise under the selective pressure of inhibitor treatment. One of the predominant on-target Bcr-Abl resistance mutations derives from point mutations that introduce an isoleucine residue for a threonine at position 315 within the Abl kinase domain (T315I) also known as the ‘gatekeeper’ position. In addition to imatinib, this mutant form of BCR-Abl is profoundly resistant to all second generation Bcr-Abl TKIs (Nilotinib, Dasatinib, Bosutinib, Radotinib). Currently, there exists only one therapeutic option for patients harboring a T315I mutation— the third line Bcr-Abl TKI, Ponatinib. While effective at treating patients with T315I CML, ponatinib suffers from poor selectivity for Bcr-Abl versus a number of other protein kinases. Accordingly, ponatinib has been reported to elicit significant dose-limiting toxicities, which then limits its ability to effectively engage the target to achieve clinical efficacy.

[0005] Besides on- or off-target resistance, intolerance to Bcr-Abl TKIs also represents a major clinical challenge. The doses of more than 50% of Ph+ leukemia patients require modification due to adverse events. In fact, approximately 30% of patients are compelled to dose reduce within the first 6 months of treatment. These drug-related side effects appear early in the course of treatment and, while manageable in most cases, toxicities persist, significantly impacting the patients’quality of life, resulting in decreased compliance. Accordingly, around 40% of patients discontinue first and second generation Bcr-Abl TKIs within the first 5 years of treatment. All of the currently approved Bcr-Abl targeted therapies inhibit other tyrosine kinases, which can lead to potentially debilitating side effects. Specifically, potent inhibition of VEGFRs, PDGFRs, c-Kit and / or the c-Src family can lead to dose-limiting side effects in patients. To address these adverse effects, dose reductions, dose interruptions, and even dose discontinuations are often required during the course of therapy, however such treatment regimens ultimately result in suboptimal therapeutic benefit.

[0006] Accordingly, there remains a substantial unmet medical need for Bcr-Abl TKIs with improved selectivity to improve tolerability and enhanced potency against the wide array of resistance mechanisms in Philadelphia-positive disorders. SUMMARY OF THE INVENTION

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

[0008] In one aspect, provided herein is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient. In some embodiments, the method comprises administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the patient has a leukemia cell that has a Bcr-Abl tyrosine kinase gene and (i) the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L or any combination of these amino acid substitutions or (ii) the leukemia cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2), or both (i) and (ii),wherein formula (I) is:wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a doubleR1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)- NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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- C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is - H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1- 3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl,halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)- NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1- C6alkylene-CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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- C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, - CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms.

[0009] In some embodiments, the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T amino acid substitution.

[0010] In some embodiments, the method further comprises detecting one or more mutations in the Bcr-Abl tyrosine kinase gene. In some embodiments, detecting one or more mutations in the Bcr-Abl tyrosine kinase gene occurs before administering to the patient the compound of formula (I) or the pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises selecting the patient for treatment based on the presenece of one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions.

[0011] In some embodiments, the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors. In some embodiments, the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, bosutinib, or azacitidine, or any combination thereof. In some embodiments, the patient was previously treated with asciminib.

[0012] In some embodiments, the patient has undergone a prior allogeneic myeloablative stem cell transplant or has received a donor lymphocyte infusion. In some embodiments, the leukemia cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2). In some embodiments, the leukemia cell expresses e13a3, e19a2, e1a3, e1a2, e6a2, e8a2, e15a2, or e14a3 (b3a3) transcript, or any combination thereof. In some embodiments, the Bcr-Abl tyrosine kinase gene does not have any mutation, or has one or more mutations resulting in T315I or S348L, or both of these amino acid substitutions.

[0013] In some embodiments, the method further comprises detecting Bcr-Abl fusion transcript expressed by the leukemia cell. In some embodiments, detecting Bcr-Abl fusion transcript expressed by the leukemia cell occurs before administering to the patient the compound of formula (I) or the pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises selecting the patient for treatment based on the presenece of a Bcr-Abl fusion transcript expressed by the leukemia cell that is other than e13a2 (b2a2) or e14a2 (b3a2).

[0014] In one aspect, provided is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound offormula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting.

[0015] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 2 hours after the patient ate food. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 1 hour before the patient eats food. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient daily.

[0016] In one aspect, provided is a method of inhibiting Bcr-Abl enzymatic activity in a cell. In some embodiments, the method comprises exposing the cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cell has a Bcr-Abl tyrosine kinase gene and (i) the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions, or (ii) the cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2), or both (i) and (ii), wherein formula (I) is:wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a doubleR1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1- C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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- C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is - H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1- 3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)- NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1- C6alkylene-CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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- C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, - CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms.

[0017] In some embodiments, the compound of formula (I) is a compound of formula (I-some embodiments, the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):herein m is an integer 0 or 2; each R1is independently -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl; R2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy and / or 1-6 deuterium atoms.

[0018] In some embodiments, each R1is independently -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; and wherein each pair of R7’and R8’of R1taken 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 by -H or C1-C3alkyl.bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups.

[0020] In some embodiments, R2is -CH3, -CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or -CH3; and R4is -H, -F or -CH3. In some embodiments, each R9is independently - F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3.

[0021] In some embodiments, the compound of formula (I) is a compound of formula (I- A-i) or formula (I-A-ii)or double bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups; each pair of R7’and R8’taken 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 by -H or C1-C3alkyl; each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3.

[0022] In some embodiments, the compound of formula (I) is a compound of formula (I- A-i) or formula (I-A-ii)heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting, wherein said 5-to-10-membered heteroaryl is optionallysubstituted with 1-3 R9groups; each R9is independently -F or -OR10, and each R10is independently -H or -CH3.

[0023] In some embodiments, the compound of formula (I) is a compound of formula (I-

[0024] In some embodiments, the compound of formula (I) is a compound of formula (I- B-i) or formula (I-B-ii)-ii), wherein R2is -H, -CH3, CD3, -CHF2, or - CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3- cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the,H N and , wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy.

[0025] In some embodiments, R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; and wherein each pair of R7’and R8’of R6taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl.

[0026] In some embodiments, R5is phenyl or, each of which is optionally substituted with 1-3 R9groups. In some embodiments, each R9is independently -F, -OR10, or -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3. In some embodiments, R2is -H or -CH3; R3is -H; R3’is -H; and R4is -H or -CH3.

[0027] In some embodiments, the compound of formula (I) is a compound of formula (I- B-i) or formula (I-B-ii)-ii), wherein R2is -H or -CH3; R3is -H; R3’is-H; R4is -H or -CH3; R5is phenyl or, each of which is optionally substituted with 1-3 R9groups; R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently -F, -OR10, or -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or - CF3.

[0028] In some embodiments, the compound is selected from the group consisting of the compounds of Table 1. In some embodiments, the compound is. DESCRIPTION OF THE FIGURES

[0029] The present application can be understood by reference to the following description taken in conjunction with the accompanying figure.

[0030] FIG. 1 depicts plasma concentration of Compound 95 in healthy volunteers over time after administration of 120 mg single dose at time zero, under fasted and fed conditions.

[0031] FIG. 2 depicts fold shift in potency compared to wild type BCR::ABL1.

[0032] FIG. 3 depicts IC50values in nM + / - standard error of the mean (SEM). DETAILED DESCRIPTION

[0033] The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0034] In one aspect, provided herein is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein (i) the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T, F359C, or P465S, or any combination of these amino acid substitutions; and / or (ii) the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting.

[0035] In one aspect, provided herein is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the patient has a leukemia cell that has a Bcr-Abl tyrosine kinase gene and (i) the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L or any combination of these amino acid substitutions or (ii) the leukemia cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2), or both (i) and (ii).

[0036] In one aspect, provided herein is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting.

[0037] In one aspect, provided is a method of inhibiting Bcr-Abl enzymatic activity in a cell, the method comprising exposing the cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cell has one or moremutations in the Bcr-Abl tyrosine kinase gene resulting in A337T, F359C, or P465S, or any combination of these amino acid substitutions.

[0038] In one aspect, provided is a method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cell has a Bcr-Abl tyrosine kinase gene and (i) the Bcr-Abl tyrosine kinase gene has one or more mutations iresulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions or (ii) the cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2), or both (i) and (ii). I. Definitions

[0039] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0040] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.;and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0041] The terms “individual”, “subject” and “patient” refer to mammals and includes 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, cows, and humans. In some embodiments, patient refers to a human.

[0042] 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.

[0043] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration.

[0044] As used herein, the term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (e.g., C1-C6means one to six carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term “alkyl” may encompass C1-C6alkyl, C2-C6alkyl, C3-C6alkyl, C4-C6alkyl, C5-C6alkyl, C1- C5alkyl, C2-C5alkyl, C3-C5alkyl, C4-C5alkyl, C1-C4alkyl, C2-C4alkyl, C3-C4alkyl, C1-C3alkyl, C2-C3alkyl, or C1-C2alkyl.

[0045] The term “cycloalkyl,” “carbocyclic,” or “carbocycle” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6cycloalkyl 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 meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C5-12alkane, etc. In some embodiments, “cycloalkyl” encompasses C3-C7cycloalkyl, C4-C7cycloalkyl, C5-C7cycloalkyl, C5-C7cycloalkyl, C3-C6cycloalkyl, C4-C6cycloalkyl, C5-C6cycloalkyl, C3-C5cycloalkyl, C4-C5cycloalkyl, or C3-C4cycloalkyl. In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) isa cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.

[0046] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. A “heteroalkyl” can contain up to three units of unsaturation, and also include mono- and poly-halogenated 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, - -O-CH3, -Si(CH3)3, -CH2- -OCH3, and - 3)-CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3.

[0047] The term “heterocycloalkyl,” “heterocyclic,” or “heterocycle” refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms. Unless otherwise stated, a “heterocycloalkyl,” “heterocyclic,” or “heterocycle” ring can be a monocyclic, a bicyclic, bridged or fused ring system, spirocyclic or a polycylic ring system. Non-limiting examples of “heterocycloalkyl,” “heterocyclic,” or “heterocycle” 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, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycloalkyl,” “heterocyclic,” or “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkyl” encompasses 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-memberedheterocycloalkyl, 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” may be characterized by the number of carbon atoms in the ring, provided that the ring contains at least one heteroatom. For example, in some embodiments, “heterocycloalkyl” encompasses C3-C9heterocycloalkyl, C3-C8heterocycloalkyl, C3-C7heterocycloalkyl, C3-C6heterocycloalkyl, C3-C5heterocycloalkyl, C3-C4heterocycloalkyl, C4-C9heterocycloalkyl, C4-C8heterocycloalkyl, C4- C7heterocycloalkyl, C4-C6heterocycloalkyl, C4-C5heterocycloalkyl, C5-C9heterocycloalkyl, C5-C8heterocycloalkyl, C5-C7heterocycloalkyl, C5-C6heterocycloalkyl, C6-C9heterocycloalkyl, C6-C8heterocycloalkyl, C6-C7heterocycloalkyl, C7-C9heterocycloalkyl, C7- C8heterocycloalkyl, orC8-C9heterocycloalkyl. It should be recognized that “heterocycloalkyl” as described by the number of ring atoms may also be described by number of carbon atoms in the ring. For example, a piperazinyl ring may be described as a C4heterocycloalkyl ring or a 6-membered heterocycloalkyl ring; an azetidinyl or oxetanyl ring may each be described as a C3heterocycloalkyl ring or a 4-membered heterocycloalkyl ring.

[0048] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group will have 10 or fewer carbon atoms.

[0049] The term “heteroalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, asexemplified by -CH2-CH2-S-CH2CH2-, -CH2-S-CH2-CH2-NH-CH2-, -O-CH2- -, -CH2- 2-O-CH2- and -S-CH2- -. For heteroalkylene groups, heteroatoms canalso occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0050] The term “heterocycloalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heterocycloalkyl. For heterocycloalkylene groups, heteroatoms can also occupy either or both of the chain termini.

[0051] The terms “alkoxy” and “alkylamino” are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively.

[0052] The term “heterocycloalkoxy” refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein.

[0053] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-C4haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0054] The term “haloalkyl-OH” refers to a haloalkyl group as described above which is also substituted by one or more hydroxyl groups. The term “haloalkyl-OH” is meant to include haloalkyl substituted by one hydroxyl group, as well as haloalkyl substituted by multiple hydroxyl groups. For example, the term “haloalkyl-OH” includes -CH(F)OH, - CH2CFHCH2OH, -CH(OH)CF3, and the like.

[0055] The term “alkyl-OH” refers to an alkyl substituted by one or more hydroxyl groups. The term “alkyl-OH” is meant to include alkyl substituted by one hydroxyl group, as well as alkyl substituted by multiple hydroxyl groups. For example, the term “alkyl-OH” includes -CH2OH, -CH(OH)CH3, -CH2CH2OH, -C(CH3)2OH, and the like.

[0056] The term “alkyl-CN” refers to an alkyl substituted by one or more cyano groups. The term “alkyl-CN” is meant to include alkyl substituted by one cyano group, as well as alkyl substituted by multiple cyano groups. For example, the term “alkyl-CN” includes -CH2CN, -CH2CH2CN, -CH(CN)CH3, and the like.

[0057] The term “aryl” means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together. In some embodiments, “aryl” encompasses C6-C14aryl, C8-C14aryl, C10-C14aryl, C12-C14aryl, C6-C12aryl, C8-C12aryl, C10-C12aryl, C6-C10aryl, C8-C10aryl, or C6-C8aryl. In some embodiments, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other embodiments, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, in some embodiments, a 1,2,3,4- tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, in some embodiments, a 1,2,3,4-tetrahydroquinolin-8-yl group (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 group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered 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., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some embodiments, aryl is phenyl or naphthyl. In certain embodiments, aryl is phenyl.

[0058] The term “heteroaryl” refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom as valency permits. In some embodiments, both rings of a polycyclic heteroaryl group are aromatic. In other embodiments, polycyclic heteroaryl groups may include a non- aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, in some embodiments, a 4,5,6,7- tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, 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 group.

[0059] Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the term “heteroaryl” encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl.

[0060] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted groupor moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0061] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0062] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0063] As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0064] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0065] As used herein, a wavy line “ ” that intersects a bond in a chemical structureindicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.

[0066] As used herein, the representation of a group (e.g., Xa) in parenthesis followed by a subscript integer range (e.g., (Xa)0-1) means that the group can have the number of occurrences as designated by the integer range. For example, (Xa)0-1means the group Xacan be absent or can occur one time.

[0067] “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0068] “Enantiomers” refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

[0069] Stereochemical definitions and conventions used herein generally follow 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 can contain asymmetric 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 the present disclosure. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). - A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0070] As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0071] As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure.

[0072] The term “co-crystal” as used herein refers to a solid that is a crystalline single phase material composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. A co-crystal consists of two or more components that form a unique crystalline structure having unique properties. Co- crystals are typically characterized by a crystalline structure, which is generally held together by freely reversible, non-covalent interactions. As used herein, a co-crystal refers to a compound of the present disclosure and at least one other component in a defined stoichiometric ratio that form a crystalline structure.

[0073] As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006.

[0074] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, 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 and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines,naturally- -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0075] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0076] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0077] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as2H (“D”),3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I and125I. Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with3H or14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0078] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resultingfrom the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0079] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease.

[0080] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0081] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0082] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groupslisted in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. II. Compounds

[0083] In one aspect, provided herein is a compound of formula (I),or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a double bond to CR5; R0is a groupm is an integer from 0 to 3; each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8- membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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- C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1- C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8- membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)- NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene- CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene- CN, or C1-C6heteroalkyl;each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms.

[0084] In one aspect, provided herein is a compound of formula (I)or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a double bond to CR5;R0is a groupm is an integer from 0 to 3; each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl; R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1- C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl;each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene- CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene- CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms.

[0085] In some embodiments of the present aspect, R0is. In someembodiments wherein R0is, m is an integer 0, 1, 2 or 3. In some embodiments, m is 0. In other embodiments, m is 1. In yet other embodiments, m is 2. In stillyet other embodiments, m is 3. In other embodiments of the present aspect, R0 is.

[0086] In some embodiments, the compound of formula (I) is a compound of formula (I- A) or formula (I-B):

[0087] In some embodiments, each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl.

[0088] In some embodiments, each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, each R1is independently -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl. In some embodiments, each R1is independently -D, -F, C1-C3alkyl. In some embodiments, each R1is independently C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, or C1-C3alkylene-CN. In some embodiments, each R1is independently C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C2alkylene- (C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’. In some embodiments, each R1is independently C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’.In some embodiments, each R1is independently C1-C3alkylene-OH, C1-C3alkylene-CN, or C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH. In some embodiments, each R1is independently -F, C1- C3alkylene-NR7’R8’, or C1-C3alkylene-OH, wherein each pair of R7’and R8’of R1taken together with the nitrogen atom to which they are attached independently form 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, each R1is independently -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH, wherein each pair of R7’and R8’of R1taken 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 by H or C1-C3alkyl. In some embodiments, each R1is independently -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH. In certain embodiments, each R1is –F. In some embodiments, each R1is independently C1-C3alkylene-NR7’R8’. In certain embodiments, each R1is independently optionally substituted –C1-C2alkylene-N- morpholinyl or optionally substituted –C1-C2alkylene-N-piperazinyl. In some embodiments, each R1is independently optionally substituted, optionally substituted, optionally substituted, optionally substituted,optionally substituted, or optionally substituted. embodiments, each R1is independently optionally substituted, optionally. so e e o e s, eac s epe e y ,. In certain embodiments, each R1is independently,. In certain other embodiments, each R1is independently,In still other embodiments, each R1 is independentlyembodiments, each R1is independently C1-C3alkylene-OH. In certain other embodiments, each R1is independently –C1-C2alkylene-OH. In certain embodiments, each R1is independently -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, or -CH(CN)CH2CH3. In certain other embodiments, each R1is independently -CH2OH or- CH2CH2OH.

[0089] In some embodiments of the present aspect, X is CR3and Y is NR2. In some embodiments wherein X is CR3and Y is NR2,R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms, and R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or –CN.

[0090] In some embodiments, R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R2is –H or C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R2is –H or C3-C6cycloalkyl. In some embodiments, R2is C1-C3alkyl or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R2is -H. In some embodiments, R2is C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In certain embodiments, R2is –CH3, -CH2CH3, -CH2CH2CH3, or - CH(CH3)2, wherein said –CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2 is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms.In some embodiments, R2is C3-C6cycloalkyl. In certain embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0091] In some embodiments, R2is -H, -CH3, -CD3, -CHF2, or -CH2CH3. In some embodiments, R2is -CH3, -CD3, -CHF2, or -CH2CH3. In some embodiments, R2is -H, -CD3, - CHF2, or -CH2CH3. In some embodiments, R2is -H, -CH3, -CHF2, or -CH2CH3. In some embodiments, R2is -H, -CH3, -CD3, or -CH2CH3. In some embodiments, R2is -H, -CH3, - CD3, or -CHF2. In some embodiments, R2is -CH3, -CD3, or -CHF2. In some embodiments, R2is -CH3or -CH2CH3. In some embodiments, R2is –H or –CH3.

[0092] In some embodiments, R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or –CN. In some embodiments, R3is -H, C1-C3alkyl, C3-C6cycloalkyl, or halogen. In some embodiments, R3is -H, C1-C3alkyl, C3-C6cycloalkyl, or –CN. In some embodiments, R3is - H, C1-C3alkyl, halogen, or –CN. In some embodiments, R3is -H, C3-C6cycloalkyl, halogen, or –CN. In some embodiments, R3is C1-C3alkyl, C3-C6cycloalkyl, halogen, or –CN. In some embodiments, R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or –CN. In some embodiments, R3is -H, -F, -CH3, or –CN. In some embodiments, R3is -H, -F, or -CH3. In some embodiments, R3is -H, -F, or –CN. In some embodiments, R3is -H, -CH3, or –CN. In some embodiments, R3is -F, -CH3, or –CN. In some embodiments, R3is -H or -F. In some embodiments, R3is –H or -CH3. In some embodiments, R3is -H or –CN. In some embodiments, R3is –F or -CH3. In some embodiments, R3is -F or –CN. In some embodiments, R3is -CH3or –CN. In some embodiments, R3is –H. In some embodiments, R3is –F. In some embodiments, R3is -CH3. In some embodiments, R3is –CN.

[0093] In some embodiments, R2is -CH3, -CD3, or -CH2CH3, and R3is -H, -F, -CH3, or – CN. In some embodiments, R2is -CH3, Cand R3is -H, -F, -CH3, or –CN. In some embodiments, R2is -CD3, and R3is -H, -F, -CH3, or –CN. In some embodiments, R2is - CH2CH3, and R3is -H, -F, -CH3, or –CN. In some embodiments, R2is -CH3, -CD3, or - CH2CH3, and R3is -H. In some embodiments, R2is -CH3, -CD3, or -CH2CH3, and R3is -F. In some embodiments, R2is -CH3, -CD3, or -CH2CH3, and R3is -CH3. In some embodiments, R2 is -CH3, -CD3, or -CH2CH3, and R3is –CN. In some embodiments, R2is -CH3, -CD3, or - CH2CH3, and R3is -H, -F, -CH3, or –CN. In some embodiments, R2is -CH3, and R3is -H or - CH3. In some embodiments, R2is -CH3, and R3is -H. In some embodiments, R2is -CH3, and R3is -CH3. In some embodiments, R2is -H or -CH3,and R3is –H. In some embodiments, R2is -H,and R3is –H. In some embodiments, R2is -CH3,and R3is –H.

[0094] In other embodiments of the present aspect, X is NR3’and Y is CR4. In some embodiments wherein X is NR3’and Y is CR4, R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or – CN, and R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms.

[0095] In some embodiments, R3’ is -H, C1-C3alkyl, or C3-cycloalkyl. In some embodiments, R3’ is -H, C1-C3alkyl, or –CN. In some embodiments, R3’ is -H, C3- cycloalkyl, or –CN. In some embodiments, R3’ is C1-C3alkyl, C3-cycloalkyl, or –CN. In some embodiments, R3’ is -H or C1-C3alkyl. In certain embodiments, R3’is –H or -CH3. Insome embodiments, R3’ is -H or C3-cycloalkyl. In some embodiments, R3’ is -H or –CN. In some embodiments, R3’ is C1-C3alkyl or C3-cycloalkyl. In some embodiments, R3’ is C1-C3alkyl or –CN. In some embodiments, R3’ is C3-cycloalkyl, or –CN. In some embodiments, R3’ is –H. In some embodiments, R3’ is C1-C3alkyl. In certain embodiments, R3’ is –CH3, - CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In certain embodiments, R3’is -CH3. In some embodiments, R3’ is C3-cycloalkyl. In some embodiments, R3’ is–CN.

[0096] In some embodiments, R4is -H or C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R4is -H, or halogen. In some embodiments, R4is C1-C3alkyl or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R4is -H. In some embodiments, R4is C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In some embodiments, R4is –CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2, wherein said –CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2 is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms. In certain embodiments, R4is CH3. In some embodiments, R4is halogen. In certain embodiments, R4is –F, -Cl, or –Br. In certain other embodiments, R4is – F. In some embodiments, R4is -H, -F or -CH3. In some embodiments, R4is -H, -CH3, -CD3, - CHF2, -CH2CH3, or halogen. In some embodiments, R4is -H, -CH3, -CD3, -CHF2, or -CH2CH3. In some embodiments, R4is -H, -CH3, -CD3, -CHF2, or halogen. In some embodiments, R4is - H, -CH3, -CD3, -CH2CH3, or halogen. In some embodiments, R4is -H, -CH3, -CHF2, - CH2CH3, or halogen. In some embodiments, R4is -H, -CD3, -CHF2, -CH2CH3, or halogen. In some embodiments, R4is -CH3, -CD3, -CHF2, -CH2CH3, or halogen. In some embodiments, R4is -H or halogen. In some embodiments, R4is -CH3or -CH2CH3. In some embodiments, R4is -CH3, -CD3, or -CHF2.

[0097] In some embodiments, R3’is –H or -CH3, and R4is -H, -F or -CH3. In some embodiments, R3’is –H, and R4is -H, -F or -CH3. In some embodiments, R3’is -CH3, and R4is -H, -F or -CH3. In some embodiments, R3’is –H or -CH3, and R4is -H. In some embodiments, R3’is –H or -CH3, and R4is -F. In some embodiments, R3’is –H or -CH3, and R4is -CH3. In certain embodiments, R3’is –H, and R4is -H. In certain embodiments, R3’is –H, and R4is -F. In certain embodiments, R3’is –H, and R4is -CH3. In certain embodiments, R3’is -CH3, and R4is -H. In certain embodiments, R3’is -CH3, and R4is -F. In certain other embodiments, R3’is - CH3, and R4is -CH3.

[0098] In some embodiments, R5is C6-C14aryl or 5- to 10-membered heteroaryl, wherein said C6-C14aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups. In some embodiments, R5is a C6-C14aryl, wherein said C6-C14aryl is optionally substituted with 1-5 R9groups. In some embodiments, R5is phenyl, wherein said phenyl is optionally substituted with 1-5 R9groups. In some embodiments, R5is 5- to 10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups. In some embodiments, R5is a 5-to-10-membered heteroaryl selected from the group consisting of:said C6-C14aryl or said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups. In some embodiments, R5is a 5-to-10-membered heteroaryl selected from the group, wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups. In some embodiments, R5is a 5-to-10-membered heteroaryl selected from the group consisting of:, wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups. In some embodiments, R5is a 5-to-10-membered heteroaryl selected from the group consisting of:, wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups. In some embodiments, R5is a 5-to-10-membered heteroarylselected from the group consisting of:, wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups.

[0099] In some embodiments, R5is a 5-to-10-membered heteroaryl selected from the group consisting of:said 5-to-10-membered heteroaryl is optionally substituted with 1-5 R9groups. In some embodiments, R5is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to-10-memberedbond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups. In some embodiments, R5is phenyl or 5-to-10-membered heteroaryl,wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups.

[0100] In some embodiments, R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene- NR7R8, C1-C6alkylene-NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene- (4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl.

[0101] In some embodiments, R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene- NR7R8, C1-C6alkylene-NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3- C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl.

[0102] In some embodiments, R6is C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene- (4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8,or C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, R6is C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene- (C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0- C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1- C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1-C6alkylene-OH, or C1-C6alkylene-CN. In some embodiments, R6is C1-C6alkyl, C3-C6cycloalkyl, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene- (C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0- C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’.In some embodiments, R6is C1-C6alkyl, C3-C6cycloalkyl, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’.In some embodiments, R6is C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1-C6alkylene- OH, or C1-C6alkylene-CN. In some embodiments, R6is C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(4- to 8-memberedheterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C7heterocycloalkylene)- (C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)- NR7’R8’.In some embodiments, R6is C1-C6alkylene-NR7R8, C1-C6alkylene-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’.In other embodiments, R6is C1-C6alkylene-OH or C1-C6alkylene-CN. In some embodiments, R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’. In certain embodiments, R6is C1-C3alkyl or C1- C3alkylene-NR7’R8’, wherein each pair of R7’and R8’of R6taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In certain other embodiments, R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’, wherein each pair of R7’and R8’of R6taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, R6is C1-C3alkyl. In certain embodiments, R6is –CH3, -CH2CH3, -CH2CH2CH3, or - CH(CH3)2. In certain other embodiments, R6is -CH2CH3. In some embodiments, R6is C1-C3alkylene-NR7’R8’. In certain embodiments, each R6is independently optionally substituted – C1-C2alkylene-N-morpholinyl or optionally substituted –C1-C2alkylene-N-piperazinyl. In some embodiments, each R6is independently optionally substituted, optionallysubstituted, optionally substituted, optionally substituted, optionally substituted, or optionally substituted. In certain embodiments, each R6is independently optionally substituted, optionally substituted, optionally substituted,or optionally substituted. In some embodiments, each R6is independently

[0103] In some embodiments, each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl. In some embodiments, each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl. In some embodiments, each R7is independently –H. In some embodiments, each R7is independently C1-C3alkyl. In certain embodiments, each R7is independently –CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.In some embodiments, each R7is independently C3-C6cycloalkyl. In certain embodiments, R7is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, each R7is independently C2-C3haloalkyl.In certain embodiment, each R7is independently C2-C3haloalkyl, wherein the each halogen atom of each C2-C3haloalkyl is independently –F, -Cl, or –Br. In some embodiments, each R7is independently C2-C3alkylene-CN. In certain embodiments, each R7is independently - CH2CH2CN, -CH(CN)CH3, -CH2CH2CH2CN, -CH2CH(CN)CH3, -CH(CN)CH2CH3, or - CH(CH2CN)CH3. In some embodiments, each R7is independently C2-C3heteroalkyl. In certain embodiments, each R7is 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)CH2CH3, -CH2NHCH3, - CH2NHCH2CH3,-CH2CH2NHCH3, -CH(NHCH3)CH3, -CH(CH2NH2CH3, -CH2CH2SH, - CH(SH)CH3, -CH2CH2CH2SH, -CH2CH(SH)CH3, or -CH(SH)CH2CH3,-CH2SCH3, - CH2SCH2CH3, -CH2CH2SCH3, -CH(SCH3)CH3, or -CH(CH2SH)CH3.

[0104] In some embodiments, each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl. In some embodiments, each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl. In some embodiments, each R8is independently –H. In some embodiments, each R8is independently C1-C3alkyl. In certain embodiments, each R8is independently –CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3) .In some embodiments, each R8 2 is independently C3-C6cycloalkyl. In certain embodiments, R8is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, each R8is independently C2-C3haloalkyl. In certain embodiment, each R8is independently C2-C3haloalkyl, wherein the each halogen atom of each C2-C3haloalkyl is independently –F, -Cl, or –Br. In some embodiments, each R8is independently C2-C3alkylene-CN. In certain embodiments, each R8is independently - CH2CH2CN, -CH(CN)CH3, -CH2CH2CH2CN, -CH2CH(CN)CH3, -CH(CN)CH2CH3, or - CH(CH2CN)CH3. In some embodiments, each R8is independently C2-C3heteroalkyl. In certain embodiments, each R8is 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)CH2CH3, -CH2NHCH3, - CH2NHCH2CH3,-CH2CH2NHCH3, -CH(NHCH3)CH3, -CH(CH2NH2CH3, -CH2CH2SH, - CH(SH)CH3, -CH2CH2CH2SH, -CH2CH(SH)CH3, or -CH(SH)CH2CH3, -CH2SCH3, - CH2SCH2CH3, -CH2CH2SCH3, -CH(SCH3)CH3, or -CH(CH2SH)CH3.

[0105] In some embodiments, each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, each pair of R7’and R8’of R1taken together with the nitrogen atom to which they are attached 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 by -H or C1-C3alkyl. In some embodiments, each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl. In some embodiments, each pair of R7’and R8’of R1taken 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 by -H or C1-C3alkyl.

[0106] In some embodiments, each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2. In some embodiments, each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or –CN. In some embodiments, each R9is independently -F, -Cl, -OR10, -CH3, or –CN. In some embodiments, each R9is independently -F, -OR10, or -CH3. In some embodiments, each R9is independently -F or -OR10. In certain embodiments, each R9is independently, -F, -OH, –OCH3, or –OCD3.

[0107] In some embodiments, each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms. In some embodiments, each R10is independently -H, C1- C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionallysubstituted with hydroxyl and / or C1-C3alkoxy and / or 1-6 deuterium atoms. In some embodiments, each R10is independently –H, -CH3, -CD3, -CH2CH3, or cyclopropyl, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3. In some embodiments, each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3. In some embodiments, each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3. In some embodiments, each R10is independently -H or -CH3.

[0108] In some embodiments, the compound of formula (I) is a compound of formula (I- A), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing:

[0109] In some embodiments, the compound of formula (I) or formula (I-A) is a compound of formula (I-A-i) or (I-A-ii):wherein m is an integer 0 or 2;each R1is independently -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1- C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7’R8’,C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl; R2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of: ,wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy and / or 1-6 deuterium atoms.

[0110] In some embodiments, each R1is independently -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; and wherein each pair of R7’and R8’of R1taken 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 by H or C1-C3alkyl.

[0111] In some embodiments, R5is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, ,single or double bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups.

[0112] In some embodiments, R2is -CH3, CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or -CH3; and R4is -H, -F or -CH3.

[0113] In some embodiments, each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3.

[0114] In some embodiments, the compound of formula (I) is a compound of formula (I- A-i) or formula (I-A-ii), wherein m is an integer 0 or 1;R1is -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; R2is -CH3, CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or - CH3; R4is -H, -F or -CH3; R5is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to- 10-membered heteroaryl is selected from the group consisting of:, ,single or double bond, and wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups; each pair of R7’and R8’taken together with thenitrogen 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 by H, or C1-C3alkyl; each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently - H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3.

[0115] In some embodiments, the compound of formula (I) is a compound of formula (I- A-i) or formula (I-A-ii), wherein m is an integer 0 or 1; R1is -F; R2is -CH3; R3is -H or -CH3; R3’is -H or -CH3; R4is -CH3; R5is a 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:an, wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups; each R9is independently -F or -OR10, and each R10is independently -H or -CH3.

[0116] In some embodiments, the compound of formula (I) is a compound of formula (I- B), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing:

[0117] In some embodiments, the compound of formula (I) or formula (I-B) is a compound of formula (I-B-i) or (I-B-ii):wherein R2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, , , , , ,, wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; R6is C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)- (C0-C2alkylene)-NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, andeach R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy.

[0118] In some embodiments, R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; and wherein each pair of R7’and R8’of R6taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl.

[0119] In some embodiments, R5is phenyl or 5-to-10-membered heteroaryl, wherein said5-to-10-membered heteroaryl is selected from the group consisting of:, whereinsaid phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups.

[0120] In some embodiments, each R9is independently -F, -OR10, -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3.

[0121] In some embodiments, R2is -H or -CH3; R3is -H; R3’is -H; and R4is -H or -CH3.

[0122] In some embodiments, the compound of formula (I) is a compound of formula (I- B-i) or formula (I-B-ii), wherein R2is -H or -CH3; R3is -H; R3’is -H; R4is -H or -CH3; R5is phenyl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl isselected from the group consisting of:, wherein said phenyl or said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups; R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently -F, -OR10, -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3.

[0123] In some embodiments, provided is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Table 1

[0124] Although certain compounds described in Table 1 are presented as specific stereoisomers and / or in a non-stereochemical form, it is understood that any or all non- stereochemical forms and any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of Table 1 are herein described. In some embodiments, the compound described herein is selected from Compound Nos. 1-147.

[0125] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, hydrates, or isotopomers, of the compounds described. The present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.

[0126] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination ofdescriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to R0of formula (I) may be combined with every description, variation, embodiment, or aspect of X, Y, m, R1, R2, R3, R3’, R4, R5, R6, R7, R7’, R8, R8’, R9, and / or R10the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of formula (I), where applicable, apply equally to any of formulae (I-A), (I-A-i), (I-B), (I-B-i) and (I-B-ii) detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. III. General Synthetic Methods

[0127] The compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be prepared by a variety of procedures known in the art. Exemplary methods of making the compounds are described in International Patent Application Publication No. WO2022 / 076975, which is incorporated herein by reference in its entirety. IV. Pharmaceutical Compositions and Formulations

[0128] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.

[0129] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0130] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1. In one variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 5% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, and without limitation, a composition of 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.

[0131] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. In some embodiments, the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein.

[0132] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray 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.

[0133] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, with a pharmaceutically acceptablecarrier. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.

[0134] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0135] Any of the compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet.

[0136] Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. I n another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In someembodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

[0137] Compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order. A compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.). Furthermore, co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery. V. Methods of Use

[0138] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and / or for conducting quality control assays.

[0139] In one aspect, provided herein is a method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient. In some embodiments, the method comprises administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T, F359C, or P465S, or any combination of these amino acid substitutions. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase generesulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions. In some embodiments, the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in F359C and F359V amino acid substitutions.

[0141] In some embodiments, the patient has a leukemia cell that has a Bcr-Abl tyrosine kinase gene. In some embodiments, the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L or any combination of these amino acid substitutions. In some embodiments, the leukemia cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2).

[0142] In some embodiments, the method further comprises detecting one or more mutations in the Bcr-Abl tyrosine kinase gene. In some embodiments, detecting one or more mutations in the Bcr-Abl tyrosine kinase gene occurs before administering to the patient the compound of formula (I) or the pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises selecting the patient for treatment based on the presenece of one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions. In some embodiments, the method further comprises collecting a blood or bone marrow sample from the patient. In some embodiments, the blood sample is a peripheral blood sample. In some embodiments, the method further comprises extracting nucleic acid from the sample. In some embodiments, the nucleic acid is DNA. In some embodiments, the nucleic acid is RNA. In some embodiments, the method further comprises sequencing the nucleic acid. In some embodiments, sequencing is conducted with Sanger sequencing. In some embodiments, sequencing is conducted with next generation sequencing.

[0143] In some embodiments, the patient has undergone a prior allogeneic myeloablative stem cell transplant. In some embodiments, the patient has received a donor lymphocyte infusion.

[0144] In some embodiments, the leukemia cell expresses e13a3, e19a2, e1a3, e1a2, e6a2, e8a2, e15a2, or e14a3 (b3a3) transcript, or any combination thereof. In some embodiments, the leukemia cell expresses e13a3, e19a2, e1a3, e1a2, e6a2, e8a2, e15a2, e14a3 (b3a3), e13a1, e1a4, or e1a5 transcript, or any combination thereof.

[0145] In some embodiments, the Bcr-Abl tyrosine kinase gene does not have any mutation, or has one or more mutations resulting in T315I or S348L, or both of these amino acid substitutions.

[0146] In some embodiments, the method further comprises detecting Bcr-Abl fusion transcript expressed by the leukemia cell. In some embodiments, detecting Bcr-Abl fusion transcript expressed by the leukemia cell occurs before administering to the patient the compound of formula (I) or the pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises selecting the patient for treatment based on the presenece of a Bcr-Abl fusion transcript expressed by the leukemia cell that is other than e13a2 (b2a2) or e14a2 (b3a2).

[0147] In some embodiments, the method further comprises collecting a blood or bone marrow sample from the patient. In some embodiments, the blood sample is a peripheral blood sample. In some embodiments, the method further comprises conducting a cytogenetic analysis on the bone marrow sample. In some embodiments, the method further comrpises seqeuncing the sample. In some embodiments, the method further comprises extracting nucleic acid from the sample. In some embodiments, the nucleic acid is DNA. In some embodiments, the nucleic acid is RNA. In some embodiments, the method further comprises sequencing the nucleic acid. In some embodiments, sequencing is conducted with Sanger sequencing. In some embodiments, sequencing is conducted with next generation sequencing.

[0148] In some embodiments, the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors. In some embodiments, the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, or bosutinib, or any combination thereof. In some embodiments, the patient was previously treated with asciminib.

[0149] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 2 hours after the patient ate food. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes after the patient ate food. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, isadministered to the patient less than about 1 hour before the patient eats food. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes before the patient eats food. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient daily.

[0150] In one aspect, provided is a method of inhibiting Bcr-Abl enzymatic activity in a cell. In some embodiments, the method comprises exposing the cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T, F359C, or P465S, or any combination of these amino acid substitutions. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T amino acid substitution. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in T315I, M244V, A337T, E355G, F359C, F359V, or P465S, or any combination of these amino acid substitutions. In some embodiments, the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in F359C and F359V amino acid substitutions.

[0151] In some embodiments, the cell is a leukemia cell.

[0152] In some embodiments, the cell has a Bcr-Abl tyrosine kinase gene. In some embodiments, the Bcr-Abl tyrosine kinase gene has one or more mutations iresulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L. In some embodiments, the cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2).

[0153] In one aspect, provided herein is a method of inhibiting Bcr-Abl tyrosine kinase enzymatic activity, comprising contacting an effective amount of a compound or composition provided herein, to the Bcr-Abl tyrosine kinase. In some embodiments, provided herein is a method of inhibiting Bcr-Abl tyrosine kinase in a cell, comprising administering an effective amount of a compound or composition of the disclosure to the cell. In some embodiments, provided herein is a method of inhibiting Bcr-Abl tyrosine kinase in an individual in need thereof, comprising administering an effective amount of a compound or composition of the disclosure to the individual. In some variations, the compounds provided herein are selective for inhibiting Bcr-Abl tyrosine kinase. As such, in some embodiments, provided herein is amethod of selectively inhibiting Bcr-Abl tyrosine kinase, as compared to other tyrosine kinases, including but not limited to c-KIT, FGFR, PDGFR, SRC, CSFR1, or VEGFR.

[0154] The compounds and compositions described herein may be used in a method of treating a disease or disorder mediated by Bcr-Abl tyrosine kinase activity. In some embodiments, the compound or composition is administered according to a dosage described herein.

[0155] In some embodiments, provided herein is a method for treating a disease or disorder mediated by Bcr-Abl tyrosine kinase activity comprising administering to an individual in need of treatment an effective amount of a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, the disease or disorder is a cancer mediated by Bcr-Abl tyrosine kinase activity. In some embodiments, the disease or disorder is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In some embodiments, the disease or disorder is a cancer, such as leukemia. In some variations, the cancer is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia.

[0156] In certain embodiments, the leukemia is chronic myeloid leukemia. Chronic myeloid leukemia may be characterized by the state of disease progression, as determined by blast cells. In still further embodiments, the chronic myeloid leukemia is chronic phase CML, accelerated phase CML, or blastic phase CML. In some embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia.

[0157] In some embodiments, the disease or disorder mediated by Bcr-Abl tyrosine kinase activity is refractory or resistant 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 resistant to treatment with one or more Bcr-Abl tyrosine kinase inhibitors selected from the group consisting of imatinib, nilotinib, dasatinib, bafetinib, bosutinib, radotinib, asciminib, and ponatinib. First-line treatment as described herein includes the use of imatinib; second- and third-line treatments as described herein include the use of nilotinib, dasatinib, bafetinib, bosutinib, radotinib, asciminib, and / or ponatinib. Insome variations of the foregoing, the chronic myeloid leukemia is refractory chronic myeloid leukemia.

[0158] Resistant subtypes of Bcr-Abl tyrosine kinase-mediated diseases or disorders may be associated with any number of Bcr-Abl dependent or Bcr-Abl independent resistance mechanisms. In some embodiments wherein the disease or disorder mediated by Bcr-Abl tyrosine kinase activity is refractory to treatment, the disease or disorder 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 result in 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 disorder mediated by Bcr- Abl tyrosine kinase is associated with one or more specific point mutations in the Bcr-Abl tyrosine kinase gene resulting in specific amino acid substitutions selected from the group consisting of: M244V, L248V, G250E, G250A, Q252H, Q252R, Y253F, Y253H, E255K, E255V, D276G, F311L, T315N, T315A, F317V, F317L, M343T, M351T, E355G, F359A, F359V, V379I, F382L, L387M, H396P, H396R, S417Y, E459K, F486S, and T315I. In certain embodiments, the refractory disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with a mutation resulting in the T315I substitution. In still further embodiments, the refractory disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with a T315I mutation at the onset of treatment and I315M mutation following ponatinib. In other embodiments, the refractory disease or disorder mediated by Bcr-Abl tyrosine kinase is associated with one or more mutations leading to amino acid substitutions within the P-loop (M244V, G250E, Q252H, Y253H / F, E255K / V).

[0159] In some embodiments, provided is a method for treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (I), or any variation thereof as described herein. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous 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 myelogenousleukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia is refractory. In certain embodiments, the leukemia is chronic myeloid leukemia. In still further embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia. In other embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia is refractory due to an associated T315I mutation. In certain embodiments of the foregoing, the chronic myeloid leukemia is refractory chronic myeloid leukemia associated with a T315I mutation.

[0160] In one aspect, provided herein is a method of treating cancer in an individual in need thereof, wherein modulation of Bcr-Abl tyrosine kinase activity inhibits or ameliorates the pathology and / or symptomology of the cancer, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method of treating cancer, wherein modulation of Bcr-Abl tyrosine kinase activity inhibits the pathology and / or symptomology of the cancer, in an individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one embodiment, provided herein is a method of treating a cancer, wherein modulation of Bcr-Abl tyrosine kinase activity ameliorates the pathology and / or symptomology of the cancer, in an individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein.

[0161] In another aspect, provided herein is a method of preventing cancer, wherein modulation of Bcr-Abl tyrosine kinase activity prevents the pathology and / or symptomology of the cancer, in an individual, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In another aspect, provided herein is a method of delaying the onset and / or development of a cancer that is mediated by Bcr-Abl tyrosine kinase activity in an individual (such as a human) who is at risk for developing the cancer. It is appreciated that delayed development may encompass prevention in the event the individual does not develop the cancer.

[0162] In one aspect, provided herein is a method of delaying the onset and / or development of cancer in an individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the cancer is a leukemia. In certain embodiments, the cancer is chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous 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 myelogenous leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia is refractory. In certain embodiments, the leukemia is chronic myeloid leukemia. In still further embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia. In other embodiments, the chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia is refractory due to an associated T315I mutation. In still yet other embodiments, the chronic myeloid leukemia is refractory chronic myeloid leukemia associated with a T315I mutation. In one aspect, provided herein is a method of delaying the onset and / or development of chronic myeloid leukemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one variation, provided herein is a method of delaying the onset and / or development of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or composition provided herein. In one variation, provided herein is a method of delaying the onset and / or development of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous 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.

[0163] In one aspect, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in therapy. In some embodiments, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt,solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or pharmaceutical composition comprising such compound, for use in the treatment of cancer. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such compound, for use in the treatment of chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such compound, for use in the treatment of chronic myeloid leukemia (CML). In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such compound, for use in the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising such compound, for use in the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia associated with a T315I mutation.

[0164] In another embodiment, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer. In another embodiment, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, for use in the manufacture of a medicament for the treatment of chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia. In some embodiments, the medicament is for the treatment of chronic myeloid leukemia. In some embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL),acute myelogenous leukemia (AML), or mixed phenotype acute leukemia. In certain embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia. In other embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous leukemia (AML), or mixed phenotype acute leukemia associated with a T315I mutation. In some embodiments, the medicament is for the treatment of refractory chronic myeloid leukemia associated with a T315I mutation.

[0165] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is 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.

[0166] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents, including anti-microtubular therapies (e.g. paclitaxel, vincristine), topoisomerase inhibitors (e.g. adriamycin), alkylating agents (e.g. busulfan, cyclophosphamide), nucleotide synthesis inhibitors (hydroxyurea), DNA synthesis inhibtiors (e.g. cytarabine), protein synthesis inhibitors (e.g. omacetaxine), developmental signaling pathway inhibitors (e.g. sonidegib, Hedgehog pathway), pro-apoptotic agents (e.g. venetoclax), Abl myristoyl-pocket binding inhibitors (e.g. asciminib), MEK1 / 2 inhibitors (e.g. trametinib, binimetinib), AKT inhibitors (e.g. ipatasertib), PI3K inhibitors (e.g. apelisib) and radiation. VI. Dosing and Method of Administration

[0167] The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a pharmaceuticallyacceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount.

[0168] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0169] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg / kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.

[0170] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.

[0171] A compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, 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, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.VII. Articles of Manufacture and Kits

[0172] The present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed.

[0173] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer, including chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), acute myelogenous 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, the cancer is refractory chronic myeloid leukemia associated with a T315I mutation.

[0174] The kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.

[0175] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

[0176] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of acompound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0177] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual. ENUMERATED EMBODIMENTS

[0178] The following enumerated embodiments are representative of some aspects of the invention. 1. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein (i) the patient has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T, F359C, or P465S, or any combination of these amino acid substitutions in leukemia cells; or (ii) the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting, or both (i) and (ii), wherein formula (I) is:wherein: X is NR3’or CR3, Y is NR2or CR4,wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a double bond to CR5;m is an integer from 0 to 3; each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene- NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5- to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene- NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms. 2. The method of embodiment 1, wherein the patient has one or more mutations in the Bcr- Abl tyrosine kinase gene resulting in A337T, F359C, and / or P465S amino acid substitution. 3. The method of embodiment 2, wherein the patient has one or more mutations in the Bcr- Abl tyrosine kinase gene resulting in A337T amino acid substitution. 4. The method of embodiment 2 or 3, wherein the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors.5. The method of any one of embodiments 2 to 4, wherein the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, or bosutinib, or any combination thereof. 6. The method of any one of embodiments 2 to 5, wherein the patient was previously treated with asciminib. 7. The method of any one of embodiments 1 to 6, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting. 8. The method of embodiment 7, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 2 hours after the patient ate food. 9. The method of embodiment 7 or 8, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 1 hour before the patient eats food. 10. The method of any one of embodiments 1 to 9, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient daily. 11. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cell has one or more mutations in the Bcr-Abl tyrosine kinase gene resulting in A337T, F359C, or P465S, or any combination of these amino acid substitutions, wherein formula (I) is:wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a double bond to CR5;m is an integer from 0 to 3;each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene- NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5- to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene- NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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 withC1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms. 12. The method of embodiment 11, wherein the cell is a leukemia cell. 13. The method of any one of embodiments 1 to 12, wherein the compound of formula (I) is a compound of formula (I-A):14. The method of any one of embodiments 1 to 13, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):wherein m is an integer 0 or 2; each R1is independently -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1- C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl; R2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl,, ,, wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy and / or 1-6 deuterium atoms. 15. The method of any one of embodiments 1 to 14, wherein each R1is independently -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; and wherein each pair of R7’and R8’of R1taken 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 ofN and O, and wherein the nitrogen atom of any primary or secondary amine present in the heterocyclic ring is optionally substituted by -H or C1-C3alkyl. 16. The method of any one of embodiments 1 to 13 and 15, wherein, wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10- membered heteroaryl is optionally substituted with 1-3 R9groups. 17. The method of any one of embodiments 1 to 16, wherein R2is -CH3, -CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or -CH3; and R4is -H, -F or -CH3. 18. The method of any one of embodiments 1 to 17, wherein each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3. 19. The method of any one of embodiments 1 to 13 and 15 to 18, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):-ii), wherein m is an integer 0 or 1; R1is -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; R2is -CH3, -CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or -CH3; R4is -H, -F or -CH3;, wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10- membered heteroaryl is optionally substituted with 1-3 R9groups; each pair of R7’and R8’taken 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 by -H or C1-C3alkyl; each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3. 20. The method of any one of embodiments 1 to 19, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):wherein m is an integer 0 or 1; R1is -F; R2is -CH3; R3is -H or -CH3; R3’is -H or -CH3; R4is -CH3; R5is a 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups; each R9is independently -F or -OR10, and each R10is independently -H or -CH3. 21. The method of any one of embodiments 1 to 12, wherein the compound of formula (I) is a compound of formula (I-B):22. The method of any one of embodiments 1 to 12 and 21, wherein the compound of formula (I) is a compound of formula (I-B-i) or formula (I-B-ii):wherein R2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, , , , , ,, wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; R6is C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8,or C1-C2alkylene-(C4-C6heterocycloalkylene)- (C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy. 23. The method of any one of embodiments 1 to 12, 21, and 22 wherein R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; andwherein each pair of R7’and R8’of R6taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl. 24. The method of any one of embodiments 1 to 12 and 21 to 23 wherein R5is phenyl or, each of which is optionally substituted with 1-3 R9groups. 25. The method of any one of embodiments 1 to 12 and 21 to 24, wherein each R9is independently -F, -OR10, or -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3. 26. The method of any one of embodiments 1 to 12 and 21 to 25, wherein R2is -H or -CH3; R3is -H; R3’is -H; and R4is -H or -CH3. 27. The method of any one of embodiments 1 to 12 and 21 to 26, wherein the compound of formula (I) is a compound of formula (I-B-i) or formula (I-B-ii):wherein R2is -H or -CH3; R3is -H;R3’is -H; R4is -H or -CH3; R5is phenyl or, each of which is optionally substituted with 1-3 R9groups; R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently -F, -OR10, or -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3. 28. The method of any one of embodiments 1 to 12, wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from the group consisting of: ; ; ; ;; ; ; ; ; ; ; ; ;; ; ; ; ; ; ; ; ;; ; ; ; ; ; ; ;; ; ; ; ; ; ; ;, ; ; ; ; ; ;; ; ; ; ; ; ;; ; ; ; ; ; ; ;; ; ; ,and pharmaceutically acceptable salts of any of the foregoing. 29. The method of any one of embodiments 1 to 12, wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from the group consisting of: ; ;; ; ; ; ; ; ; ; ;; ; ; ; ; ; ; ;; ; ; ; ; ; ; ; ;; ; ; ; ; ; ; ;; ; ; ; ; , ; ;; ; ; ; ; ; ;O O F F F F F F F; ; ; ; ; ; ;,and pharmaceutically acceptable salts of any of the foregoing. 30. The method of any one of embodiments 1 to 12, wherein the compound, or a pharmaceutically acceptable salt thereof, ispharmaceutically acceptable salt thereof. EXAMPLES

[0179] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure.

[0180] The Examples below are based on Compound 95. Example 1. Antiproliferative activity of Compound 95 compared to approved ABL tyrosine kinase inhibitors in Ba / F3 cells harboring various BCR::ABL1 mutations

[0181] Cells were treated with compounds, and cell viability was measured as a metric of kinase inhibition. Ba / F3 cell lines were tested. The Ba / F3 cell line is an IL-3-dependentmouse cell line. Ba / F3 cells were engineered to express various mutant human BCR-ABL proteins rendering the cells IL-3 independent.

[0182] Ba / F3 cell lines engineered to express various mutant forms of BCR-ABL (T315I, M244V, A337T, E355G, F359C, F359V and P469S) were grown in RPMI + 10% FBS. Ba / F3 cells were harvested at 50-80% confluence then counted and seeded at 600 cells per well in 384-well tissue culture plates.

[0183] Compounds were dissolved in DMSO and were added to the plated cells in each well using a TECAN liquid handler. Compounds were tested at concentrations of 5 µM to 0.16 nM, using three-fold dilutions. The final proportion of DMSO never exceeded 0.1%.

[0184] Plates were placed in a 37 , 5% CO2 incubator for 72 hours. Plates were thenremoved from the incubator and equilibrated for 15 minutes at room temperature. 40 µL of CellTiter Glo 2 reagent (Promega) was added to measure the relative level of metabolically active cells by quantifying intracellular ATP concentrations. Plates were incubated for 30 minutes at room temperature, and luminescence was measured.

[0185] Percent viability was normalized to a vehicle control only employing the following formula: % viability = 100 x (Lum Sample) / (Lum HC). The high control values (“HC”) was generated from lysate from wells with cells treated with 0.25% DMSO. IC50values were calculated in GraphPad Prism using algorithm to fit a Hill equation to dose- response data using the following equation: Y=100 / [1+10^((LogIC50-X)*HillSlope)].

[0186] Cell viability was measured with CellTiter Glo luminescent assay. Values are expressed as fold-shift in IC50from BCR::ABL1WT, as summarized in Table 2 below. This data shows that compound 95 maintains activity against T315I and other BCR::ABL1 mutations known to confer resistance to asciminib and other tyrosine kinase inhibitors. Most frequent mutations at baseline in patients resistant to asciminib in ASCEMBL study are F359C and F359V. See Réa D et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138:2031- 2041. Table 2. Fold-shift from native BCR::ABL1Example 2. Molecular response (MR) in patients with CML without T315I mutation by 24 weeks after daily treatment with Compound 95 (tosylate salt)

[0187] The standard means of monitoring response in patients with CML is measurement in peripheral blood of BCR::ABL1 transcripts by quantitative polymerase chain reaction (qPCR) measurement. The ratio of BCR::ABL1 transcripts to ABL transcripts is normalized to control gene transcripts and converted to the International Scale (IS) which can then be used to monitor molecular response (MR). Major molecular response (MMR) is defined as < or = 0.1% BCR:ABL on the IS. Molecular response by 24 weeks was reported after daily treatment with Compound 95. A total of 18 patients were evaluable. Evaluable patients had baseline typical BCR::ABL1 transcript without T315I mutation and postbaseline assessment of BCR::ABL1 transcript at 24 weeks or achieved MMR within 24 weeks or discontinued treatment before 24 weeks without achieving MMR. For patients with MMR at baseline, only postbaseline assessments beyond 70 days were included in the analysis. These patients were heavily pre-treated. The 24 week cumulative MMR rate for these patients was 44% (8 / 18).

[0188] Table 3 below summarizes the change in MMR by 24 weeks. After daily treatment of Compound 95, 7 patients showed improved MR category, where two improved by one category, four improved by two categories, and one improved by three categories. Ten patients stayed in the same MR category.Table 3. 24 week MR shifta Deep response (from MR3 to MR5) was observed in this patient with lack of efficacy to prior asciminib and A337T mutation by local lab testing (below the threshold for central mutation testing). b Worsening of transcript level from 6.3% at baseline to 13% was observed after 4 weeks in this patient with E255V mutation, who previously discontinued asciminib and ponatinib due to lack of efficacy. Example 3. Compound 95’s pharmacokinetic (PK) profile supporting once daily dosing with flexible administration requirements

[0189] Linear PK was observed in healthy volunteers (HV) and patients. No time- dependent PK was observed in either HVs or cancer patients. Both the maximum concentration (Cmax; the highest concentration of the drug in the bloodstreatm after administration) and the area under the curve (AUC) increased dose-proportionally. High concordance between HV and patient PK was observed.

[0190] Fast and complete absorption with no significant food effect was observed. Mean terminal t1 / 2 was ~12 hours in healthy volunteers. Similar effective t1 / 2 was observed in patients (10-20 hours), suggesting a daily dose (QD) regimen.

[0191] Minimal risk of drug-drug interactions (DDIs) was found. Compound 95 is not an inhibitor (competitive or time-dependent) or inducer of major CYP enzymes, or of UGT1A1. Compound 95 is not a substrate for major CYP enzymes, BCRP, or P-gp. There is no correlation between adverse events (AEs) and PK parameters in patients.

[0192] Food effect study at 120 mg single dose in HVs showed that: (i) AUCinfunder fasting conditions were similar to that under fed conditions, with a fed / fasted AUC ratio of 1.2; and (ii) Cmaxunder fasting conditions were similar to that under fed conditions, with a fed / fasted Cmaxratio of 0.8. See FIG. 1. Example 5. Preliminary safety and efficacy of Compound 95 in patients with CML driven by atypical fusion transcripts

[0193] Patients with previously treated chronic phase CML who had an atypical BCR::ABL1 fusion transcript received a tosylate salt of Compound 95 orally at doses from 20 mg to 160 mg daily. Testing for molecular response is non-standardized for atypical transcripts and was therefore assessed locally.

[0194] Six patients were enrolled with atypical transcripts. Four patients had a baseline transcript available and thus could be assessed for efficacy.

[0195] Peripheral blood or bone marrow aspirate leukocytes can serve as the sample source for detecting atypical transcripts, with RNA or DNA extracted for analysis. The assay can detect the presence of atypical BCR-ABL1 fusions either at the RNA level (by reverse transcription followed by amplification or sequencing) or at the DNA / cytogenetic level (by probe-based hybridization). Methods that can be employed include reverse-transcription PCR and quantitative real-time PCR with fusion-specific primers and probes, digital PCR for absolute copy number determination, nested PCR for enhanced sensitivity, and next- generation sequencing approaches that allow characterization and quantification of known or novel junctions. Additional single-molecule and long-read technologies (e.g., barcoded hybridization counting, SMRT or nanopore sequencing) can also be used to directly observe fusion isoforms. As a complementary approach, fluorescence in situ hybridization (FISH) can be employed to visualize the BCR-ABL1 translocation in interphase or metaphase nuclei, thereby providing confirmation of the rearrangement independent of transcript type. Other approaches may also be used to measure atypical transcript levels.

[0196] One patient with e13a3 without BCR::ABL1 mutations was enrolled. The patient discontinued prior imatinib and nilotinib due to lack of efficacy, had a concurrent diagnosis of MDS (treated with dasatinib plus azacitidine), a prior allogeneic myeloablative stem cell transplant, and was last treated with asciminib (discontinued due to lack of efficacy). The patient received Compound 95 at 80 mg once daily (QD) (224 days on study), achieved a > 1 log decrease in transcript and has not experienced any Treatment-Emergent Adverse Events (TEAEs).

[0197] One patient with e13a3 transcript and T315I / S348L mutations was enrolled. The patient discontinued prior nilotinib and ponatinib due to lack of efficacy, had an allogeneic myeloablative stem cell transplant and was subsequently treated with ponatinib and asciminib (alternating; discontinued due to intolerance and / or lack of efficacy). The patient received Compound 95 at 120 mg QD (449 days on study), had a decrease in transcript from 0.95% to 0.15%, and has not experienced any TEAE >G2.

[0198] One patient with e19a2 transcript and a T315I mutation was enrolled. The patient discontinued prior nilotinib, dasatinib, ponatinib, asciminib and a combination of asciminib and ponatinib due to lack of efficacy. The patient received Compound 95 at 80 mg QD with dose escalation to 120 mg QD (505 days on study), achieved a >1 log decrease in transcript and has not experienced any TEAE >G2.

[0199] One patient with e1a3 transcript without BCR::ABL1 mutations was enrolled. The patient discontinued prior bosutinib due to intolerance (although best molecular response was >10%) and prior dasatinib, ponatinib and asciminib due to lack of efficacy. The last therapy prior to Compound 95 was allogeneic myeloablative stem cell transplant. The patient received Compound 95 at 80 mg twice daily (BID) (80 days on study), had a decrease in transcript from 43% to 18% and has not experienced any TEAE >G2. This patient also received donor lymphocyte infusion.

[0200] Two patients with e1a2 transcript were enrolled. Both patients had no baseline transcript available and are therefore not efficacy evaluable. However, on study, transcripts remained stable. One of these patients discontinued prior bosutinib and dasatinib due to lack of efficacy, received Compound at 120 mg QD (176 days on study) and has not experienced any TEAE >G2. The other patient discontinued prior imatinib, radotinib and dasatinib due tolack of efficacy, received Compound 95 at 20 mg QD with dose escalation up to 120 mg QD (537 days on study) and has not experienced any TEAE >G2.

[0201] Compound 95 demonstrated efficacy in patients with atypical transcripts, including in patients with the e13a3 transcript, which is resistant to TKIs targeting the myristoyl pocket.

[0202] Various methods such as digital PCT, RT-dPCR, RT-PCR, PCR, molecular genetics testing, qPCR, Sanger-Sequencing, BCR::ABL1 specific quantitative realtime PCR, specific quantitative realtime PCR, realtime PCR, quantitative realtime PCR, next generation sequencing, and interphase fluorescence in situ hybridization were used to assess efficacy of Compound 95 in these patients. Example 6. Activity of Compound 95 across a cell panel of BCR::ABL1 resistance mutations

[0203] Compound 95 was assessed for its ability to address certain of the most prevalent BCR::ABL1 clinical resistance mutations for both active site TKIs and / or STAMP inhibitors (Ursan et al, 2015). Specifically, GI50 values were determined for Compound 95, asciminib and the approved active site TKIs against a panel of Ba / F3 cell lines dependent upon either native BCR::ABL1 or the indicated clinical resistance mutations for growth (FIG. 2). As shown, Compound 95 was highly active against all resistance mutations within the SH3 or SH2 contact regions, the A-Loop or the myristoyl pocket. As expected, Compound 95 was not active against the P-loop mutants. Importantly, only Compound 95 and ponatinib could effectively address the T315I gatekeeper resistance mutant with only a 3- or 5-fold loss in potency relative to native BCR::ABL1. Compound 95’s resistance mutant profile was highly complementary to asciminib’s profile. An expanded mutant panel with IC50values is provided in FIG. 3. G250E, Y253F, Y253H, E255K, and E255V are mutations within the P- loop; V299L is a mutation within the SH3 contact; T315I, F317V, and F317L are mutations within the ATP binding site; A337T and P465S are mutations within the myristoyl pocket; M351T, E355G, F359C, F359I, and F359V are mutations within the SH2 contact; and H396P is a mutation within the A-loop.

[0204] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of theabove teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

CLAIMS What is claimed:

1. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the patient has a leukemia cell that has a Bcr-Abl tyrosine kinase gene and (i) the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L or any combination of these amino acid substitutions or (ii) the leukemia cell expresses a Bcr- Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2), or both (i) and (ii), wherein formula (I) is:wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a double bond to CR5;m is an integer from 0 to 3; each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene- NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5- to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene- NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are optionallysubstituted 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms.

2. The method of claim 1, wherein the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions.

3. The method of claim 2, wherein the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T amino acid substitution.

4. The method of any one of claims 1 to 3, further comprising detecting one or more mutations in the Bcr-Abl tyrosine kinase gene.

5. The method of any one of claims 1 to 4, further comprising selecting the patient for treatment based on the presenece of one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions.

6. The method of any one of claims 1 to 5, wherein the patient was previously treated with 1, 2, 3, 4, 5, or more tyrosine kinase inhibitors.

7. The method of any one of claims 1 to 6, wherein the patient was previously treated with dasatinib, imatinib, asciminib, ponatinib, nilotinib, bosutinib, or azacitidine, or any combination thereof.

8. The method of any one of claims 1 to 7, wherein the patient has undergone a prior allogeneic myeloablative stem cell transplant or has received a donor lymphocyte infusion.

9. The method of any one of claims 1 to 8, wherein the leukemia cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2).

10. The method of claim 9, wherein the leukemia cell expresses e13a3, e19a2, e1a3, e1a2, e6a2, e8a2, e15a2, e14a3 (b3a3), e13a1, e1a4, or e1a5 transcript, or any combination thereof.

11. The method of any one of claims 1 to 10, further comprising detecting Bcr-Abl fusion transcript expressed by the leukemia cell.

12. The method of any one of claims 1 to 11, further comprising selecting the patient for treatment based on the presenece of a Bcr-Abl fusion transcript expressed by the leukemia cell that is other than e13a2 (b2a2) or e14a2 (b3a2).

13. A method of treating chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or a mixed phenotype acute leukemia in a patient, the method comprising administering to the patient the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting.

14. The method of any one of claims 1 to 12, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient without fasting.

15. The method of claim 13 or 14, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 2 hours after the patient ate food.

16. The method of any one of claims 13 to 15, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient less than about 1 hour before the patient eats food.

17. The method of any one of claims 1 to 16, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the patient daily.

18. A method of inhibiting Bcr-Abl enzymatic activity in a cell, comprising exposing the cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cell has a Bcr-Abl tyrosine kinase gene and (i) the Bcr-Abl tyrosine kinase gene has one or more mutations iresulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions or (ii) the cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2), or both (i) and (ii), wherein formula (I) is:(I), wherein: X is NR3’or CR3, Y is NR2or CR4, wherein when X is NR3’then Y is CR4, Y has a double bond to CR5, and X has a single bond to CR5; or when X is CR3then Y is NR2, Y has a single bond to CR5, and X has a double bond to CR5;R0is a groupm is an integer from 0 to 3; each R1is independently -D, -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene- NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)- (C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene moieties in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; R2is -H, C1-C3alkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R3is -H, C1-C3alkyl, C3-C6cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, -C3-C6cycloalkyl, or -CN; R4is -H, C1-C3alkyl, or halogen, wherein said C1-C3alkyl is optionally substituted with 1-3 fluorine atoms and / or 1-6 deuterium atoms; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said C6-C14aryl or said 5- to-10-membered heteroaryl is optionally substituted with 1-5 R9groups; R6is -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylene-NR7R8, C1-C6alkylene- NR7’R8’, C1-C6alkylene-OH, C1-C6alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7R8, C1-C2alkylene-(4- to 8-membered heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’,C1-C2alkylene-(C3- C7heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C3-C7heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each R8is independently -H, C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6alkylene-CN, or C1-C6heteroalkyl; each pair of R7’and R8’taken together with the nitrogen atom to which they are attached 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, -NR7R8, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, -CN, S(O)nC1-C3alkyl, or S(O)nC3-C6cycloalkyl, wherein n is an integer from 0 to 2; and each R10is independently -H, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl, C1-C3alkoxy, and / or 1-6 deuterium atoms.

19. The method of claim 18, wherein the cell is a leukemia cell.

20. The method of claim 18 or 19, wherein the Bcr-Abl tyrosine kinase gene has one or more mutations resulting in A337T, F359C, P465S, V299L, F359I, P465S, or S348L, or any combination of these amino acid substitutions.

21. The method of any one of claims 18 to 20, wherein the cell expresses a Bcr-Abl fusion transcript other than e13a2 (b2a2) or e14a2 (b3a2).

22. The method of claim 21, wherein the leukemia cell expresses e13a3, e19a2, e1a3, e1a2, e6a2, e8a2, e15a2, e14a3 (b3a3), e13a1, e1a4, or e1a5 transcript, or any combination thereof.

23. The method of any one of claims 1 to 22, wherein the compound of formula (I) is a compound of formula (I-A):

24. The method of any one of claims 1 to 23, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):wherein m is an integer 0 or 2;each R1is independently -F, C1-C3alkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1- C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7’R8’,C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8, or C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkylene, and heterocycloalkylene in R1are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl; R2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl,,, wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy and / or 1-6 deuterium atoms.

25. The method of any one of claims 1 to 24, wherein each R1is independently -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; andwherein each pair of R7’and R8’of R1taken 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 by -H or C1-C3alkyl.

26. The method of any one of claims 1 to 25, wherein, wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10- membered heteroaryl is optionally substituted with 1-3 R9groups.

27. The method of any one of claims 1 to 26, wherein R2is -CH3, -CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or -CH3; and R4is -H, -F or -CH3.

28. The method of any one of claims 1 to 27, wherein each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3.

29. The method of any one of claims 1 to 28, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):wherein m is an integer 0 or 1; R1is -F, C1-C3alkylene-NR7’R8’, or C1-C3alkylene-OH; R2is -CH3, -CD3, or -CH2CH3; R3is -H, -F, -CH3, or -CN; R3’is -H or -CH3; R4is -H, -F or -CH3;,wherein indicates a single or double bond, and wherein said phenyl or said 5-to-10- membered heteroaryl is optionally substituted with 1-3 R9groups; each pair of R7’and R8’taken 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 by -H or C1-C3alkyl; each R9is independently -F, -Cl, -OR10, -CH3, or -CN, and each R10is independently -H, -CH3, -CD3, or -CH2CH3, wherein said -CH3or said -CH2CH3is optionally substituted with hydroxyl and / or -OCH3.

30. The method of any one of claims 1 to 29, wherein the compound of formula (I) is a compound of formula (I-A-i) or formula (I-A-ii):wherein m is an integer 0 or 1; R1is -F; R2is -CH3; R3is -H or -CH3;R3’is -H or -CH3; R4is -CH3; R5is a 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, wherein said 5-to-10-membered heteroaryl is optionally substituted with 1-3 R9groups; each R9is independently -F or -OR10, and each R10is independently -H or -CH3.

31. The method of any one of claims 1 to 22, wherein the compound of formula (I) is a compound of formula (I-B):

32. The method of any one of claims 1 to 22, wherein the compound of formula (I) is a compound of formula (I-B-i) or formula (I-B-ii):whereinR2is -H, -CH3, CD3, -CHF2, or -CH2CH3; R3is -H, C1-C3alkyl, C3-cycloalkyl, halogen, or -CN; R3’is -H, C1-C3alkyl, C3-cycloalkyl, or -CN; R4is -H, -CH3, -CD3, -CHF2, -CH2CH3, or halogen; R5is C6-C14aryl or 5-to-10-membered heteroaryl, wherein said 5-to-10-membered heteroaryl is selected from the group consisting of:, wherein indicates a single or double bond, and wherein said C6-C14aryl or said 5-to-10- membered heteroaryl is optionally substituted with 1-5 R9groups;R6is C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkylene-NR7R8, C1-C3alkylene-NR7’R8’, C1-C3alkylene-OH, C1-C3alkylene-CN, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)- NR7R8, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-NR7’R8’, C1-C2alkylene-(C3-C6cycloalkylene)-(C0-C2alkylene)-OH, C1-C2alkylene-(C4-C6heterocycloalkylene)-(C0-C2alkylene)-NR7R8,or C1-C2alkylene-(C4-C6heterocycloalkylene)- (C0-C2alkylene)-NR7’R8’, wherein the alkyl, alkylene, cycloalkyl, cycloalkylene, and heterocycloalkylene moieties in R6are 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2- C3alkylene-CN, or C2-C3heteroalkyl; each R7is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each R8is independently -H, C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkyl-CN, or C2-C3heteroalkyl; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently halogen, -OR10, C1-C3alkyl, -CF2H, -CF3, C3-C6cycloalkyl, or -CN, and each R10is independently -H, C1-C3alkyl, -CD3, -CF2H, -CF3, or C3-C6cycloalkyl, wherein said C1-C3alkyl is optionally substituted with hydroxyl and / or C1-C3alkoxy.

33. The method of any one of claims 1 to 22, 31, and 32 wherein R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; and wherein each pair of R7’and R8’of R6taken 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 ofN, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene- CN, or C2-C3heteroalkyl.

34. The method of any one of claims 1 to 22 and 31 to 33 wherein R5is phenyl or, each of which is optionally substituted with 1-3 R9groups.

35. The method of any one of claims 1 to 22 and 31 to 34, wherein each R9is independently -F, -OR10, or -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3.

36. The method of any one of claims 1 to 22 and 31 to 35, wherein R2is -H or -CH3; R3is -H; R3’is -H; and R4is -H or -CH3.

37. The method of any one of claims 1 to 22 and 31 to 36, wherein the compound of formula (I) is a compound of formula (I-B-i) or formula (I-B-ii):wherein R2is -H or -CH3; R3is -H; R3’is -H; R4is -H or -CH3; R5is phenyl or, each of which is optionally substituted with 1-3 R9groups; R6is C1-C3alkyl or C1-C3alkylene-NR7’R8’; each pair of R7’and R8’taken 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-C3alkyl, C3-C6cycloalkyl, C2-C3haloalkyl, C2-C3alkylene-CN, or C2-C3heteroalkyl; each R9is independently -F, -OR10, or -CH3, and each R10is independently -H, -CH3, -CD3, -CF2H, or -CF3.

38. The method of any one of claims 1 to 22, wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from the group consisting of: ;; ; ; ; ; ;; ; ; ; ; ; ;; ; ; ; ; ;; ; ; ; ; ; ;; ; ; ; ; ;; ; ; ; ; ,; ; ; ; ;F F F; ; ; ; ;; ; ; ; ; ;; ; ,and pharmaceutically acceptable salts of any of the foregoing.

39. The method of any one of claims 1 to 22, wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from the group consisting of: ; ;; ; ; ; ; ; ;; ; ; ; ; ;; ; ; ; ; ;; ; ; ; ; ; ;F ; ; ; ; ; ;F; ; ; ; ; ;; , ; ; ;; ; ; ; ;F F F F F F; ; ; ; ; ;; ; ; ; ; ,and pharmaceutically acceptable salts of any of the foregoing.

40. The method of any one of claims 1 to 22, wherein the compound, or a pharmaceutically acceptable salt thereof, ispharmaceutically acceptable salt thereof.

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