Fused bicyclic heterocyclic or heteroaryl amide compounds

Abstract

Provided herein are novel compounds (e.g., Formula K), pharmaceutical compositions, and methods of use for treating a variety of diseases or disorders, such as cancer.

Description

FUSED BICYCLIC HETEROCYCLIC OR HETERO ARYL AMIDE COMPOUNDS

[0001] In various embodiments, the present disclosure generally relates to novel compounds, compositions comprising the same, methods of preparing and methods of using the same, e.g., for inhibiting PolO enzyme activity and / or for treating or preventing a disease or disorder described herein.BACKGROUND

[0002] DNA polymerase theta (PolO) is encoded by the POLQ gene and mediates one of the three major double strand break (DSB) repair pathways: theta-mediated end joining (TMEJ). DNA repair deficient cancers often become dependent on backup DNA repair pathways. When non-homologous end joining (NHEJ) and / or homologous recombination (HR) in a cancer cell are not functioning properly, PolO is usually overexpressed and TMEJ is activated to provide a backup pathway for DSB repairs for the cancer cell's survival (see e.g., Barszczewska-Pietraszek, G. et al. Int. J. Mol. Sci. 24:319 (2023)). TMEJ pathway activation is also observed in NHEJ-proficient cells.

[0003] PolO is a promising target for anticancer drug development, especially in cancers with DNA repair deficiency. PolO knockout in non-cancerous cells had minimal effect. However, PolO overexpression has been identified in various human cancers, such as breast cancer, lung cancer, ovarian cancer, etc. It has also been reported that PolO overexpression is associated with poor clinical outcomes in breast or liver cancer patients with HR deficiency. Inhibition of PolO was shown to kill cancer cells both in vitro and in vivo. In addition, inhibition of PolO was shown to activate the cGAS-STING pathway and can be used in combination with an immune checkpoint inhibitor for treating BRCA-deficient cancer. See e.g., Patterson-Fortin, J. et al. Nature Communications 14: 1390 (2023). Additionally, inhibition of PolO can enhance the effect of a poly (ADP-ribose) polymerase (PARP) inhibitor and can overcome PARP inhibitor resistance.BRIEF SUMMARY

[0004] In various embodiments, the present disclosure is based in part on the discovery of certain novel bicyclic heterocyclic or heteroaryl amide compounds that can be PolO inhibitors and can be used for inhibiting PolO enzyme activity in a cell (e.g., a cancer cell) and / or for treating or preventing a disease or disorder associated with PolO, such as cancer, as described herein.

[0005] In some embodiments, the present disclosure provides a compound of Formula A, or a pharmaceutically acceptable salt thereof:Formula A, wherein the variables are defined herein. In some embodiments, the compound of Formula A can be characterized as having a structure according to a subformula selected from Formula I, 1-1, 1-la, I-lb, I-lc, I-ld, Lie, I-lf, I-lg, II, 11-1, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6, as defined herein.

[0006] In some embodiments, the present disclosure provides a compound of Formula K, or a pharmaceutically acceptable salt thereof:Formula K wherein the variables are defined herein. In some embodiments, the compound of Formula K can be characterized as having a structure according to a subformula selected from Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b, as defined herein.

[0007] In some embodiments, the present disclosure also provides a compound selected from Table 1 herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure also provides a compound selected from Examples 1-266 herein, or a pharmaceutically acceptable salt thereof.

[0008] Some embodiments of the present disclosure are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1-la, I-lb, I-lc, I-ld, I-le, I-lf, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K- 9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K- 5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be formulated for different routes of administration, such as for oral administration or parenteral injection.

[0009] Certain embodiments of the present disclosure are directed to a method of treating a disease or disorder associated with Pol0, such as a cancer herein. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula A (e.g., Formula I, I- 1, I-la, I-lb, I-lc, I-ld, I-le, I-lf, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition herein.

[0010] Certain embodiments of the present disclosure are directed to a method of treating a cancer. In some embodiments, the cancer is a homologous recombination (HR) deficient cancer. In some embodiments, the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRCA gene, and / or reduced function of BRCA protein. In some embodiments, the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1-la, I-lb, I-lc, I-ld, I-le, I- If, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, any of the compounds listed in Table1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition herein.

[0011] The administering in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In some embodiments, the administering is orally. In some embodiments, the administering is a parenteral injection, such as an intravenous injection.

[0012] Compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered as the only active ingredient(s). In some embodiments, the method herein further comprises administering to the subject an additional therapeutic agent, such as additional anticancer agents described herein, for example, a PARP inhibitor, a signal transduction inhibitor, a chemotherapeutic agent, and / or an immune checkpoint inhibitor.

[0013] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention herein.DETAILED DESCRIPTION

[0014] In various embodiments, provided herein are novel compounds, pharmaceutical compositions, methods of preparation and methods of use. The compounds of the present disclosure are generally Pol6 inhibitors, which are also useful for treating various diseases or disorders, such as those described herein, e.g., cancer.CompoundsFormula A

[0015] In some embodiments, the present disclosure provides a compound of Formula A, or a pharmaceutically acceptable salt thereof:wherein:J1is S, O, N, CR10Aor NR10B;J2is C or N;J3is C or N;Z is N or CR10A, preferably, Z is N; provided that the 5-membered ring containing Z, J1, J2, and J3is a heteroaryl ring having 1-3 ring heteroatoms;Ring A is a phenyl ring or 5-10-membered heteroaryl ring having 1 to 4 ring heteroatoms independently selected from N, O, and S;Ring B is an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, or an optionally substituted phenyl ring, or an optionally substituted 5 or 6-membered heteroaryl ring having 1-3 ring heteroatoms each independently N, S, or O; preferably, Ring B is an optionally substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms;R1is an optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted 3-10 membered carbocyclic, or an optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably, R1is ortho to the amide group (-C(O)-NH-) shown in Formula A; the subscript m is an integer of 0-4, as valency permits;R2at each occurrence is independently deuterium, halogen, OH, NH2, CN, SF5, COOH, CONH2, SO2NH2, R20, OR20, SR20, N(R20)(R21), SO2R20, SO2N(R20)(R21), N(R21)SO2R20, COR20, CON(R20)(R21), or N(R21)COR20, wherein R20at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; and R21at each occurrence is independently hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3- 6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted Ci-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; or as applicable, R20and R21together with the intervening atom (e.g., the nitrogen atom) or atoms are joined to form an optionally substituted 4-8 membered heterocyclic ring; or two instances of R2are joined to form an optionally substituted 4-7 membered ring; wherein:R10Aat each occurrence is independently hydrogen, deuterium, halogen, CN, or a C1-3 alkyl optionally substituted with deuterium or F; andR10Bis hydrogen or a C1-3 alkyl optionally substituted with deuterium or F. As used herein, a variable attached to a nitrogen or oxygen atom or a sulfur atom in a nonoxidized form, should preferably not connect with the nitrogen or oxygen atom or the sulfur atom through a carbon atom of a carbon carbon double bond of an alkenyl or a carbon carbon triple bond of an alkynyl, and thus such variable preferably does not include a C2 alkenyl or C2 alkynyl.

[0016] In some embodiments, the compound of Formula A (including any of the applicable sub-formulae as described herein) can comprise one or more asymmetric centers and / or axial chirality, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. In some embodiments, the compound of Formula A can exist in the form of an individual enantiomer and / or diastereomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, when applicable, the compound of Formula A (including any of the applicable sub-formulae as described herein) can exist as an individual enantiomer substantially free of the other enantiomer, such as having an enantiomeric excess ("ee") of greater than 60%, preferably, greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, or greater than 99% ee. In some embodiments, when applicable, the compound of Formula A (including any of the applicable sub-formulae as described herein) can also exist as a mixture of stereoisomers in any ratio, such as a racemic mixture.

[0017] In some embodiments, the compound of Formula A (including any of the applicable sub-formulae as described herein) can exist as an isotopically labeled compound, particularly, a deuterated analog, wherein one or more of the hydrogen atoms of the compound of Formula A is / are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD3 analog when the compound has a CH3 group. Without wishing to be bound by theories, it is believed that in certain situations, substitution withdeuterium can lead to a deuterated analog with a better pharmacokinetic profile. Deuterated analogs can be generally prepared by using commercially available deuterating reagents.

[0018] It should be apparent to those skilled in the art that in certain cases, the compound of Formula A may exist as a mixture of tautomers. The present disclosure is not limited to any specific tautomer. Rather, the present disclosure encompasses any and all of such tautomers whether or not explicitly drawn or referred to.

[0019] In Formula A (including any applicable subformulae), the 5 -membered ring containing Z, J1, J2, and J3is a heteroaryl ring having 1-3, such as 2 ring heteroatoms. Typically, Z in the 5-membered ring is N. In some embodiments, Z is N, and the 5- membered ring has one additional ring heteroatom, such as an additional ring oxygen, sulfur, or nitrogen. In some embodiments, J1is CR10A(e.g., CH). In some embodiments, Z is N and J1is CR10A(e.g., CH). In some preferred embodiments, the 5 -membered ring is a thiazole ring, wherein Z is N, J1is S, and J2and J3are C. In some embodiments, the 5-membered ring can be an oxazole, imidazole, or pyrazole ring. For example, in some embodiments, Z is N, J1is CR10A(e.g., CH), and J2is C and J3is N. In some embodiments, Z is N, J1is CR10A(e.g., CH), and J3is C and J2is N. Typically, in embodiments wherein J1is CR10A, R10Ais hydrogen, halogen, or methyl optionally substituted with deuterium or F, preferably, R10Ais hydrogen. In some embodiments, Z can be CR10A, wherein R10Ais defined herein.

[0020] In Formula A (including any applicable subformulae), Ring B is typically an optionally substituted phenyl ring, or an optionally substituted 5 or 6-membered heteroaryl ring having 1-3 ring heteroatoms each independently N, S, or O. For example, Ring B can be a benzene, pyridine, pyridone (e.g., pyridin-2-one), pyrazine, pyridazine, or pyrimidine ring, each of which is optionally substituted. To be clear, as used herein, a pyridone is considered a 6-membered heteroaryl ring. When substituted, the phenyl or 5 or 6-membered heteroaryl ring can preferably be substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, NHz, SFs, CN, or -Y]-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and each of Y2and Y3at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl. Preferably, in the definition of variables or substituents herein, or the combination ofsubstituents and / or variables herein, a carbon atom of a carbon-carbon double bond of an alkenyl or carbon-carbon triple bond of an alkynyl group is not directly bonded with an oxygen or nitrogen atom. To be clear, unless otherwise specified or contrary from context, as used herein, a bivalent structure herein, such as a -Y1- as defined herein, can connect to the remainder of the molecule in either direction. For example, when -Y1- is stated to be C(O)NY3, then the moiety -YJ-Y2can be -C(O)N(Y3)-Y2or -N(Y3)C(O)-Y2. Other similar expressions should be understood similarly.

[0021] In some preferred embodiments, the optionally substituted Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 3-10 membered carbocyclic or heterocyclic ring, phenyl, or 5 or 6-membered heteroaryl, referred to in the definition of Y2and Y3herein, can be independently unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently selected from deuterium, halogen, OH, NH2, SF5, CN, or -Y1A-Y2A, wherein Y1Ais null, O, S, NH, NY3A, C(O), SO2, C(O)NH, C(O)NY3A, P(O)Y3A, SO2NH, or SO2NY3A, and each of Y2Aand Y3Aat each occurrence is independently (i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring, (ii) C2-6 alkenyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring, (iii) C2-6 alkynyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring, (iv) C1-6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring, (v) a 3-8 membered carbocyclic or heterocyclic optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, CM alkyl, CM alkoxy, or a 3-6 membered ring; or (vi) a phenyl or 5 or 6-membered heteroaryl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, OH, CN, CM alkyl, CM alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring); wherein each of the 3-6 membered ring referred to in (i)-(vi) can be independently selected from 3-6 membered carbocyclic or heterocyclic ring, phenyl, or a 5, or 6-membered heteroaryl, and wherein each of the CM alkyl, CM alkoxy, or 3-6 membered ring referred to in (i)-(vi) is independently unsubstituted or substituted with one or more (e.g., 1-3) substituents independently selected from deuterium, halogen (e.g., F), CN, OH, oxo (as applicable), CM alkyl (e.g., methyl) optionally substituted with deuterium or F, CMheteroalky] (e.g., methoxy) optionally substituted with deuterium or F, or 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl.

[0022] In some preferred embodiments, the optionally substituted Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 3-10 membered carbocyclic or heterocyclic ring, phenyl, or 5 or 6-membered heteroaryl, referred to in the definition of Y2and Y3herein, can be independently unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently selected from deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, C 1-4 heteroalkyl optionally substituted with deuterium or F, or a 3-6 membered ring (e.g., 3-6 membered carbocyclic or heterocyclic ring, phenyl, or 5, or 6- membered heteroaryl) optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C 1-4 heteroalkyl optionally substituted with deuterium or F.

[0023] In some preferred embodiments, each occurrence of the C1-6 heteroalkyl as referred to in the definition of Y2, Y3, Y2A, or Y3A, is independently a C1-6 alkoxy, NH(CI-6 alkyl), N(C 1-4 alkyl) (Ci -4 alkyl), -(C1-5 alkyIene)-O-(Ci-5 alkyl), -(C1-5 alky!ene)-NH(Ci-5 alkyl), -(Ci-4 alkylene)-N(Ci-4 alkyl)(Ci4 alkyl), -(C1-5 alkyIene)-S-(Ci-5 alkyl), -(C1-5 alkylene)-SO2-(Ci-5 alkyl), SO2(Ci-6 alkyl), P(0)(Ci-4alkyl)(Ci4 alkyl), SO2NH(CI-6 alkyl), SO2N(CI-4alkyl)(Ci-4 alkyl), -(C1-5 alkylene)-SO2NH-(Ci-5 alkyl), or -(C1-4 alkylene)- SO2N(CI-4 alkyl )(CI-4 alkyl), provided that the total number of carbons are no greater than 6, not counting any optional substituents. It should be noted that for "N(Ci-4 alkyl)(Ci-4 alkyl)", the two C1-4 alkyl can be the same or different, for example, both N(CH?)2 and N(CH3)(C2Hs) are within the definition of N(Ci-4 alkyl )(CM alkyl) herein. Unless otherwise specified or contrary from context, other similar expressions herein of a variable containing two or more groups of the same type (e.g., two alkyl groups) which are also designated as having the same range of carbon atoms should be understood similarly, i.e., the two or more groups are independently selected and can be the same or different.

[0024] In some preferred embodiments, each occurrence of the C1-4 heteroalkyl as referred to in the definition of Y2, Y3, Y2A, or Y3A, is independently a C1-4 alkoxy, NH(CI-4 alkyl), N(CI-3 alkyl)(Ci-3 alkyl), -(C1-3 alkylene)-O-(Ci-3 alkyl), -(C1-3 alkylene)-NH(Ci-3 alkyl), -(Ci-2 alkylene)-N(Ci-2 alkyl)(Ci-2 alkyl), -(Ci-3 alkylene)-S-(Ci-3 alkyl), -(C1-3 alkylene)-SO2-(Ci-3 alkyl), SCHCi 4 alkyl), P(O)(Ci-3alkyI)(Ci-3alkyl), SO2NH(C 1-4 alkyl),SO2N(CI-3alkyl)(Ci-3 alkyl), -(C1-3 alkylene)-SO2NH-(Ci-3 alkyl), or -(C1-2 alkylene)-SO2N(CI-2alkyl)(Ci-2 alkyl), provided that the total number of carbons are no greater than 4, not counting any optional substituents.

[0025] In some preferred embodiments, the compound of Formula A (including any applicable subformulae) can be characterized as having a structure according to Formula I:Formula I wherein:J4is CR11or N;J5is CR12or N;J6is CR13Aor N, and J7is CR14or N; orJ6is NR13Band J7is C(O); provided that the bicyclic ring containing J1, J2, J3, J4, J5, J6, and J7is a heteroaryl ring having 1-4 ring heteroatoms in addition to the ring nitrogen atom shown in Formula I;R11, R12, R13A, and R14are each independently hydrogen, deuterium, halogen, OH, NH2, SF5, CN, or -Y'-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and Y2and Y3are each independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl; andR13Bis hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl, wherein J1, J2, J3, Ring A, R1, m, and R2are defined herein.

[0026] To be clear, a bicyclic ring having J6as NR13Band J7as C(O) is considered a heteroaryl ring if the bicyclic ring is aromatic when J6- J7is replaced with C=N. For example,the bicyclic ring of O is considered a heteroaryl ring herein, as when theC(O)-NR13Bportion of the ring (i.e., a J6-J7) is replaced with C=N, the resulting ring has a structure ofwhich is aromatic.

[0027] In some preferred embodiments, J1in Formula I is S, and J2and J3are C, and the compound can have a structure according to Formula I- 1 :Formula I- 1, wherein the variables are defined herein. The bond between J6and J7can be a single bond when J6is NR13Band J7is C(O). In other embodiments, wherein J6is CR13Aor N, and J7is CR14or N, the bond between J6and J7is a double bond.

[0028] In some embodiments, in Formula I or I- 1, J4is N.

[0029] In some embodiments, in Formula I or 1-1, J5is N.

[0030] In some embodiments, in Formula I or I- 1, J7is N.

[0031] In some embodiments, in Formula5is CR12, and J7is CR14.

[0032] In some embodiments, in Formula4is CR11, and J7is CR14.

[0033] In some embodiments, in Formula4is CR11, and J5is CR12.

[0034] In some embodiments, in Formulaare both N, and J5is CR12.

[0035] In some embodiments, in Formula I or I- 1, J4and J5are both N, and J7is CR14.

[0036] In some embodiments, in Formula I or I- 1, J4is CR11, and J5and J7are both N.

[0037] Typically, in embodiments where J4is CR11, R11is hydrogen. In some embodiments, R11can be deuterium, halogen, OH, NH2, SB, CN, or -Y'-Y2, as defined herein. For example, in some embodiments, R11can be halogen, such as F or Cl, CN, an optionally substituted C1-6 alkyl, or an optionally substituted C1-6 heteroalkyl. In some embodiments, R11can be halogen, CN, a CM alkyl optionally substituted with deuterium or F, or a C1-4 heteroalkyl (e.g., a C1-4 alkoxy) optionally substituted with deuterium or F.

[0038] Typically, in embodiments where J5is CR12, R12is hydrogen. In some embodiments, R12can be deuterium, halogen, OH, NH2, SF5, CN, or -Y'-Y2, as definedherein. For example, in some embodiments, R12can be halogen, such as F or Cl, CN, an optionally substituted CM alkyl, or an optionally substituted Ci-6 heteroalkyl. In some embodiments, R12can be halogen, CN, a CM alkyl optionally substituted with deuterium or F, or a CM heteroalkyl (e.g., a C1-4 alkoxy) optionally substituted with deuterium or F.

[0039] Typically, in embodiments where J7is CR14, R14is hydrogen. In some embodiments, R14can be deuterium, halogen, OH, NH2, SF5, CN, or -Y'-Y2, as defined herein. For example, in some embodiments, R14can be halogen, such as F or Cl, CN, an optionally substituted CM alkyl, or an optionally substituted C1-6 heteroalkyl. In some embodiments, R14can be halogen, CN, a CM alkyl optionally substituted with deuterium or F, or a CM heteroalkyl (e.g., a CM alkoxy) optionally substituted with deuterium or F.

[0040] Typically, in Formula I or 1-1 , J6is CR13A, wherein R13Ais defined herein. For example, in some embodiments, the compound of Formula I or 1-1 can be characterized as having a structure according to Formula I- la:Formula I- la, wherein R13A, Ring A, R1, m, and R2are defined herein.

[0041] In some embodiments, the compound of Formula I or I- 1 can be characterized as having a structure according to Formula I- lb:Formula I- lb, wherein R13A, Ring A, R1, m, and R2are defined herein.

[0042] In some embodiments, the compound of Formula I or 1-1 can be characterized as having a structure according to Formula I-lc:Formula I-lc, wherein R13A, Ring A, R1, m, and R2are defined herein.

[0043] In some embodiments, the compound of Formula I or I- 1 can be characterized as having a structure according to Formula I- Id:wherein R13A, Ring A, R1, m, and R2are defined herein.

[0044] In some embodiments, the compound of Formula I or I- 1 can be characterized as having a structure according to Formula I-le:wherein R13A, Ring A, R1, m, and R2are defined herein.

[0045] In some embodiments, the compound of Formula I or 1-1 can be characterized as having a structure according to Formula I- If:wherein R13A, Ring A, R1, m, and R2are defined herein.

[0046] In some embodiments according to Formula I or 1-1 (e.g., Formula I- la, I- lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and R13Ais hydrogen.

[0047] In some embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and R13Ais halogen, such as F, Cl, or Br.

[0048] In some embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and R13Ais CN.

[0049] In some embodiments according to Formula I or T-l (e.g., Formula I- 1 a, I-lb, T-l c, I- Id, I-le, or I- If), J6is CR13A, and R13Ais -Y:-Y2as defined herein. For example, in some embodiments, R13Ais -Y'-Y2, wherein Y1is null, in other words, R13Ais Y2as defined herein. In some embodiments, R13Ais Y2, wherein Y2is an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl, or an optionally substituted C2-6 alkynyl. In some embodiments, RI3Ais Y2, wherein Y2is an optionally substituted C1-6 heteroalkyl.

[0050] In some embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I- If), J6is CR13A, and R13Ais -Y -Y2, wherein Y1is O, NH, or NY3, wherein Y2and Y3are defined herein.

[0051] In some preferred embodiments, R13Ais Y2, wherein Y2is an optionally substituted 3-10 membered carbocyclic or heterocyclic ring. Suitable 3-10 membered carbocyclic or heterocyclic rings are not particularly limited and include those described herein, which can be monocyclic or have a fused, spiro, or bridged bicyclic structure. In some embodiments, the 3-10 membered carbocyclic ring can have two rings in which one of the rings is phenyl and the other ring is fused to the phenyl ring. In some embodiments, the 3-10 membered heterocyclic ring can have 1-4 ring heteroatoms each independently N, O, or S, wherein the S atom is optionally oxidized such as existing as S=O, SO2, etc. In some embodiments, the 3-10 membered heterocyclic ring can have two rings in which one of the rings is phenyl or 5, or 6-membered heteroaryl, and the other ring is fused to the phenyl or heteroaryl ring.

[0052] In some embodiments, Y2can be a C3-7 cycloalkyl, which is optionally substituted with one or more substituents herein, e.g., one or more substituents independently selected from halogen (e.g., F), OH, C1-4 alkyl optionally substituted with deuterium or F, or CM heteroalkyl optionally substituted with deuterium or F. In some embodiments, Y2can be an unsubstituted C3-6 cycloalkyl, such as cyclopropyl.

[0053] In some embodiments, Y2can be a 4-10 membered heterocyclic ring, such as a 4- 8 membered heterocyclic ring (e.g., tetrahydropyran, piperidine, etc.) having 1-3 ring heteroatoms each independently N, O, or S, wherein the S atom is optionally oxidized (e.g., as SO2), which is optionally substituted with one or more substituents herein, e.g., one or more substituents independently selected from halogen (e.g., F), OH, CM alkyl optionally substituted with deuterium or F, or C 1-4 heteroalkyl optionally substituted with deuterium orF. In some embodiments, Y2can be a tetrahydropyran or piperidine, which is optionally substituted with a CM alkyl optionally substituted with deuterium or F.

[0054] In some preferred embodiments, R13Ais Y2, wherein Y2is an optionally substituted phenyl. In some preferred embodiments, R13Ais Y2, wherein Y2is an optionally substituted 5-membered heteroaryl having 1-4 ring heteroatoms each independently N, O, or S, such as an optionally substituted pyrazolyl. In some preferred embodiments, R13Ais Y2, wherein Y2is an optionally substituted 6-membered heteroaryl having 1 or 2 ring nitrogens, such as an optionally substituted pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

[0055] In some embodiments according to Formula I or 1-1 (e.g., Formula I- la, I- lb, I-lc, I-ld, I-le, or I- If), J6is CR13A, and R13Acan be hydrogen, halogen (e.g., Cl, Br, etc.), CN, an optionally substituted CM alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted C1-4 heteroalkyl, SF5, an optionally substituted C3-7 cycloalkyl, or an optionally substituted 4-10 membered heterocyclic ring having 1 -3 ring heteroatoms each independently N, O, or S. In some preferred embodiments, when substituted, the CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 heteroalkyl, C3-7 cycloalkyl, or 4-10 membered heterocyclic ring, is substituted with one or more (e.g., 1-3) substituents each independently selected from deuterium, halogen (e.g., F), OH, SFs, CN, oxo, CONR30R31, N(R30)C(O)R31, SO2NR30R31, N(R30)SOIR31, SR31, OR31, SO2R31, C 1-4 alkyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl, wherein each of R30and R31at each occurrence is independently hydrogen, CM alkyl optionally substituted with deuterium or F, or a 3-6 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl; or as applicable, R30and R31together with the intervening atom or atoms are joined to form an optionally substituted 4-8 membered heterocyclic ring (e.g., optionally substituted with deuterium, F, OH, and / or methyl). For example, in some embodiments, R13Acan be hydrogen, halogen (e.g., Cl or Br), CN, C1-4 alkyl optionally substituted with deuterium or F (e.g., CF2H or CF3), cyclopropyl, CM alkoxy optionally substituted with deuterium or F (e.g., OCF2H or OCF3), or a 4-10 membered heterocyclic ring having 1-3 ring heteroatoms each independently N, O, or S, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkyl optionally substituted with deuterium or F(e.g., CF2H or CF3), or CM alkoxy optionally substituted with deuterium or F (e.g., OCF2H or OCF3). In some embodiments, R13Acan be a 4-10 membered heterocycloalkyl ring having 1- 3 ring heteroatoms each independently N, O, or S, such as a monocyclic 4-8 membered heterocycloalkyl, e.g., a tetrahydropyran or piperidinyl ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, Cu alkyl optionally substituted with deuterium or F (e.g., CF2H or CF3), and CM alkoxy optionally substituted with deuterium or F (e.g., OCF2H or OCF3).

[0056] In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I- la, I- lb, Lie, Lid, Lie, or 1-11), J6is CR13A, and R13Ais an optionally substituted phenyl. In some embodiments, the phenyl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G1, or -X’-X^G1, wherein X1is null, CM alkylene or CM heteroalkylene, andX2is O, S, NH, NG1, C(O), SO2, C(O)NH, C(O)NG1, SO2NH, or SO2NG1, and wherein G1at each occurrence is independently an optionally substituted CM alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted CM heteroalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted 4-7 membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N, O, or S, or an optionally substituted 5 or 6-membered heteroaryl having 1-3 ring heteroatoms each independently N, O, or S. Preferably, when substituted, the Ci- 4 alkyl, C2-4 alkenyl, C2-4 alkynyl, CM heteroalkyl, C3-6 cycloalkyl, 4-7 membered heterocyclic ring, or 5 or 6-membered heteroaryl is substituted with one or more (e.g., 1- 3) substituents each independently selected from deuterium, halogen (e.g., F), OH, CN, oxo, Ci -4 alkyl optionally substituted with deuterium or F, CM alkoxyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl. In some embodiments, the phenyl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G1, or -X’-X^G1, wherein X1is null, CH2, or CH2CH2, wherein X2and G1are defined herein. In some embodiments, the phenyl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium,halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SFs, SCF3, G1, NHG1, NGV, OG1, or SO2G1, wherein G1is defined herein.

[0057] In some preferred embodiments according to Formula I or I- 1 (e.g., Formula I- la, I-lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and R13Ais an optionally substituted 5 or 6 membered heteroaryl, e.g., pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some embodiments, the 5 or 6 membered heteroaryl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G1, or -X^X-G1, wherein X1is null, CM alkylene or CM heteroalkylene, andX2is O, S, NH, NG1, C(O), SO2, C(O)NH, C(O)NG!, SO2NH, or SO2NG1, and wherein G1at each occurrence is independently an optionally substituted CM alkyl, an optionally substituted CM alkenyl, an optionally substituted CM alkynyl, an optionally substituted CM heteroalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted 4-7 membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N, O, or S, or an optionally substituted 5 or 6-membered heteroaryl having 1-3 ring heteroatoms each independently N, O, or S. Preferably, when substituted, the Ci- 4 alkyl, C2-4 alkenyl, C2-4 alkynyl, CM heteroalkyl, C3-6 cycloalkyl, 4-7 membered heterocyclic ring, or 5 or 6-membered heteroaryl is substituted with one or more (e.g., 1- 3) substituents each independently selected from deuterium, halogen (e.g., F), OH, CN, oxo, Ci -4 alkyl optionally substituted with deuterium or F, CM alkoxyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl. In some embodiments, the 5 or 6 membered heteroaryl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G1, or -X1-X2-G1, wherein X1is null, CH2, or CH2CH2, wherein X2and G1are defined herein. In some embodiments, the 5 or 6 membered heteroaryl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, SCF3, G1, NHG1, NG’G1, OG1, or SO2G], wherein G1is defined herein.

[0058] In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I- la, I-lb, I-lc, I- Id, I-le, or I-lf), J6is CR13A, and R13Ais an optionally substituted phenyl,pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some embodiments, the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl is unsubstituted or substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, SCF3, G2, NHG2, NG2G2, OG2, or SO2G2, wherein G2at each occurrence is independently an optionally substituted CM alkyl, an optionally substituted C3-6 cycloalkyl, or an optionally substituted 4-7 membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N, O, or S. Preferably, when substituted, the CM alkyl, C3-6 cycloalkyl, or 4-7 membered heterocyclic ring, is substituted with one or more (e.g., 1-3) substituents each independently selected from deuterium, halogen (e.g., F), OH, CN, oxo, Ci -4 alkyl optionally substituted with deuterium or F, CM alkoxyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl.

[0059] In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, Lie, Lid, Lie, or Llf), J6is CR13A, and RI3Ais selected from the following:wherein n is an integer of 0-3, and(i) G3at each occurrence is independently deuterium, halogen (e.g., F or Cl), CN, CM alkyl, O-(Ci-4alkyl), S02-(CM alkyl), OH, NH2, NH(CMalkyl), N(CM alkyl)(Ci-4alkyl), 3-4 membered carbocyclic or heterocyclic ring, O-(3-4 membered carbocyclic or heterocyclic ring), (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring) or O- (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring), wherein each of the aforementioned C 1-4 alkyl is independently optionally substituted with 1-7 deuterium or F, and wherein the CM alkylene or 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, F, OH, or methyl; or (ii) one instance of G3is S-(CM alkyl),wherein the CM alkyl is optionally substituted with 1 -7 deuterium or F, e.g., one G3is SCF2 or SCF3, and any remaining G3is as defined in (i). In some embodiments, the 3-4 membered carbocyclic or heterocyclic ring is cyclopropyl or cyclobutyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, one instance of G3is CM alkyl optionally substituted with 1-7 deuterium or F or C 1-4 alkoxy optionally substituted with 1-7 deuterium or F, such as OCH3, OCF2H, OCF3, CF3, CH3, CF2H, or CH2CF3, and any other instance(s) of G3, if present, is defined above. For example, in some embodiments, when n is 2, the remaining instance of G3can be a halogen.

[0060] In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and R13Ais a pyridinyl (e.g., 2-pyridinyl, 3- pyridinyl, or 4-pyridinyl) substituted with (i) 1 or 2 substituents independently selected from deuterium, halogen (e.g., F or Cl), CN, CM alkyl, O-(Ci-4 alkyl), SO2-(CM alkyl), OH, NH2, NH(CI-4 alkyl), or N(CM alkyl)(Ci-4 alkyl), or (ii) one substituent is S-(CM alkyl), SF5, cyclopropoxy, or cyclobutoxy, and any remaining substituent(s) is as defined in (i); wherein each of the aforementioned CM alkyl is independently optionally substituted with 1-7 deuterium or F. For example, in some embodiments, RIn some embodiments,Preferably, the pyridinyl is substituted with one substituent selected fromOCH3, OCF2H, OCF3, CF3, CH3, CF2H, or CH2CF3, and optionally a further substituent selected from F or Cl.

[0061] In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, Lid, Lie, or I-lf), J6is CR13A, and R13Ais a 2-pyridinyl substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and optionally a further substituent selected from F or Cl, for example, selected from the following:

[0062] In some preferred embodiments according to Formula I or 1-1 (e.g., Formula Lla,I-lb, I-lc,some preferred embodiments according to Formula I or 1-1 (e.g., Formula Lla, I-lb, Lie, Lid, Lie, or I-lf),some preferred embodiments according toFormula I or 1-1 (e.g., Formula Lla, I-lb, I-lc, Lid, Lie, or I-lf), J6is CR13A, and R13Ais In some preferred embodiments according to Formula I or 1-1 (e.g., Formula Lla, Lib, I-lc, I-Id, I-le, or I-lf),some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I- Id, Lie, or I-lf), J6is CR13A,In some preferred embodiments according to Formula I or I- 1(e.g., Formula Lla, I-lb, I-lc, Lid, Lie, or I-lf),In some preferred embodiments according to Formula I or 1-1 (e.g., Formula Lla, I-lb, Lie,I-ld, I-le, or I-lf), J6is CR13A, and R13Ais. In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, I-ld, I-le, or I-lf), J6is CR13A, and R13Ais. In some preferred embodiments according to Formula I or I- 1(e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I-lf), I6is CR13A, and R13Ais. in some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-Id, I-le, or I-lf),some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I-lf), J6is CR13A,some preferred embodiments according to Formula I or I- 1(e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I-lf),some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, I-Id, I-le, or I-lf),

[0063] In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la,I-lb, I-lc, I-ld, I-le, or I-lf), J6is CR13A, and R13Ais a 3-pyridinyl substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and optionally a further substituent selected from F or Cl, for example, selected from the following:In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-Id, I-le, or I-lf),some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I- If), J6is CR13A, and. In some preferred embodiments according to Formula I or 1-1 (e.g.,Formula I-la, I-lb, I-lc, I-ld, I-le, or I-lf),some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or

[0064] In some preferred embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I-lf), J6is CR13A, and R13Ais a 4-pyridinyl substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3,CF2H, or CH2CF3, and optionally a further substituent selected from F or Cl, for example,

[0065] In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and RI3Ais a phenyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which is substituted with (i) 1 or 2 substituents independently selected from deuterium, halogen (e.g., F or Cl), CN, CM alkyl, O-(Ci-4 alkyl), SO2-(CM alkyl), OH, NH2, NH(CIM alkyl), or N(CIM alkyl)(Ci-4 alkyl), or (ii) one substituent is S-(C 1-4 alkyl), SF5, cyclopropoxy, or cyclobutoxy, and any remaining substituent(s) is as defined in (i); wherein each of the aforementioned C1-4 alkyl is independently optionally substituted with 1-7 deuterium or F. In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I- Id, I-le, or I- If), J6is CR13A, and R13Ais a pyrimidinyl which is substituted with 1 or 2 substituents independently selected from deuterium, halogen (e.g., F or Cl), CN, C1.4 alkyl, O-(Ci-4alkyl), SO2-(Ci-4alkyl), OH, NH2, NH(CIM alkyl), or N(CI-4alkyl)(Ci-4 alkyl), wherein each of the aforementioned CM alkyl is independently optionally substituted with 1-7 deuterium or F. In some more specific embodiments according to Formula I or 1- 1 (e.g., Formula I-l a, I-lb, I- lc, I-ld, I-le, or I-lf), J6is CR13A, and R13Ais a pyridazinyl, which is substituted with 1 or 2 substituents independently selected from deuterium, halogen (e.g., F or Cl), CN, C1-4 alkyl, O-(Ci-4 alkyl), SO2-(CIM alkyl), OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl) (C 1-4 alkyl), wherein each of the aforementioned C1-4 alkyl is independently optionally substituted with 1-7 deuterium or F. In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I-ld, I-le, or I-lf), J6is CR13A, and R13Ais a pyrazinyl which is substituted with 1 or 2 substituents independently selected from deuterium, halogen (e.g., F or Cl), CN, CM alkyl, O-(Ci-4 alkyl), SO2-(CM alkyl), OH, NH2, NH(CM alkyl), or N(CM alkyl)(Ci-4 alkyl), wherein each of the aforementioned C1-4 alkyl is independently optionally substituted with 1-7 deuterium or F. In some preferred embodiments, RI3Ais selected from the following:some preferred embodiments,some preferred embodiments, R13A, ,

[0066] In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, I- lb, Lie, Lid, Lie, or I-lf), J6is CR13A, and R13Ais a pyrazolyl, optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), Ci -4 alkyl, 3-4 membered carbocyclic or heterocyclic ring, or (Ci-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring), wherein the CM alkyl, CM alkylene, or 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1- 3) substituents independently deuterium, F, OH, or methyl. In some preferred embodiments,R13Ais selected from the following:

[0067] In some more specific embodiments according to Formula I or 1-1 (e.g., Formula I-la, Lib, Lie, Lid, Lie, or Llf), J6is CR13A, and R13Ais a 5-7 membered heterocyclic ring, such as a tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, etc., which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F), oxo, CM alkyl, 3-4 membered carbocyclic or heterocyclic ring, or (CM alkylene)-(3- 4 membered carbocyclic or heterocyclic ring), wherein the CM alkyl, CM alkylene, or 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 - 3) substituents independently deuterium, F, OH, or methyl. In some preferred embodiments, R13Ais selected from the following:

[0068] In some embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-l c,I- Id, I-le, or I- If), J6is CR13A, and R13Acan be L-RKas defined herein in connection with Formula K or its subformulae. In some embodiments according to Formula I or 1-1 (e.g., Formula I-la, I-lb, I-lc, I- Id, I-le, or I-lf), J6is CR13A, and R13Acan also be any of the respective groups of the compounds shown in Table 1 or Examples 1-266 herein.

[0069] In some embodiments, in Formula I or I- 1, J6is NR13Band J7is C(O).

[0070] For example, in some embodiments, the compound of Formula I or 1-1 can be characterized as having a structure according to Formula I-lg:Formula I-lg, wherein the variables are defined herein.

[0071] In some embodiments, in Formula I or 1-1, J6is NR13B, and RI3Bis an optionally substituted Ci-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl, preferably, when substituted, the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C1-6 heteroalkyl, 3-10 membered carbocyclic or heterocyclic ring, phenyl, or 5 or 6- membered heteroaryl is substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, NH2, SF5, CN, or -Y'-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and each of Y2and Y3at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl.

[0072] In some embodiments, the compound of Formula I can also have a bicyclic heteroaryl in which one of the fused rings is a pyrazole or imidazole ring. For example, in some embodiments, J1in Formula I can be CH, and one of J2and J3is C and the other of J2and J3is N.

[0073] In some embodiments according to Formula A (including any applicable subformulae), Ring B can also be an optionally substituted 5-7 membered carbocyclic or heterocyclic ring. For example, in some embodiments, Ring B can be a 5-7 membered ho carbocyclic ring, such as a cyclohexylene ring, ’ , which is optionally substituted.

[0074] For example, in some embodiments, the compound of Formula A has a structure according to Formula II:Formula II, wherein: nl is 0, 1, 2, 3, or 4,RB1at each occurrence is independently deuterium, halogen, OH, CN, NH2, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl, preferably, when substituted, the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 3-10 membered carbocyclic or heterocyclic ring, phenyl, or 5 or 6- membered heteroaryl is substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, NH2, SF5, CN, or -Y]-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and each of Y2and Y3at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl; and the other variables are defined herein.

[0075] In some embodiments, nl in Formula II is 0.

[0076] In some embodiments, nl in Formula II is 1, and the compound has a structure according to Formula II- 1 :Formula II- 1, wherein the variables are defined herein. In some embodiments, RB1is an optionally substituted phenyl or 5 or 6-membered heteroaryl. In some embodiments, RB1is an optionally substituted phenyl, such as phenyl or 4-chlorophenyl. When substituted, the phenyl or 5 or 6-membered heteroaryl ring can preferably be substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, NH2, SF5, CN, or YJ-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and each of Y2and Y3at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6- membered heteroaryl.

[0077] In some embodiments, Ring B can be a 5-7 membered heterocyclic ring having 1 or 2 ring heteroatoms, such a, which is optionally substituted.

[0078] For example, in some embodiments, the compound of Formula A has a structure according to Formula III:wherein: n2 is 0, 1, 2, 3, or 4,RC1at each occurrence is independently deuterium, halogen, OH, CN, NH2, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6alkynyl, an optionally substituted Ci-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl, preferably, when substituted, the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 3-10 membered carbocyclic or heterocyclic ring, phenyl, or 5 or 6- membered heteroaryl is substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, NH2, SF5, CN, or -Y'-Y2. wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and each of Y2and Y3at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl; and the other variables are defined herein.

[0079] In some embodiments according to Formula III, n2 is 0.

[0080] In some embodiments according to Formula III, and the compound has a structure according to Formula III- 1 :Formula III- 1, wherein RC2is an optionally substituted C1-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted Ci-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl, and the other variables are defined herein. In some embodiments, RC2is an optionally substituted phenyl or 5 or 6-membered heteroaryl. When substituted, the phenyl or 5 or 6-membered heteroaryl ring can preferably be substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, NH2, SF5, CN, or - Y’-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and Y2and Y3are each independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C 1-6 heteroalky], an optionally substituted3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl.

[0081] Ring A in Formula A (e.g., Formula I, II, or III, or any of the subformulae) is typically a phenyl ring or a 5 or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as pyridine ring. In some embodiments, Ring A in Formula A can also be a fused bicyclic heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S.

[0082] In some embodiments, Ring A in Formula A (e.g., Formula I, II, or III, or any of the subformulae) is a phenyl, pyridinyl, pyrimidinyl, or imidazo[l,2-a]pyridinyl ring.

[0083] In some preferred embodiments, Ring A in Formula A (e.g., Formula I, II, or III, or any of the subformulae) is a phenyl ring.

[0084] In some preferred embodiments, Ring A in Formula A (e.g., Formula I, II, or III, or any of the subformulae) is a pyridinyl ring.

[0085] For example, in some embodiments, the compound of Formula A can have a structure according to Formula Al:Formula Al wherein the variables are defined herein.

[0086] In some embodiments, the compound of Formula A can have a structure according to Formula A2:Formula A2 wherein the variables are defined herein.

[0087] In some embodiments, the compound of Formula A can have a structure according to Formula A3 :wherein the variables are defined herein.

[0088] In some embodiments, the moietyFormula Al, A2, orA3, or any of the subformulae described herein, has the respective definition of any of those described herein for Formula I (e.g., 1-1, 1-la, I- lb, I-lc, I- Id, I-le, or I-lf), Formula II (e.g., II- 1), or Formula III (e.g., Ill- 1).

[0089] In some embodiments, the subscript "m" in Formula A (e.g., any of the applicable subformulae) is 0 or 1, typically 1. Typically, when m is 1, R2is meta to R1.

[0090] For example, in some embodiments, the compound of Formula Al can have a structure according to Formula Ala:wherein the variables are defined herein.

[0091] In some embodiments, the compound of Formula A2 can have a structure according to Formula A2a:wherein the variables are defined herein.

[0092] Typically, in embodiments according to Formula A (e.g., any of the applicable subformulae), R2at each occurrence is independently deuterium, halogen, CN, OH, (Ci-4 alkylene)-CN, GA, or Xa-Xb-GA,wherein:Xaat each occurrence is independently null, C1-4 alkylene, or C 1-4 heteroalkylene;Xbat each occurrence is independently null, O, NH, N(GB), C(O), C(O)O, C(O)NH, C(O)N(GB), NHC(O), N(GB)C(O), SO2, SO2NH, or SO2N(GB); andGAat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, CM alkyl, CM alkoxy, or a 3-6 membered ring;(iii) a 3-7 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein the C1-4 alkyl or C 1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F;GBat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring) optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F, orwhen applicable, GAand GBare joined to form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, CM alkyl optionally substituted with F, or CM alkoxy optionally substituted with F.

[0093] In some preferred embodiments, in Formula A (e.g., any of the applicable subformulae), one instance of R2is a CM alkyl optionally substituted with deuterium, F, and / or OH, e.g., methyl, difluoromethyl, or hydroxymethyl, and if present, any remaining instance(s) of R2is as defined herein, preferably, selected from halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F.

[0094] In some embodiments, in Formula A (e.g., any of the applicable subformulae), one instance of R2is a 5 or 6-membered heteroaryl, which is optionally substituted with 1-3 substituents each independently halogen, OH, CN, CM alkyl, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein the CM alkyl or C1-4 alkoxy is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F), OH, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein each of the 3-5 membered carbocyclic or heterocyclic ring, when present, is independently optionally substituted with deuterium, F, OH, and / or methyl, and if present, any remaining instance(s) of R2is as defined herein, preferably, selected from halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F.

[0095] In some embodiments, in Formula A (e.g., any of the applicable subformulae), one instance of R2is -(CM alkylene)-C(O)NHGA, -(CM alkylene)-C(O)N(GA)(GB) or -(CM alkyl ene)-CN, wherein GAand GBare defined herein. In some embodiments, GAand GBare each independently a CM alkyl optionally substituted with deuterium, F and / or OH, and if present, any remaining instance(s) of R2is as defined herein, preferably, selected from halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F. For example, in some embodiments, m is 1, and R2can be CH2C(O)NHCH3or CH2C(O)N(CH3)2.

[0096] In some embodiments, in Formula A (e.g., any of the applicable subformulae), R2can also have any of the R2definitions as defined in connection with Formula K and its subformulae. For example, in any of the embodiments described herein, m is 1 , and R2in Formula A (e.g., any of the applicable subformulae), can have a structure according to M-l toM-13 as defined herein below in connection with Formula K and its subformulae. In some embodiments, m is 1, and R2in Formula A (e.g., any of the applicable subformulae), can have a structuredefined herein.

[0097] In Formula A (e.g., any of the applicable subformulae), R1is typically an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl. For example, in some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is an optionally substituted pyridinyl. In some embodiments, R1is an optionally substituted pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[l,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5- b]pyridinyl, benzo[d]thiazole, indazolyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, [l,2,4]triazolo[l,5- b]pyridazinyl, or tetrazolo[l,5-a]pyridinyl. When substituted, the optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl, e.g., optionally substituted phenyl or pyridinyl, is preferably substituted with one or more (e.g., 1-3) substituents independently selected from: deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C1-4 alkylene)-CN, Gc, or Xc-Xd-Gc, wherein:Xcat each occurrence is independently null, Ci-4 alkylene, or C 1-4 heteroalkylene;Xdat each occurrence is independently null, O, NH, N(GD), C(O), C(O)O, C(O)NH, C(O)N(GD), NHC(O), N(GD)C(O), P(O)(GD), SO2, SO2NH, or SO2N(GD); and Gcat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, CM alkyl, C' 1-4 alkoxy, or a 3-6 membered ring;(iii) a 3-7 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring;(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein the C1-4 alkyl or C1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) is independently optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F;GDat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F, or when applicable, Gcand GDtogether with the heteroatom they are both attached to are joined to form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F. In some embodiments, the one or more substituents for the optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl are each independently selected from: deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C1-4 alkylene)-CN, Gc, or Xc-Xd-Gc, wherein Xcis null, and Xdand Gcare defined herein. In some embodiments, the one or more substituents for the optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl are each independently selected from: halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, C1-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(Ci-4 alkyl), or N(Ci-4 alkyl)(Ci-4 alkyl). In some embodiments, the one or more substituents for the optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl can include onesubstituent of SCF3, with the remaining substituent(s) as defined herein. In some embodiments, the one or more substituents for the optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl are each independently selected from: halogen, CM alkyl optionally substituted with deuterium, F and / or OH, CM alkoxy optionally substituted with deuterium or F, C3-4 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-3 alkyl), or N(CI-3 alkyl)(Ci-3 alkyl). In some more specific embodiments, , the one or more substituents for the optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl are each independently selected from: methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxy ethyl, preferably, the substituents are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

[0098] In some embodiments, in Formula A (e.g., any of the applicable subformulae), R1can be a phenyl or pyridinyl substituted with one substituent. In such embodiments, the one substituent is preferably ortho to ring A. For example, in some embodiments, R1can bewherein Rlbcan be halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, C1-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CM alkyl), or N(CM alkyl)(Ci-4alkyl).

[0099] In some embodiments, in Formula A (e.g., any of the applicable subformulae), R1can be a phenyl or pyridinyl substituted with two substituents. Typically, the two substituents are para to each other, with one of the substituents ortho to ring A.

[0100] For example, in some embodiments, the compound of Formula A can have a structure according to Formula Alb:Formula Alb,wherein Rlaand Rlbare each independently halogen, Ci-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, Ci -6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)(Ci-4 alkyl), and the other variables are defined herein.

[0101] In some embodiments, the compound of Formula A can have a structure according to Formula Ale:Formula Ale, wherein Rlaand Rlbare each independently halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, C1-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CM alkyl)(Ci-4 alkyl), and the other variables are defined herein.

[0102] In some embodiments, the compound of Formula A can have a structure according to Formula A2b:Formula A2b, wherein Rlaand Rlbare each independently halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, Ci-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)(Ci-4 alkyl), and the other variables are defined herein.

[0103] In some embodiments, the compound of Formula A can have a structure according to Formula A2c:Formula A2c, wherein Rlaand Rlbare each independently halogen, Ci-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, Ci-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)(Ci-4 alkyl), and the other variables are defined herein.

[0104] In some embodiments, the moiety ofin Formula Ala, Alb,Ale, A2a, A2b, or A2c, has the respective definition of any of those described herein for Formula I (e.g., 1-1, 1-la, I-lb, I-lc, I- Id, I-le, or I- If), Formula II (e.g., II- 1), or Formula III (e.g., Ill- 1), preferably, any of those described herein for Formula I-la, I-lb, I-lc, I- Id, I-le, or I- If.

[0105] To illustrate, in some embodiments, the moietyFormulaA2b can have the respective definition of any of those described herein for Formula I-la, I- 1b, I-lc, I-ld, I-le, or I- If, and in such embodiments, the compound of Formula A2b can have a structure according to any of the following Formula A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6:Formula A2b- 1 Formula A2b-2Formula A2b-5 Formula A2b-6 wherein Rla, Rlb, R2, and R13Aare defined herein.

[0106] In some preferred embodiments, in Formula Alb, Ale, A2b, A2b-1, A2b-2, A2b- 3, A2b-4, A2b-5, A2b-6, or A2c, Rlaand Rlbare each independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxy ethyl, more preferably, Rlaand Rlbare each independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, and cyclopropyl.

[0107] In some preferred embodiments, in Formula Alb, Ale, A2b, A2b-1, A2b-2, A2b- 3, A2b-4, A2b-5, A2b-6, or A2c, Rlbis C1-2 alkoxy optionally substituted with 1-3 deuterium or F, preferably, RIbis methoxy, ethoxy, or difluoromethoxy.

[0108] In some preferred embodiments, in Formula Alb, Ale, A2b, A2b-1, A2b-2, A2b- 3, A2b-4, A2b-5, A2b-6, or A2c, Rlais halogen, C1-3 alkyl optionally substituted with 1-3 deuterium or F, or cyclopropyl, preferably, Rlais methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, or cyclopropyl.

[0109] In some preferred embodiments, in Formula Alb, Ale, A2b, A2b-1, A2b-2, A2b- 3, A2b-4, A2b-5, A2b-6, or A2c, Rlbis C1-2 alkoxy optionally substituted with 1-3 deuterium or F, preferably, Rlbis methoxy, ethoxy, or difluoromethoxy; and Rlais halogen, C1-3 alkyl optionally substituted with 1-3 deuterium or F, or cyclopropyl, preferably, Rlais methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, or cyclopropyl.Formula K

[0110] In some embodiments, the present disclosure provides a compound of Formula K, or a pharmaceutically acceptable salt thereof:Formula K wherein:Ring A is a phenyl ring or 5-10-membered heteroaryl ring having 1 to 4 ring heteroatoms independently selected from N, O, and S;R1is an optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted 3-10 membered carbocyclic, or an optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably, R1is ortho to the amide group (-C(O)-NH-) shown in Formula K; the subscript m is an integer of 0-4, as valency permits;R2at each occurrence is independently deuterium, halogen, OH, NH2, CN, SF5, COOH,), or N(R2I)COR20, wherein R20at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted Ci-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; and R21at each occurrence is independently hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; or as applicable, R20and R21together with the intervening atom (e.g., the nitrogen atom) or atoms are joined to form an optionally substituted 4-8 membered heterocyclic ring; or two instances of R2are joined to form an optionally substituted 4-7 membered ring;RJis hydrogen, halogen, optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure;L is CM alkylene, C2-4 alkenylene, C2-4 alkynylene, or C 1-4 heteroalkylene, each of which is optionally substituted with deuterium and / or F, andRKis hydrogen, deuterium, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure.

[0111] In some embodiments, the compound of Formula K (including any of the applicable sub-formulae as described herein) can comprise one or more asymmetric centers and / or axial chirality, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. In some embodiments, the compound of Formula K can exist in the form of an individual enantiomer and / or diastereomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, when applicable, the compound of Formula K (including any of the applicable sub-formulae as described herein) can exist as an individual enantiomer substantially free of the other enantiomer, such as having an enantiomeric excess ("ee") of greater than 60%, preferably, greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, or greater than 99% ee. In some embodiments, when applicable, the compound of Formula K (including any of the applicable sub-formulae as described herein) can also exist as a mixture of stereoisomers in any ratio, such as a racemic mixture.

[0112] In some embodiments, the compound of Formula K (including any of the applicable sub-formulae as described herein) can exist as an isotopically labeled compound, particularly, a deuterated analog, wherein one or more of the hydrogen atoms of the compound of Formula K is / are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD3 analog when the compound has a CH3 group. Without wishing to be bound by theories, it is believed that in certain situations, substitution with deuterium can lead to a deuterated analog with a better pharmacokinetic profile. Deuterated analogs can be generally prepared by using commercially available deuterating / deuterated reagents.

[0113] It should be apparent to those skilled in the art that in certain cases, the compound of Formula K may exist as a mixture of tautomers. The present disclosure is not limited toany specific tautomer. Rather, the present disclosure encompasses any and all of such tautomers whether or not explicitly drawn or referred to.

[0114] In some preferred embodiments, L in Formula K is C2-4 alkynylene, which is optionally substituted with deuterium and / or F. For example, in some preferred embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-l:Formula K-l.

[0115] In some embodiments, L can also be a C3-4 alkynylene, optionally substituted with deuterium and / or F, such abonded with RK. For example, in some embodiments, L-RKcan be

[0116] In some embodiments, L in Formula K is C1-4 alkylene, which is optionally substituted with deuterium and / or F. The C1-4 alkylene can be linear or branched. For example, in some embodiments, L can be linear C1-4 alkylene, such as CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2.

[0117] In some embodiments, L in Formula K is C2-4 alkenylene, which is optionally substituted with deuterium and / or F. For example, in some embodiments, L can be a C2 alkenylene,

[0118] In some embodiments, L in Formula K is C1-4 heteroalkylene, which is optionally substituted with deuterium and / or F. For example, in some embodiments, L can be, wherein the oxygen atom can be bonded with RKor to the thiazolopyrazine ring.

[0119] In some preferred embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be an optionally substituted C3-8 cycloalkyl. Typically, the C3-8 cycloalkyl is a monocyclic ring. However, in some embodiments, the C3-8 cycloalkylcan also be a bicyclic ring structure, such as a fused, bridged, or spiro bicyclic ring structure. When substituted, the C3-8 cycloalkyl is preferably substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from deuterium, halogen, OH, CN, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C 14 heteroalkyl, or a 3-10 membered ring, wherein each of the CM alkyl, C2-4 alkenyl, C24 alkynyl, CM heteroalkyl, or 3-10 membered ring is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with deuterium and / or F, CM heteroalkyl optionally substituted with deuterium and / or F, and 3-6 membered ring (e.g., carbocyclic, heterocyclic, heteroaryl, or phenyl ring), wherein the 3-6 membered ring at each occurrence is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with deuterium and / or F, and C 1-4 heteroalkyl optionally substituted with deuterium and / or F.

[0120] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one or more, e.g., 1-5 or 1-3, substituents independently selected from deuterium, F, OH, CN, CM alkyl optionally substituted with F, C 1-4 heteroalkyl optionally substituted with F, or 3-6 membered ring optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with F, and CM heteroalkyl optionally substituted with F.

[0121] For example, in some more specific embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be selected from:. Tn some embodiments, RKin Formula K(e.g., any of the subformulae described herein, as applicable) can, which istypically in a trans configuration, such aPreferably, RKis

[0122] For example, in some preferred embodiments, the compound of Formula K-l can have a structure according to Formula K-la-1 or K-la-2:Formula K-la-2 wherein the variables are defined and preferred herein. In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be an optionally substituted 4-8 membered heterocyclyl. Typically, the 4-8 membered heterocyclyl has 1-3 ring heteroatoms each independently O, S, or N, wherein the sulfur atom, if present, is optionally oxidized. The 4-8 membered heterocyclyl is typically a monocyclic ring. In some embodiments, the 4-8 membered heterocyclyl can also be a fused, bridged, or spiro bicyclic ring structure. When substituted, the 4-8 membered heterocyclyl is preferably substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from deuterium, halogen, OH, oxo, CN, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C 1-4 heteroalkyl, or a 3-10 membered ring, wherein each of the C1-4 alkyl, C2 4 alkenyl, C2-4 alkynyl, C 1-4 heteroalkyl, or 3-10 membered ring is independentlyoptionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with deuterium and / or F, CM heteroalkyl optionally substituted with deuterium and / or F, and 3-6 membered ring (e.g., carbocyclic, heterocyclic, heteroaryl, or phenyl ring), wherein the 3-6 membered ring at each occurrence is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with deuterium and / or F, and C 1-4 heteroalkyl optionally substituted with deuterium and / or F.

[0123] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) is 4-6 membered heterocyclyl having one or two ring heteroatoms, each independently O, S, or N, wherein the sulfur atom, if present, is optionally oxidized, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more (e.g., 1-3) substituents independently selected from deuterium, F, oxo, OH, CN, CM alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (CM alkylene)-(3-6 membered ring), or (CM heteroalky lene)- (3-6 membered ring), wherein the CM alkylene or C 1-4 heteroalkylene is optionally substituted with deuterium and / or F, and wherein each of the 3-6 membered ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, Ci -4 alkyl optionally substituted with F, and CM heteroalkyl optionally substituted with F.

[0124] For example, in some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be a monocyclic 4-6 membered heterocyclyl having one ring heteroatom, which is O, and the 4-6 membered heterocyclyl is unsubstituted or substituted with 1-3 substituents each independently deuterium, F, OH, CM alkyl optionally substituted with deuterium and / or F, or CM heteroalkyl optionally substituted with deuterium and / or F.

[0125] For example, in some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be selected from:

[0126] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be an optionally substituted 5 or 6-membered heteroaryl.Typically, a 5-membered hetaryl has 1 -3 ring heteroatoms each independently O, S, or N; and a 6-membered heteroaryl has 1 or 2 ring nitrogen atoms. When substituted, the 5 or 6- membered heteroaryl is preferably substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from deuterium, halogen, OH, CN, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 heteroalkyl, or a 3-10 membered ring, wherein each of the CM alkyl, C2-4 alkenyl, C2-4 alkynyl, CM heteroalkyl, or 3-10 membered ring is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, C1-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, and 3-6 membered ring (e.g., carbocyclic, heterocyclic, heteroaryl, or phenyl ring), wherein the 3-6 membered ring at each occurrence is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, C1-4 alkyl optionally substituted with deuterium and / or F, and C 1-4 heteroalkyl optionally substituted with deuterium and / or F.

[0127] In some embodiments, RKin Formula K (e.g., any of the suhformulae described herein, as applicable) can be a 5 -membered heteroaryl having 1-4 ring heteroatoms, each independently O, S, or N, wherein the 5-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from F, Cl, OH, CN, CM alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (C1-4 alkylene)-(3-6 membered ring), or (Ci-4heteroalkylene)-(3-6 membered ring), wherein the C1-4 alkylene or C 1-4 heteroalkylene is optionally substituted with deuterium and / or F, and wherein each of the 3-6 membered ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, C1-4 alkyl optionally substituted with F, and CM heteroalkyl optionally substituted with F. The 3-6 membered ring at each occurrence can be independently a 3-6 membered carbocyclic, 4-6 membered heterocyclic, 5 or 6-membered heteroaryl, or phenyl ring.

[0128] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be a 5-membered heteroaryl selected from pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, which is optionally substituted, as valency permits, with 1-3 substituents independently selected from F, Cl, OH, CN, C1-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (C1-2 alkylene)-(3-6 membered ring), or (Ci-2 heteroalkylene)-(3-6 membered ring), wherein the C1-2 alkylene or C 1-2 heteroalkylene is optionally substituted with deuteriumand / or F, and wherein, preferably, the 3-6 membered ring at each occurrence is independently selected from (a) C3-6 cycloalkyl optionally substituted with methyl and / or F; or (b) 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, and wherein the 4-6 membered heterocyclyl is optionally substituted with 1 -3 substituents independently selected from deuterium, F, OH, oxo, CN, C 1-4 alkyl optionally substituted with F, or C 1-4 heteroalkyl optionally substituted with F.

[0129] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) canwherein: q is 0, 1, 2, or 3; andG10at each occurrence is independently F, Cl, CN, Ci-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (C1-2 alkylene)- (3 -6 membered ring), or (C1-2 heteroalkylene)-(3-6 membered ring), wherein the C1-2 alkylene or C 1-2 heteroalkylene is optionally substituted with deuterium and / or F, and wherein, preferably, the 3-6 membered ring at each occurrence is independently selected from (a) C3-6 cycloalkyl optionally substituted with methyl and / or F; or (b) 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, and wherein the 4-6 membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from deuterium, F, OH, oxo, CN, C1-4 alkyl optionally substituted with F, or CM heteroalkyl optionally substituted with F. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0130] For example, in some embodiments, the compound of Formula K-l can have a structure according to Formula K-lb:Formula K-lb wherein the variables are defined and preferred herein.

[0131] In some embodiments, the compound of Formula K-l can have a structure according to Formula K-lc:wherein the variables are defined and preferred herein.

[0132] It should be understood that in Formula K-lb or K-lc, or similar structures or partial structures herein, the G10group(s), when present, can be attached to any of the available positions of the pyrazole ring, including ring nitrogen atom.

[0133] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be selected from:wherein:G10Aat each occurrence is independently C M alkyl optionally substituted with deuterium and / or F, 3-6 membered ring, or (C1-2 alkylene)-(3-6 membered ring), wherein the C1-2 alkylene or C 1-2 heteroalkylene is optionally substituted with deuterium and / or F, and wherein, preferably, the 3-6 membered ring at each occurrence is independently selectedfrom (a) C3-6 cycloalkyl optionally substituted with methyl and / or F; or (b) 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, and wherein the 4-6 membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from deuterium, F, OH, oxo, CN, C1-4 alkyl optionally substituted with F, or CM heteroalkyl optionally substituted with F; andG10Bat each occurrence is independently F, Cl, CN, or G10A.

[0134] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can, when L is, wherein G10Bis defined herein.

[0135] For example, in some embodiments, the compound of Formula K-l can have a structure according to Formula K-lb-1, K-lb-2, K-lb-3, or K-lb-4:Formula K-lb-2wherein the variables are defined and preferred herein.

[0136] In some embodiments, G10Aat each occurrence is independently CM alkyl (e.g., methyl) optionally substituted with deuterium and / or F, cyclopropyl, cyclobutyl, (C1-2 alkylene)-(cyclopropyl) or (C1-2 alkylene)-(cyclobutyl). For example, in some embodiments, in Formula K-lb-2 or K-lb-4, G10Ais CM alkyl optionally substituted with deuterium and / or F, such as methyl.

[0137] In some embodiments, G10Bat each occurrence is independently F, Cl, CM alkyl (e.g., methyl) optionally substituted with deuterium and / or F, cyclopropyl, cyclobutyl, (C1-2 alkylene)-(cyclopropyl) or (C1-2 alkylene)-(cyclobutyl). For example, in some embodiments, in Formula K-lb-3 or K-lb-4, G10Bis CM alkyl optionally substituted with deuterium and / or F, such as methyl.

[0138] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be selected from:

[0139] In some embodiments, RKin Formula K (e.g., any of the subformulae described1 / Q herein, as applicable) can be or .

[0140] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be a 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, e.g., pyridyl, pyrimidyl, etc., wherein the 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from F, Cl, OH, CN, Ci-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (C1-4 alkylene)-(3-6 membered ring), or (C 1-4 heteroalky lene)-(3 -6 membered ring), wherein the C1-4 alkylene or C 1-4 heteroalkylene is optionally substituted with deuterium and / or F, and wherein each of the 3-6 membered ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, Ci-4 alkyl optionally substituted with F, and CM heteroalkyl optionally substituted with F. For example, in some specific embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be

[0141] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can also be hydrogen.

[0142] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can also be an optionally substituted Ci-6 alkyl. When substituted, the Ci-6 alkyl can be preferably substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from deuterium, halogen, OH, CN, C24 alkenyl, C24 alkynyl, C1-4 heteroalkyl, or a 3-10 membered ring, wherein each of the C2-4 alkenyl, C2-4 alkynyl, C1-4 heteroalkyl, or 3-10 membered ring is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, C 1-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, and 3-6 membered ring (e.g., carbocyclic, heterocyclic, heteroaryl, or phenyl ring), wherein the 3-6 membered ring at each occurrence is independently optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, Ci -4 alkyl optionally substituted with deuterium and / or F, and C 1-4 heteroalkyl optionally substituted with deuterium and / or F.

[0143] In some embodiments, RKin Formula K (e.g., any of the subformulae described herein, as applicable) can also be a C M alkyl optionally substituted with deuterium and / or F. For example, in some embodiments, L-RKin Formula K (e.g., any of the subformulae described herein, as applicable) can be

[0144] Typically, RJin Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K- lb-4) is hydrogen.

[0145] For example, in some embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-2:Formula K-2, wherein the variables are defined and preferred herein.

[0146] In some embodiments, ring A in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K- la-1, K-la-2, K-lb, K-lc, K- lb-1, K-lb-2, K-lb-3, or K-lb-4) can be a phenyl ring. In some embodiments, ring A in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K- 1, K-2, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4) can be a 5 or 6- membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S. In some embodiments, ring A can be a pyridinyl, pyrimidinyl, or imidazo[l,2- a]pyridinyl ring.

[0147] In some preferred embodiments, ring A in in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-la-1, K-la-2, K- 1b, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4) is a phenyl ring or a pyridyl ring. ForR1(R2)m— (" A H example, in some embodiments, the moiety of in Formula K is selected from:

[0148] In some embodiments, the compound of Formula K can be characterized as having a structure of Formula K-3 :Formula K-3, wherein the variables are defined and preferred herein.

[0149] In some embodiments, the compound of Formula K can be characterized as having a structure of Formula K-5 :Formula K-5, wherein the variables are defined and preferred herein.

[0150] The integer m in Formula K is typically 1 or 2. When m is 1, R2is typically meta to R1. For example, in some embodiments, the

[0151] In some embodiments, m can also be 0.

[0152] In some embodiments, m can also be 2 or 3, where two instances of R2are joined to form an optionally substituted 4-7 membered ring and the remaining R2, if present, is as defined herein. In some embodiments, the 4-7 membered ring can be a 5-membered heterocyclic ring having one or two ring heteroatoms each independently O, N, or S, which isoptionally substituted, e.g., with one or more substituents each independently selected from deuterium, F, or methyl. For example, in some embodiments, the moiety of

[0153] In some embodiments, the compound of Formula K can be characterized as having a structure of Formula K-4:Formula K-4, wherein the variables are defined and preferred herein.

[0154] In some embodiments, the compound of Formula K can be characterized as having a structure of Formula K-6:Formula K-6, wherein the variables are defined and preferred herein.

[0155] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R2at each occurrence is independently deuterium, halogen, CN, OH, (CM alkylene)-CN, GA, or Xa-Xb-GA, wherein:Xaat each occurrence is independently null, Ci-4 alkylene, or C 1-4 heteroalkylene;Xbat each occurrence is independently null,, O, NH, N(GB), C(O), C(O)O, C(O)NH, C(O)N(GB), NHC(O), N(GB)C(O), SO2, S(=O)(=NH), S(=O)(=NGB), SO2NH, or SO2N(GB); andGAat each occurrence is independently:(i) Ci-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, C(0)-NH(CI-4 alkyl), C(O)- N(CI-4 alkyl )( CI -4 alkyl), or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, oxo, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring;(iii) a 3-8 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, C1-4 alkyl, C1-4 alkoxy, C(0)NH2, C(O)-NH(Ci-O4 alkyl), C(0)-N(Ci-4 alkyl )( C I -4 alkyl), ^ ' 4) , wherein the nitrogen containing Ring E is a 4-8 membered heterocyclic ring, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein each of the C1-4 alkyl or C 1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) or Ring E is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F;GBat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F, orwhen applicable, GAand GBare joined to form a 4-8 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, Ci-4 alkyl optionally substituted with F, or CM alkoxy optionally substituted with F.

[0156] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R2at each occurrence is independently GA, wherein GAis defined herein. In some embodiments, one instance of R2can be (CMI - QA alkylene)-GAor « , wherein GAis defined herein; and any remaining R2can be independently any of those defined herein, such as F or Cl.

[0157] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R2at each occurrence is independently a CM alkyl optionally substituted with deuterium, F, and / or OH, e.g., methyl, difluoromethyl, or hydroxymethyl.

[0158] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R2at each occurrence is independently a 5 or 6- membered heteroaryl, which is optionally substituted with 1-3 substituents each independently halogen, OH, CN, CM alkyl, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein the CM alkyl or CM alkoxy is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F), OH, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein each of the 3-5 membered carbocyclic or heterocyclic ring, when present, is independently optionally substituted with deuterium, F, OH, and / or methyl.

[0159] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R2at each occurrence is independently -(CM alkylene)-C(O)NHGA, -(CM alkylene)-C(O)N(GA)(GB) or -(CM alkylene)-CN, wherein GAand GBare defined herein. For example, in some embodiments, GAand GBare each independently a CM alkyl optionally substituted with deuterium, F and / or OH. In some embodiments, GAand GB, together with the nitrogen atom they are both attached to, arejoined to form a 4-8 membered heterocyclic ring, which is optionally substituted as described herein.

[0160] In some specific embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la- 2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is CN, halogen, SCF3, Ci-3alkyl optionally substituted with 1-3 substituents each independently CN, OH, F, or C1-3 alkoxy optionally substituted with F. For example, in some embodiments, R2is CN, CH2- CN, CH2-OCH3, CH2-OCF3, methyl, difluoromethyl, SCF3, or Cl.

[0161] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is -(Ci-4 alkylene)-GA1, whereinGA1is C(O)NH2, C(O)OH, C(O)NH(C 1-4 alkyl), C(0)N(CM alky 1)(CM alkyl),or, wherein the nitrogen containing Ring E is a 4-8 membered heterocyclic ring, wherein each of the C1-4 alkyl in C(O)NH(Ci-4 alkyl) or C(O)N(Ci-4 alkyl)(Ci-4 alkyl) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C 1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, wherein the 3-4 membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and wherein each of the Ring E is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F.In some embodiments, the CM alkylene is a straight chain alkylene, for example, R2can be -CH2-GA1. In some embodiments, the CM alkylene can be a branched alkylene, for example, R2can be -CH(CH3)-GA1or -CH(CH2CH3)-GA1.

[0162] For example, in some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la- 2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is selected from the following:

[0163] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is a 5-membered heteroaryl having 2-4 ring heteroatoms, such as pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, etc., which is optionally substituted. When substituted, the 5-membered heteroaryl is preferably substituted with 1 or 2 substituents, as valency permits, each independently deuterium, halogen, OH, CN, CM alkyl, CM heteroalkyl (such as CM alkoxy), a 3-6 membered carbocyclic or heterocyclic ring, (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); or (CM heteroalkylene)-(3-6 membered carbocyclic or heterocyclic ring); wherein the CM alkyl, CM alkylene, CM heteroalkyl, or C 1-4 heteroalkylene is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen (e.g., F) or OH; and wherein each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F.

[0164] In some preferred embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la- 2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is pyrazolyl, which is optionally substituted with one or two substituents, with one substituent being (i) a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and the other substituent, if present, is halogen, CN, or CM alkyl optionally substituted 1-3 substituents each independently deuterium, F, or OH.

[0165] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb,K-lc, K-lb-1 , K-lb-2, K-lb-3, or K-lb-4), m is 1 , and R2can have a structure according toM-l to M-5:wherein: ql is 0, 1, 2, or 3, preferably, 1 or 2; andG4at each occurrence is independently halogen; CN; OH; a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a CM heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, oxo, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); or (Ci- 4 heteroalkylene)-(3-6 membered carbocyclic or heterocyclic ring); wherein each of the 3- 6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or CM alkyl optionally substituted with F, provided that when G4is attached to a ring nitrogen, then G4is not halogen, CN, or OH, and G4does not bond to the ring nitrogen through a heteroatom. In some embodiments, ql is 0. In some embodiments, ql is 1, and G4is CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; or (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); wherein each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or C 1-4 alkyl optionally substituted with F. In some embodiments, ql is 2, one G4is CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; or (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); wherein each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or CM alkyl optionallysubstituted with F; and the other G4is F, Cl, CN, or CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH.

[0166] In some preferred embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-.NQH2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2can beG(M-6), wherein:G4ais a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a 3-4 membered carbocyclic or heterocyclic ring; or (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein each of the 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, methyl, or methoxy. In some embodiments, the 3-4 membered carbocyclic or heterocyclic ring is a cyclopropyl or cyclobutyl ring.

[0167] For example, in some embodiments, R2is selected from the following:. n some pre erred embodiments,

[0168] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is imidazolyl, 1,3,4-oxadiazolyl, triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, or 1,2,4-oxadiazolyl, which is optionally substituted, e.g., with one or more suitable substituents described herein, such as with one or more G4groups as defined herein. In some embodiments, when substituted, the aforementionedheteroaryl is preferably substituted with one or two substituents, as valency permits, with one substituent being (i) a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and the other substituent, if present, is halogen, CN, or CM alkyl optionally substituted 1-3 substituents each independently deuterium, F, or OH. For example, in some embodiments, R2is selected from the following:

[0169] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K- lb-2, K-lb-3, or K-lb-4), m is 1, and R2is a 5-membered or 6-membered heterocyclic ring having 1-3 ring heteroatoms each independently N, O, or S, wherein the 5- membered or 6-membered heterocyclic ring contains one or two ring carbon atoms in the form of C(=O), or the 5-membered or 6-membered heterocyclic ring contains a ring sulfur atom in the form of SO2, wherein the 5-membered or 6-membered heterocyclic ring is optionally substituted. When substituted, the 5 -membered or 6-membered heterocyclic ring is preferably substituted with one or more (e.g., 1, 2, or 3) substituents: (i) each independently deuterium, halogen, OH, CN, CM alkyl, C(O)-Ci-4 alkyl, C 1-4 heteroalkyl (such as CM alkoxy), 3-6 membered carbocyclic or heterocyclic ring, (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring), or (CM heteroalky lene)-(3 -6 membered carbocyclic or heterocyclic ring); or (ii) two optional substituents, together with the ring atom(s) they are attached to, are joined to form a 3-6 membered carbocyclic or heterocyclic ring, and any remaining substituent(s) is as defined in (i); wherein the CM alkyl, CM alkylene, CM heteroalkyl, or C 1-4 heteroalkylene is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen (e.g., F) or OH; and each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN,Ci-4 alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F.

[0170] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is a 5-membered heterocyclic ring having 1-3 ring heteroatoms each independently N, O, or S, wherein the 5 -membered heterocyclic ring contains one or two ring carbon atoms in the form of C(=O), or the 5- membered heterocyclic ring contains a ring sulfur atom in the form of SO2, wherein the 5- membered heterocyclic ring is optionally substituted with 1-3 (e.g., 1 or 2) substituents each independently (i) halogen, OH, or CN; (ii) a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iii) C(O)-Ci-4 alkyl, wherein the CM alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iv) a 3-4 membered carbocyclic or heterocyclic ring; or (v) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iv) or (v) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy. More preferably, the 5- membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N or O, wherein the 5 -membered heterocyclic ring contains one or two ring carbon atoms in the form of C(=O), and the 5-membered heterocyclic ring is optionally substituted with one or two substituents each independently halogen or CM alkyl optionally substituted 1-3 substituents each independently deuterium, F, or OH.

[0171] In some preferred embodiments, the 5 -membered heterocyclic ring is a ring selected from pyrrolidinone, imidazolidinone, oxazolidinone, or hydantoin ring. For example, in some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K- lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2has a structure according to M-7 to M-9:wherein: q2 is 0-4, preferably, 0, 1, or 2; and(i) G5at each occurrence is independently halogen; CN; OH; a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; C(O)-Ci-4 alkyl, wherein the CM alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a CM heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, oxo, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); or (CM heteroalkylene)-(3-6 membered carbocyclic or heterocyclic ring); or(ii) two G5, together with the ring atom(s) they are attached to, are joined to form a 3-6 membered carbocyclic or heterocyclic ring, and any remaining G5is defined in (i) above; wherein each of the 3-6 membered carbocyclic or heterocyclic ring in (i) or (ii) is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or Ci -4 alkyl optionally substituted with F, provided that when G5is attached to a ring nitrogen, then G5is not halogen, CN, or OH, and G5does not bond to the ring nitrogen through a heteroatom. In some embodiments, q2 is 0. In some embodiments, q2 is 1, and G5is halogen (e.g., F), OH, CN, CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; or (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); wherein each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or CM alkyl optionally substituted with F. In some embodiments, q2 is 1, and G5is CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH. In some embodiments, q2 is 2, one G5is C1 1 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; or (CM alkylene)- (3-6 membered carbocyclic or heterocyclic ring); wherein each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or C 1-4 alkyl optionally substituted with F; and the other G5is F, OH, CN, or CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH. In some specific embodiments, Gsat each occurrence is independently F or CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH.

[0172] In some specific embodiments, R2is selected from the following:

[0173] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la- 1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is a 6-membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N or O, wherein the 6-membered heterocyclic ring contains one or two ring carbon atoms in the form of C(=O), wherein the 6- membered heterocyclic ring is optionally substituted with 1-3 (e.g., 1 or 2) substituents each independently (i) a C1-4 alkyl optionally substituted with one or more (e.g., 1 -3) substituents each independently deuterium, F, or OH; (ii) C(O)-Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iii) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy. In some preferred embodiments, the 6-membered heterocyclic ring is optionally substituted with one or two substituents each independently (i) Ci-4 alkyl optionally substituted 1-3 F, (ii) C(O)-Ci-4 alkyl; or (iii) cycloproplyl optionally substituted with F.

[0174] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is a 6-membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N or O, wherein the 6-membered heterocyclic ring contains one ring carbon atom in the form of C(=O), wherein two gem substituents of the 6-membered heterocyclic ring are joined to form a 3-4 membered spiro carbocyclic or heterocyclic ring, preferably, spiro cyclopropyl ring, which is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy, and the 6- membered heterocyclic ring optionally has one or more further substituents (e.g., 1 or 2) each independently (i) a Ci-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) C(0)-CM alkyl, wherein the CM alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium,F, or OH; (iii ) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy. In some preferred embodiments, the two gem substituents of the 6-membered heterocyclic ring are joined to form a spiro cyclopropyl ring, which is unsubstituted or substituted with I or 2 substituents each independently F or methyl.

[0175] In some preferred embodiments, the 6-membered heterocyclic ring is a morpholinone or piperazinone ring. For example, in some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2isM-10 or M-ll:-l l), wherein: q3 is 0-5, preferably, 0, 1, 2, or 3; and(i) G6at each occurrence is independently a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a C(0)-CM alkyl, wherein the C1-4 alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; a C1-4 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, oxo, F, or OH; a 3-6 membered carbocyclic or heterocyclic ring; (C1-4 alkylene)-(3-6 membered carbocyclic or heterocyclic ring); or (C1-4 heteroalkylene)-(3-6 membered carbocyclic or heterocyclic ring); or(ii) two G6, together with the ring atom(s) they are attached to, are joined to form a 3-6 membered carbocyclic or heterocyclic ring, and any remaining G6is defined in (i) above; wherein each of the 3-6 membered carbocyclic or heterocyclic ring in (i) or (ii) is optionally substituted with one or more (e.g., 1 or 2) substituents each independently F, OH, or Ci -4 alkyl optionally substituted with F, provided that when G6is attached to a ring nitrogen, then G6does not bond to the ring nitrogen through a heteroatom. In some embodiments, G6at each occurrence is independently (i) a C1-4 alkyl optionallysubstituted with one or more (e.g., 1 -3) substituents each independently deuterium, F, or OH; (ii) C(O)-Ci-4 alkyl, wherein the CM alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iii) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (CM alkylene) -(3 -4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy. In some embodiments, q3 is 0. In some embodiments, q3 is 1. In some embodiments, q3 is 2 or 3, wherein each G6is independently CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH. For example, in some specific embodiments, R2is selected from the following:

[0176] In some embodiments, in M-10 or M-ll, two G6are bonded to the same ring carbon atom, and the two G6, together with the carbon atom they are both attached to, are joined to form a cyclopropyl ring, and if present, any remaining G6is defined herein. For example, in some preferred embodiments, R2can be M-12 or M-13:wherein: q4 is 0, 1, or 2, preferably, 0 or 1, and G6is defined herein; preferably, G6at each occurrence is independently CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH, for example, methyl. For example, in some embodiments, R2is selected from

[0177] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb,K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is GA2or, whereinGA2is a 3-6 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1 -3) substituents each independently deuterium, halogen, oxo, OH, CN, Ci-4 alkyl, Ci-4 alkoxy, C(O)NH2, C(O)-NH(CI-4alkyl), C(O)-N(CI-4 alkyl)(Ci4 alkyl), orO, wherein the nitrogen containing Ring E is a 4-8 membered heterocyclic ring; wherein each of the CM alkyl (i.e., including the CM alkyl in C(O)-NH(CIM alkyl) or C(0)-N(CM alkyl)(Ci-4 alkyl)) or C1-4 alkoxy is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, wherein the 3-4 membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and wherein Ring E is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F.

[0178] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1, and R2is GA2, wherein GA2is defined herein, for example,

[0179] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb,K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m is 1,, wherein GA2is defined herein, for example, R2is selected from the following:

[0180] In any of the embodiments described herein, when m is 1 , the moiety ofare defined herein.

[0181] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), m can also be 2. In such embodiments, one instance of R2can be any of those described herein, e.g., any of M-l to M-13, or any of those defined in embodiments when m is specified as 1, and the other instance of R2is typically a small group, such as F, Cl, methyl optionally substituted with F, etc. In some embodiments, when m is 2, one instance of R2can be F or Cl, and the other instance of R2is defined herein.

[0182] In some preferred embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-7a or K-7b:Formula K-7b, wherein:R100is selected from(i) hydrogen; (ii) a Ci-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iii) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (Ci-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy;R101and R102are each independently halogen, CN, or (i)-(iv) as defined for R100, and wherein R1and RKare defined and preferred herein.

[0183] In some embodiments, in Formula K-7a or K-7b, R101is hydrogen.

[0184] In some embodiments, in Formula K-7a or K-7b, R102is hydrogen.

[0185] In some embodiments, in Formula K-7a or K-7b, both R101and R102are hydrogen.

[0186] In some embodiments, in Formula K-7a or K-7b, R100is C1-4 alkyl optionally substituted with deuterium or F, for example, R100is methyl, CD3, ethyl, fluorine-substituted methyl (e.g., difluoromethyl or trifluoromethyl), or fluorine-substituted ethyl, such as 2,2- difluoroethyl, 2,2,2-trifluoroethyl, etc.

[0187] In some embodiments, in Formula K-7a or K-7b, R100is cyclopropyl optionally substituted with 1 or 2 substituents, each independently F or methyl.

[0188] In some preferred embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-8a or K-8b:wherein:Z is O, NH, or NR113, pl is 0, 1, or 2;R110and Rn iare each independently hydrogen or C 1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; orR110and R111, together with the carbon atom they are both attached to, are joined to form a 3-4 membered ring, preferably, a cyclopropyl ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy;R112at each occurrence is independently a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; or when applicable, two R112, together with the carbon atom they are both attached to, are joined to form C(=O), or a 3-4 membered ring, preferably, a cyclopropyl ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and R113is (i) a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy, and wherein R1and RKare defined and preferred herein.

[0189] In some embodiments, in Formula K-8a or K-8b, Z is O.

[0190] In some embodiments, in Formula K-8a or K-8b, Z is NH.

[0191] In some embodiments, in Formula K-8a or K-8b, Z is NR113. In some embodiments, R113is C1-4 alkyl optionally substituted with deuterium or F, for example, methyl, CD3, ethyl, fluorine-substituted methyl (e.g., difluoromethyl or trifluoromethyl), or fluorine-substituted ethyl, such as 2,2-difhioroethyl, 2,2,2-trifluoroethyl etc.

[0192] In some embodiments, in Formula K-8a or K-8b, R110and R111are each independently hydrogen or methyl. For example, in some embodiments, the moiety of[019together with the carbon atom they are both attached to, are joined to form a cyclopropyl ring. For example, in some embodiments, the moiety of

[0194] Typically, in Formula K-8a or K-8b, pl is 0.

[0195] In some embodiments, in Formula K-8a or K-8b, pl is 1 or 2, and R112at each occurrence is methyl. For example, in some embodiments, the moiety of

[0196] In some embodiments, in Formula K-8a or K-8b, pl is 2, and two R112are attached to the same ring carbon, and the two R112, together with to the ring carbon they are both attached to, are joined to form a cyclopropyl ring. For example, in some embodiments, the moiety of

[0197] In some preferred embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-9a or K-9b:Formula K-9b, wherein:W is O, NH, C(R121)(R122), or NR123, p2 is 0, 1, or 2;R120at each occurrence is independently a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; or when applicable, two R120, together with the carbon atom they are both attached to, are joined to form C(=O) or a 3-4 membered spiro or fused ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy;R121and R122are each independently hydrogen or CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; or R121and R122, together with the carbon atom they are both attached to, are joined to form a 3-4 membered ring, preferably, a cyclopropyl ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; andR123is (i) a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy, and wherein R1and RKare defined and preferred herein.

[0198] In some embodiments, in Formula K-9a or K-9b, W is O.

[0199] In some embodiments, in Formula K-9a or K-9b, W is NH.

[0200] In some embodiments, in Formula K-9a or K-9b, W is NR123. In some embodiments, R123is C1-4 alkyl optionally substituted with deuterium or F, for example, methyl, CD3, ethyl, fluorine-substituted methyl (e.g., difluoromethyl or trifluoromethyl), or fluorine-substituted ethyl, such as 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc.

[0201] In some embodiments, in Formula K-9a or K-9b, W is C(R121)(R122). In some embodiments, R121and R122are each independently hydrogen or methyl, for example, both R121and R122are hydrogen.

[0202] In Formula K-9a or K-9b, p2 is typically 0.

[0203] In some embodiments, in Formula K-9a or K-9b, p2 is 1 or 2, and R120at each occurrence is methyl.

[0204] In some embodiments, in Formula K-9a or K-9b, p2 is 2, and two gem R120, and the same ring carbon they are both attached to, together represent C(=O).

[0205] In some embodiments, the moiety of

[0206] R1in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4) is typically an optionally substituted phenyl or heteroaryl. For example, in some embodiments, R1is a phenyl, pyridinyl, pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[l,2- a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, benzo[d]thiazole, indazolyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, [l,2,4]triazolo[l,5-b]pyridazinyl, or tetrazolo[l,5-a]pyridinyl, each of which is optionally substituted.

[0207] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K- 8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R1is a phenyl or pyridinyl, each of which is optionally substituted with 1-3 substituents independently selected from: deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C1-4 alkylene)-CN, Gc, or Xc-Xd-Gc, wherein:Xcat each occurrence is independently null, C1-4 alkylene, or C 1-4 heteroalkylene;Xdat each occurrence is independently null, O, NH, N(GD), C(O), C(O)O, C(O)NH, C(O)N(GD), NHC(O), N(GD)C(O), P(O)(GD), SO2, SO2NH, or SO2N(GD); and Gcat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, CM alkyl, CM alkoxy, or a 3-6 membered ring;(iii) a 3-7 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, CM alkyl, CM alkoxy, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, CMalkyl, Ci -4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein the C1-4 alkyl or C1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) is independently optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F;GDat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F, or when applicable, Gcand GDtogether with the heteroatom they are both attached to are joined to form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F.

[0208] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K- 8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R1can be a phenyl or pyridinyl, each of which is optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, C1-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, SCF3, NH2, NH(C i-4 alkyl), or N(C 1-4 alkyl) (C 1-4 alkyl).

[0209] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K- 8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R1can be a phenyl or pyridinyl, each of which is optionally substituted with one or more (e.g., 1-3)substituents independently selected from halogen, C1-4 alkyl optionally substituted with deuterium, F and / or OH, C1-4 alkoxy optionally substituted with deuterium or F, C3-4 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NHz, NH(CI-3 alkyl), or N(CI-3 alkyl)(Ci-3 alkyl).

[0210] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K- 8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R1can be a phenyl or pyridinyl, each of which is optionally substituted with 1-3 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1 -hydroxy ethyl, preferably, the substituents are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

[0211] In some embodiments, in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K- 8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, or K-lb-4), R1can bewherein Rlaand Rlbare each independently halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, C1-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, SCF3, NH2, NH(C 1-4 alkyl), or N(CM alkyl)(Ci-4 alkyl).

[0212] For example, in some embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-3a or K-3b:Formula K-3 aFormula K-3b, wherein the variables are defined and preferred herein.

[0213] In some embodiments, the compound of Formula K can be characterized as having a structure according to Formula K-5a or K-5b:wherein the variables are defined and preferred herein.

[0214] In some embodiments, in any of the applicable formulae or a partial structure, e.g., in Formula K-3a, K-3b, K-5a, or K-5b, Rlaand Rlbcan each independently be selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1 -hydroxy ethyl.

[0215] In some embodiments, in any of the applicable formulae or a partial structure, e.g., in Formula K-3a, K-3b, K-5a, or K-5b, Rlbcan be C1-4 alkoxy optionally substituted with 1-3 deuterium or F, for example, methoxy, ethoxy, or difluoromethoxy.

[0216] In some embodiments, in any of the applicable formulae or a partial structure, e.g., in Formula K-3a, K-3b, K-5a, or K-5b, Rlacan be (i) halogen (e.g., F or Cl); (ii) C1-4 alkyloptionally substituted with 1 -3 deuterium or F, e.g., methyl, tri fluoromethyl, di fluoromethyl, etc.; or (iii) cyclopropyl or cyclobutyl, optionally substituted with methyl and / or F.

[0217] Ring A, R1, R2, and m in Formula K (e.g., any of the subformulae described herein, as applicable, such as Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K- 8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b) can also have any of the definition described herein in connection with Formula A or its subformulae.

[0218] In some embodiments, the present disclosure provides compounds according to any of the following enumerated embodiments A1-A44:Embodiment Al. A compound of Formula A, or a pharmaceutically acceptable salt thereof:Formula A wherein:J1is S, O, N, CR10Aor NR10B;J2is C or N;J3is C or N;Z is N or CR10A, preferably, Z is N; provided that the 5-membered ring containing Z, J1, J2, and J3is a heteroaryl ring having 1-3 ring heteroatoms;Ring A is a phenyl ring or 5-10-membered heteroaryl ring having 1 to 4 ring heteroatoms independently selected from N, O, and S;Ring B is an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, or an optionally substituted phenyl ring, or an optionally substituted 5 or 6-membered heteroaryl ring having 1-3 ring heteroatoms each independently N, S, or O; preferably, Ring B is an optionally substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms;R1is an optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted 3-10 membered carbocyclic, or an optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably, R1is ortho to the amide group (-C(O)-NH-) shown in Formula A; the subscript m is an integer of 0-4, as valency permits;R2at each occurrence is independently deuterium, halogen, OH, NH2, CN, SF5, COOH, CONH2, SO2NH2, R20, OR20, SR20, N(R20)(R21), SO2R20, SO2N(R20)(R21), N(R21)SO2R20, COR20, COOR20, OC(O)R20,CON(R20)(R21), or N(R21)COR20, wherein R20at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted Ci-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; and R21at each occurrence is independently hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; or as applicable, R20and R21together with the intervening atom (e.g., the nitrogen atom) or atoms are joined to form an optionally substituted 4-8 membered heterocyclic ring; wherein:R10Aat each occurrence is independently hydrogen, deuterium, halogen, CN, or a C1-3 alkyl optionally substituted with deuterium or F; andR10Bis hydrogen or a C1-3 alkyl optionally substituted with deuterium or F.Embodiment A2. The compound of Embodiment At , or a pharmaceutically acceptable salt thereof, wherein J1is S, J2and J3are C, preferably, Z is N, J1is S, J2and J3are C.Embodiment A3. The compound of Embodiment At , or a pharmaceutically acceptable salt thereof, wherein (i) Z is N; (ii) J1is CH; or (iii) Z is N and J1is CH.Embodiment A4. The compound of Embodiment Al or 3, or a pharmaceutically acceptable salt thereof, wherein J2is C and J3is N.Embodiment A5. The compound of Embodiment Al or 3, or a pharmaceutically acceptable salt thereof, wherein J3is C and J2is N.Embodiment A6. The compound of any of Embodiments Al-5, or a pharmaceutically acceptable salt thereof, wherein Ring B is a benzene, pyridine,pyridone (e.g., pyridin-2-one), pyrazine, pyridazine, or pyrimidine ring, each of which is optionally substituted.Embodiment A7. The compound of any of Embodiments Al-5, or a pharmaceutically acceptable salt thereof, wherein Ring B is a cyclohexene ring,Embodiment A8. The compound of any of Embodiments Al-5, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I:Formula I wherein:J4is CR11or N;J5is CR12or N;J6is CR13Aor N, and J7is CR14or N; orJ6is NR13Band J7is C(O); provided that the bicyclic ring containing J1, J2, J3, J4, J5, J6, and J7is a heteroaryl ring having 1-4 ring heteroatoms in addition to the ring nitrogen atom shown in Formula I; R11, R12, R13A, and R14are each independently hydrogen, deuterium, halogen, OH, NH2, SF5, CN, or -Y'-Y2, wherein Y1is null, O, S, NH, NY3, C(O), SO2, C(O)NH, C(O)NY3, P(O)Y3, SO2NH, or SO2NY3, and each of Y2and Y3at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionallysubstituted C2-6 alkynyl, an optionally substituted Ci-6 heteroalky], an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl; andR13Bis hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted C1-6 heteroalkyl, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5 or 6-membered heteroaryl.Embodiment A9. The compound of Embodiment A8, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I- 1 :Formula 1-1.Embodiment A10. The compound of Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein J7is N.Embodiment All. The compound of Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein J4is N.Embodiment A12. The compound of Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein J5is N.Embodiment A13. The compound of Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein (i) J4is N, J5is CR12, and J7is CR14; (ii) J5is N, J4is CR11, and J7is CR14; or (iii) J7is N, J4is CR11, and J5is CR12.Embodiment A14. The compound of Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein (i) J4and J7are both N, and J5is CR12, preferably CH; (ii) J4and J5are both N, and J7is CR14, preferably CH; or (iii) J4is CR11, preferably CH, and J5and J7are both N.Embodiment A15. The compound of any of Embodiments A8-14, or a pharmaceutically acceptable salt thereof, wherein as applicable, (i) when J5is CR12, R12is H; (ii) when J4is CR11, R11is H; and / or (iii) when J7is CR14, R14is H.Embodiment A16. The compound of any of Embodiments A8-15, or a pharmaceutically acceptable salt thereof, wherein J6is CR13A.Embodiment A17. The compound of Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I- la, I-lb, I-lc, I- Id, I-le, or I-lf:Formula I-leFormula I- If.Embodiment A18. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is hydrogen, halogen (e.g., Cl, Br, etc.), CN, an optionally substituted CM alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted CM heteroalkyl, SF5, an optionally substituted C3-7 cycloalkyl, or an optionally substituted 4-10 membered heterocyclic ring having 1-3 ring heteroatoms each independently N, O, or S, preferably, when substituted, the CM alkyl, C2-4 alkenyl, C2-4 alkynyl, CM heteroalkyl, C3-7 cycloalkyl, or 4-10 membered heterocyclic ring, is substituted with one or more (e.g., 1-3) substituents each independently selected from deuterium, halogen (e.g., F), OH, SF5, CN, oxo, CONR30R31, N(R30)C(O)R31, SO2NR30R31, N(R30)SO2R31, SR31, OR31, SO2R31, CM alkyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl, wherein each of R30and R31at each occurrence is independently hydrogen, CM alkyl optionally substituted with deuterium or F, or a 3- 6 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl; or as applicable, R30and R31together with the intervening atom or atoms are joined to form an optionally substituted 4-8 membered heterocyclic ring (e.g., optionally substituted with deuterium, F, OH, and / or methyl); for example, R13Ais hydrogen, halogen (e.g., Cl or Br), CN, CM alkyl optionally substituted with deuterium or F (e.g., CF2H or CF3), cyclopropyl, CM alkoxy optionally substituted with deuterium or F (e.g., OCF2H or OCF3), or a 4-10 membered heterocyclic ring having 1-3 ring heteroatoms each independently N, O, or S, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkyl optionally substituted with deuterium or F (e.g., CF2H or CF3), or CM alkoxy optionally substituted with deuterium or F (e.g., OCF2H or OCF3).Embodiment A19. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is an optionally substituted phenyl or optionally substituted 5 or 6-membered heteroaryl, preferably, when substituted, the phenyl or 5 or 6-membered heteroaryl is substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SFS, G1, or -X’-X^G1, wherein X1is null, Ci-4 alkylene or Ci-4 heteroalkylene, andX2is O, S, NH, NG1, C(O), SO2, C(O)NH, C(O)NG‘, SO2NH, or SO2NG1, wherein G1at each occurrence is independently an optionally substituted CM alkyl, an optionally substituted C2.1 alkenyl, an optionally substituted C24 alkynyl, an optionally substituted C1-4 heteroalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted 4-7 membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N, O, or S, or an optionally substituted 5 or 6-membered heteroaryl having 1 -3 ring heteroatoms each independently N, O, or S, preferably, when substituted, the C1-4 alkyl, Cy alkenyl, C2-4 alkynyl, CM heteroalkyl, C3-6 cycloalkyl, 4-7 membered heterocyclic ring, or 5 or 6-membered heteroaryl is substituted with one or more (e.g., 1-3) substituents each independently selected from deuterium, halogen (e.g., F), OH, CN, oxo, C1-4 alkyl optionally substituted with deuterium or F, C1-4 alkoxyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl.Embodiment A20. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is an optionally substituted phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, preferably, when substituted, the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl is substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, SF5, SCF3, NH2, G2, NHG2, NG2G2, OG2, or SO2G2, wherein G2at each occurrence is independently an optionally substituted CM alkyl, an optionally substituted C3-6 cycloalkyl, or an optionally substituted 4-7 membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N, O, or S, preferably, when substituted, the CM alkyl, C3-6 cycloalkyl, or 4-7 membered heterocyclic ring, is substituted with one or more (e.g.,1 -3) substituents each independently selected from deuterium, halogen (e.g., F), OH, CN, oxo, Ci -4 alkyl optionally substituted with deuterium or F, Ci-4 alkoxyl optionally substituted with deuterium or F, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) optionally substituted with deuterium, F, OH, and / or methyl.Embodiment A21. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is selected from the following:wherein n is an integer of 0-3,(i) G3at each occurrence is independently deuterium, halogen (e.g., F or Cl), CN, Ci-4 alkyl, O-(Ci-4alkyl), SO2-(Ci-4alkyl), OH, NH2, NH(CMalkyl), N(CM alkyl)(C].4alkyl), 3-4 membered carbocyclic or heterocyclic ring, O-(3-4 membered carbocyclic or heterocyclic ring), (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring) or O- (C14 alkylene)-(3-4 membered carbocyclic or heterocyclic ring), wherein each of the aforementioned C1-4 alkyl is independently optionally substituted with 1-7 deuterium or F, and wherein the CM alkylene or 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, F, OH, or methyl, preferably, one instance of G3is C1-4 alkyl optionally substituted with 1-7 deuterium or F or C 1-4 alkoxy optionally substituted with 1-7 deuterium or F, such as 0CH3, 0CF2H, 0CF3, CF3, CH3, CF2H, or CH2CF3; or (ii) one instance of G3is S-(Ci-4alkyl), wherein the C1-4 alkyl is optionally substituted with 1-7 deuterium or F, e.g., one G3is SCF2or SCF3; and any remaining G3is as defined in (i).Embodiment A22. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is a pyridinyl (e.g., 2-pyridinyl or 3-pyridinyl) substituted with (i) 1 or 2 substituents independentlyselected from deuterium, halogen (e.g., F or Cl), CN, CM alkyl, O-(Ci-4 alkyl), SO2- (C1-4 alkyl), OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)(Ci-4 alkyl), or (ii) one substituent selected from S-(Ci-4 alkyl), SF5, cyclopropoxy, or cyclobutoxy, and any remaining substituent(s) as defined in (i); wherein each of the aforementioned CM alkyl is independently optionally substituted with 1-7 deuterium or F, for example, R13Acan be selected from the following:preferably, the pyridinyl is substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and optionally a further substituent selected from F or Cl.Embodiment A23. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is a phenyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which is substituted with (i) 1 or 2 substituents independently selected from deuterium, halogen (e.g., F or Cl), CN, C1-4 alkyl, O-(Ci4 alkyl), SO2-(Ci-4 alkyl), OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)(Ci-4 alkyl), or (ii) one substituent selected from S-(CM alkyl), SF5, cyclopropoxy, or cyclobutoxy, andany remaining substituent(s) as defined in (i); wherein each of the aforementioned Ci- 4 alkyl is independently optionally substituted with 1-7 deuterium or F, for example, R13Acan be selected from the following:Embodiment A24. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is a pyrazolyl, optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F, Cl, Br, etc.), Ci-4 alkyl, 3-4 membered carbocyclic or heterocyclic ring, or (Ci-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring), wherein the Ci-4 alkyl, Ci-4 alkylene, or 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, F, OH, or methyl, for example, R13Acan be selected from the following:Embodiment A25. The compound of any of Embodiments A8-17, or a pharmaceutically acceptable salt thereof, wherein R13A, when present, is a 5-7 membered heterocyclic ring, such as a tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, etc., which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F), oxo, Ci-4 alkyl, 3-4 membered carbocyclic or heterocyclic ring, or (Ci-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring), wherein the Ci-4 alkyl, Ci-4 alkylene, or 3-4 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, F, OH, or methyl, for example, R13Acan be selected from the following:Embodiment A26. The compound of any of Embodiments A 1-25, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring or a 5 or 6- membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as pyridine ring.Embodiment A27. The compound of any of Embodiments A 1-25, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl, pyridinyl, pyrimidinyl, or imidazo[l,2-a]pyridinyl ring, preferably, a phenyl or pyridinyl ring.Embodiment A28. The compound of any of Embodiments A 1-25, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula Al, A2, or A3:Embodiment A29. The compound of any of Embodiments A 1-28, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2, and R2at eachoccurrence is independently deuterium, halogen, CN, OH, (CM alkylene)-CN, GA, or Xa-Xb-GA, wherein:Xaat each occurrence is independently null, CM alkylene, or C 1-4 heteroalkylene;Xbat each occurrence is independently null, O, NH, N(GB), C(O), C(O)O, C(O)NH, C(O)N(GB), NHC(O), N(GB)C(O), SO2, SO2NH, or SO2N(GB); andGAat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, CM alkyl, CM alkoxy, or a 3-6 membered ring;(iii) a 3-7 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, CM alkyl, CM alkoxy, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, CM alkyl, Ci -4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein the CM alkyl or C 1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F;GBat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F, orwhen applicable, GAand GBare joined to form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F.Embodiment A30. The compound of Embodiment A29, or a pharmaceutically acceptable salt thereof, wherein m is 0.Embodiment A31. The compound of Embodiment Al or 29, or a pharmaceutically acceptable salt thereof, wherein m is 1, e.g., R2has a structure according to M-l to M- 13 as defined herein in connection with Formula K and its subformulae, or a structuredefined herein.Embodiment A32. The compound of Embodiment A31, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized as having a structure according to Formula Ala or A2a:Formula A2a.Embodiment A33. The compound of Embodiment A31 or 32, or a pharmaceutically acceptable salt thereof, wherein R2is a C1-4 alkyl optionally substituted with deuterium, F, and / or OH, e.g., methyl, difluoromethyl, or hydroxymethyl.Embodiment A34. The compound of Embodiment A31 or 32, or a pharmaceutically acceptable salt thereof, wherein R2is a 5 or 6-membered heteroaryl, which isoptionally substituted with 1 -3 substituents each independently halogen, OH, CN, CM alkyl, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein the CM alkyl or CM alkoxy is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F), OH, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein each of the 3-5 membered carbocyclic or heterocyclic ring, when present, is independently optionally substituted with deuterium, F, OH, and / or methyl.Embodiment A35. The compound of Embodiment A31 or 32, or a pharmaceutically acceptable salt thereof, wherein R2is -(CM alkylene)-C(O)NHGA, -(CM alkylene)- C(O)N(GA)(GB) or -(CM alkylene)-CN, preferably, GAand GBare each independently a Ci -4 alkyl optionally substituted with deuterium, F and / or OH.Embodiment A36. The compound of any of Embodiments Al-35, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl, pyridinyl, pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[l,2- a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5- b]pyridinyl, benzo[d]thiazole, indazolyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, [l,2,4]triazolo[l,5-b]pyridazinyl, or tetrazolo[l,5-a]pyridinyl, each of which is optionally substituted.Embodiment A37. The compound of any of Embodiments Al-35, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with 1-3 substituents independently selected from: deuterium, halogen, CN, OH, NH2, COOH, CONH2, (CM alkylene)-CN, Gc, or Xc- Xd-Gc, wherein:Xcat each occurrence is independently null, CM alkylene, or CM heteroalkylene;Xdat each occurrence is independently null, O, NH, N(GD), C(O), C(O)O, C(O)NH, C(O)N(GD), NHC(O), N(GD)C(O), P(O)(GD), SO2, SO2NH, or SO2N(GD); and Gcat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, CM alkyl, CM alkoxy, or a 3-6 membered ring;(iii) a 3-7 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, C1-4 alkyl, C1-4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein the C1-4 alkyl or C1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) is independently optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F;GDat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F, or when applicable, Gcand GDtogether with the heteroatom they are both attached to are joined to form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F.Embodiment A38. The compound of any of Embodiments Al-35, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, Ci -6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CM alkyl)(Ci-4 alkyl).Embodiment A39. The compound of any of Embodiments Al-35, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen, CM alkyl optionally substituted with deuterium, F and / or OH, Ci -4 alkoxy optionally substituted with deuterium or F, C3-4 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-3 alkyl), or N(CI-3 alky 1)(C 1.3 alkyl).Embodiment A40. The compound of any of Embodiments Al-35, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with 1-3 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1 -hydroxy ethyl, preferably, the substituents are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.Embodiment A41. The compound of any of Embodiments Al-35, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula Alb, Ale, A2b or A2c:Formula A2b Formula A2c,wherein Rlaand Rlbare each independently halogen, Ci-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, Ci-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4alkyl), or N(CM alkyl)(Ci-4alkyl).Embodiment A42. The compound of Embodiment A41 , or a pharmaceutically acceptable salt thereof, wherein Rlaand Rlbare each independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxy ethyl, more preferably, Rlaand Rlbare each independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, and cyclopropyl.Embodiment A43. The compound of Embodiment A41 , or a pharmaceutically acceptable salt thereof, wherein Rlbis C1-2 alkoxy optionally substituted with 1-3 deuterium or F, preferably, Rlbis methoxy, ethoxy, or difluoromethoxy.Embodiment A44. The compound of any of Embodiments A41-43, or a pharmaceutically acceptable salt thereof, wherein Rlais halogen, C1-3 alkyl optionally substituted with 1-3 deuterium or F, or cyclopropyl, preferably, Rlais methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, or cyclopropyl.

[0219] In some embodiments, the present disclosure also provides a compound selected from Table 1 below, a deuterated analog thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0220] In some embodiments, to the extent applicable, the genus of compounds described herein also excludes any specifically known single compounds prior to this disclosure. In some embodiments, to the extent applicable, any sub-genus or species of compounds prior to this disclosure that are entirely within a genus of compounds described herein can also be excluded from such genus herein.Method of Synthesis

[0221] The compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplified syntheses are also shown in the Examples section.

[0222] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis”, 4thed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Sigma- Aldrich (Milwaukee, Wisconsin, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (Wiley, 7thEdition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any of available updates as of this filing.Pharmaceutical Compositions

[0223] Certain embodiments are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure.

[0224] The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1- la, I-lb, I-lc, Lid, Lie, I-lf, 1-lg, 11, 11-1, 111, 111-1, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K- 3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington’s The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

[0225] The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula A or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating a cancer herein) of a compound selected from any of Examples 1-266, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition can comprise a compound selected from the compounds according to Examples 1-266 that have an IC50 value less than 100 nM, more preferably, less than 50 nM, as measured according to Biological Example 1.

[0226] The pharmaceutical composition herein can be formulated for delivery via any of the known routes of delivery, which include but not limited to administering orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally.

[0227] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparation of compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, com starch, com oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer’s solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0228] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3- butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.

[0229] Compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, e.g., in combinationwith an additional anticancer therapeutic agent, such as a PARP inhibitor, a signal transduction inhibitor, a chemotherapeutic agent, and / or an immune checkpoint inhibitor.

[0230] When used in combination with one or more additional therapeutic agents, compounds of the present disclosure or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can comprise one or more compounds of the present disclosure and the one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the present disclosure can be included in a kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents.

[0231] The pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, such as a cancer herein, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.Method of Treatment / Use

[0232] Compounds of the present disclosure have various utilities. For example, compounds of the present disclosure can be used as therapeutic active substances for the treatment and / or prophylaxis of a disease or disorder associated with Pol0, such as overexpression of PolO. Accordingly, some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure or pharmaceutical compositions herein for treating or preventing a disease or disorder associated with PolO in a subject in need thereof, such as for treating cancer in a subject in need thereof.

[0233] In some embodiments, the present disclosure provides a method of inhibiting PolO enzyme activity, e.g., DNA repair activity mediated by PolO, in a cell, the method comprising contacting the cell with an effective amount of the compound of present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1-la, I-lb, I-lc, I-ld, I-le, I-lf, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K- 5 a, or K-5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof). In some embodiment, contacting the cell occurs in vitro. In some embodiment, contacting the cell occurs in vivo. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is an HR deficient cell. In some embodiments, the cancer cell has overexpression of PolO. The cancer cell can be a cell of any of the cancer described herein.

[0234] In some embodiments, the present disclosure provides a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting the cell with an effective amount of the compound of present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, I-la, I-lb, I-lc, I-ld, I-le, I-lf, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof). In some embodiments, the cell is a cancer cell. In some embodiments, the cell is an HR deficient cell. In some embodiments, the cancer cell has overexpression of PolO. The cancer cell can be a cell of any of the cancer described herein.

[0235] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with PolO in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1-la, I-lb, I-lc, I-ld, I-le, I- If, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, any of the compounds listed in Table1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein. In some embodiments, the disease or disorder associated with PolO is a cancer described herein. In some embodiments, the disease or disorder associated with PolO is characterized by an overexpression of PolO. In some embodiments, the cancer is a homologous recombination (HR) deficient cancer. In some embodiments, the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein. In some embodiments, the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. In some embodiments, the cancer is selected from lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer.

[0236] In some embodiments, the present disclosure provides a method of treating a homologous recombination (HR) deficient cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1-la, I- lb, I-lc, I- Id, I-le, I-lf, I-lg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K- lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein. In some embodiments, the HR-deficient cancer is breast cancer. Breast cancer includes, but is not limited to, lobular carcinoma in situ (LCIS), a ductal carcinoma in situ (DCIS), an invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, Angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or another breast cancer, including but not limited to triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive. Insome embodiments, the HR-deficient cancer is ovarian cancer. Ovarian cancer includes, but is not limited to, epithelial ovarian carcinomas (EOC), maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinoma.

[0237] In some embodiments, the present disclosure provides a method of treating a cancer in a subject in need thereof, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRCA gene, and / or reduced function of BRCA protein, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, 1-la, Lib, Lie, Lid, Lie, Llf, Llg, II, IL1, III, IIL1, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 -266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein.

[0238] In some embodiments, the present disclosure provides a method of treating a cancer in a subject in need thereof, wherein the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy, the method comprising administering to the subject a therapeutically effective amount of the compound of present disclosure (e.g., a compound of Formula A (e.g., Formula 1, 1-1, Lla, Lib, Lie, Lid, Lie, Llf, Llg, II, II-l, III, III-l, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K- 9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K-lb-3, K-lb-4, K-3a, K-3b, K-5a, or K- 5b), any of Examples 1-266, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined herein. In some embodiments, the cancer resistant to PARP inhibitor therapy is selected from breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer. As used herein and unless otherwise specified, the phrase “cancer resistant to PARP inhibitor therapy” means that the cancer is not responding to a PARP inhibitor or that the cancer is not responding sufficiently to the PARP inhibitor or that the cancer has progressed on or after treatment with the PARP inhibitor. For example, in some cases, the subject having the cancer may at one time beresponsive to the PARP inhibitor but has become no longer responsive to such treatment or is no longer responding sufficiently to such treatment.

[0239] The compound of the present disclosure can be used alone, in combination with a different Pol0 inhibitor, or in combination with other active agents or other prophylactic or therapeutic modalities. In some embodiments, the compound of the present disclosure can be used in a combination therapy, such as in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents.

[0240] In some embodiments, the compound of the present disclosure is administered in combination with at least one additional therapeutic agent, such as a PARP inhibitor, a signal transduction inhibitor, a chemotherapeutic agent, and / or an immune checkpoint inhibitor.

[0241] In some embodiments, the additional therapeutic agent is a signal transduction inhibitor (STI) or chemotherapeutic agent. As used herein, the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. In some embodiments, chemotherapeutic agents include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. Agents involved in immunomodulation can also be used in combination with one or more compounds of the present disclosure.

[0242] In some embodiments, the compound of the present disclosure is administered in combination with one or more poly ADP ribose polymerase (PARP) inhibitors. For example, in some embodiments, the method herein is for treating a cancer in a subject who is not responsive to a PARP inhibitor therapy or has developed resistance to the PARP inhibitor, the method can comprise administering to the subject one or more compounds of the present disclosure in combination with a PARP inhibitor. Without wishing to be bound by theories, it is believed that in such embodiments, the administration of Pol0 sensitizes or resensitizes the cancer to PARP inhibitor treatment. Suitable PARP inhibitors include any of those known in the art, such as those approved for marketing by the U.S. Food and Drug Administration or a non-US counterpart agency. In some embodiments, the methodcomprises administering to the subject a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.

[0243] In some embodiments, the compound of the present disclosure is administered in combination with an immune checkpoint inhibitor. The tremendous number of genetic and epigenetic alterations that are characteristic of all cancers provides a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate amplitude (e.g., levels of cytokine production or proliferation) and quality (e.g., the type of immune response generated, such as the pattern of cytokine production) of the response, which is initiated through antigen recognition by the T-cell receptor (TCR), is regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are crucial for the prevention of autoimmunity (i.e., the maintenance of self-tolerance) and for the protection of tissues from damage when the immune system is responding to pathogenic infection. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism. Examples of immune checkpoint inhibitors include but are not limited to those targeting CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, 0X40, 4 IBB, VISTA, CD96, TGFp, CD73, CD39, A2AR, A2BR, IDO1, TD02, Arginase, B7-H3, and / or B7-H4. For example, in some embodiments, the method comprises administering to the subject an anti-PD-1 antibody, such as pembrolizumab or nivolumab, and / or an anti-PD- L1 antibody, such as avelumab or atezolizumab. In some embodiments, the method comprises administering to the subject an anti-CTLA-4 antibody, such as ipilimumab. Cellbased modulators of anti-cancer immunity are also contemplated. Agents that may be combined with a PolO inhibitor also include those described in WO2020243459A1, W02022118210A1, WO2022259204A1, and WO2023067515A1.

[0244] As understood herein, the term "combination" refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0245] Dosing regimen including doses for the methods described herein can vary and be adjusted, which can depend on the recipient of the treatment, the disorder, condition ordisease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.Definitions

[0246] It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

[0247] It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.

[0248] Suitable groups for the variables in compounds of Formula A, Formula K, or a subformula thereof, as applicable, are independently selected. Non-limiting useful groups for the variables in compounds of Formula A, Formula K, or a subformula thereof, as applicable, include any of the respective groups, individually or in any combination, as shown in the Examples or in the specific compounds described in Table 1 herein. In addition, it is to be understood that the definition of a variable in Formula A or Formula K can have the same definition for the variable defined in a subformula of Formula A or Formula K, respectively. Similarly, unless otherwise specified or contrary from context, the definition of a subformula of Formula A or Formula K can have the same definition for the variable defined in connection with Formula A or Formula K or another subformula of Formula A or Formula K, respectively.

[0249] The described embodiments of the present disclosure can be combined. Such combination is contemplated and within the scope of the present disclosure. For example, it is contemplated that the definition(s) of any one or more of Z, J1, J2, J3, R1, R2, Ring A, Ring B, and m of Formula A can be combined with the definition of any one or more of the other(s) of Z, J1, J2, J3, R1, R2, Ring A, Ring B, and m, as applicable, and the resulted compounds from the combination are contemplated and within the scope of the present disclosure.

[0250] The symbol, when displayed perpendicular to (or otherwise crossing) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule. It should be noted that for a divalent structure (or multivalent structure), the immediately connected group or groups or appropriate variable(s) shown in a formula may be shown in the divalent structure (or multivalent structure) beyond the symbol, to indicate direction of attachment. When the immediately connected group(s) or variable is not shown for either- Il l - of the two attaching points of a divalent structure, it should mean that either direction of attachment to the remainder of the molecule is allowed, unless otherwise specified or obviously contrary from context.

[0251] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.

[0252] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), chiral supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. When a stereochemistry is specifically drawn, unless otherwise contradictory from context, it should be understood that with respect to that particular chiral center or axial chirality, the compound can existpredominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer(s), for example, the compound can have an enantiomeric excess of greater than 60%, greater than 80%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. The presence and / or amounts of stereoisomers can be determined by those skilled in the art in view of the present disclosure, including through the use of a chiral HPLC or chiral SFC. As understood by those skilled in the art, when a is shown in the chemical structures herein, unless otherwise contradictory from context, it is to designate that the corresponding chiral center is enantiomerically pure or enriched in either of the configurations or is enantiomerically pure or enriched in the as-dawn configuration, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer(s). Also, when no stereochemistry is specifically drawn, and no is used in the chemical structures, unless otherwise contradictory from context, it should be understood that such structures include the corresponding compound in any stereoisomeric forms, including individual isomers substantially free of other isomers and mixtures of various isomers including racemic mixtures.

[0253] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “Ci-e” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, Ci-5, CM, C1-3, C1-2, C2-6, C2-5, C2M, C2-3, Cw>, C3-5, C3M, C4^, C4-5, and Cw>.

[0254] As used herein, the term “compound(s) of the present disclosure” refers to any of the compounds described herein according to Formula A (e.g., Formula 1, 1-1, Lla, Lib, I-lc, Lid, Lie, Llf, Llg, II, II-l, III, IIL1, Al, A2, A3, Ala, Alb, Ale, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), Formula K (e.g., Formula K-l, K-2, K-3, K-4, K-5, K-6, K-7a, K-7b, K-8a, K-8b, K-9a, K-9b, K-la-1, K-la-2, K-lb, K-lc, K-lb-1, K-lb-2, K- lb-3, K-lb-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1-266, or any of the specific compounds disclosed in Table 1 herein, isotopically labeled compound(s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is / are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD3 analog when the compound has a CH3 group), possible regioisomers, possible geometric isomers, possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, pharmaceutically acceptable estersthereof, and / or possible pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HC1 salt or base addition salt such as Na salt). Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound(s) is in association with water or solvent, respectively.

[0255] Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to2H,3H,13C,14C,15N,180,32P, 35S,18F,36C1, and125I. Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention.

[0256] As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.

[0257] As used herein, the term "alkyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl can include one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated. In one embodiment, the alkyl group is a straight chain C1-10 alkyl group. In another embodiment, the alkyl group is a branched chain C3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C1-4 alkyl group. For example, a C1-4 alkyl group includes methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, and the like.

[0258] As used herein, the term "alkenyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, for example, one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C2-6 alkenyl group. In another embodiment, the alkenyl group is a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0259] As used herein, the term "alkynyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one or more, for example, one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C2-6 alkynyl group. In another embodiment, the alkynyl group is a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0260] As used herein, the term "alkoxy" as used by itself or as part of another group refers to a radical of the formula ORal, wherein Ralis an alkyl.

[0261] As used herein, the term "cycloalkoxy" as used by itself or as part of another group refers to a radical of the formula ORaI, wherein Ralis a cycloalkyl.

[0262] As used herein, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a Ci-10 haloalkyl group. In one embodiment, the haloalkyl group is a C1-6 haloalkyl group. In one embodiment, the haloalkyl group is a C1-4 haloalkyl group.

[0263] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, in which one or more of the carbons has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) S, O. P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent(s) can replace one or more hydrogen atoms attached to the carbon atom(s) and / or the heteroatom(s) of the heteroalkyl. In some embodiments, the heteroalkyl is a C 1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of C1-4 heteroalkyl include, but are not limited to, C4 heteroalkyl such as -C^-CHi-NfCHq-CHi, C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2- S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2heteroalkyl such as -CH2-CH2-OH, -CH2-CH2-NH2, - CH2-NH(CH3), -O-CH2-CH3 and Ci heteroalkyl such as, -CH2-OH, -CH2-NH2, -O-CH3. Preferably, the C1-4 heteroalkyl (or CM heteroalkylene) herein contains 1 or 2 heteroatoms,such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2- CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R or the like.

[0264] In some preferred embodiments, unless otherwise specified or contrary from context, a C1-6 heteroalkyl herein can be a C1-6 alkoxy, NH(CI-6 alkyl), N(CI-4 alkyl)(Ci-4 alkyl), -(C1-5 alkylene)-O-(Ci-5 alkyl), -(C1-5 alkylene)-NH(Ci-5 alkyl), -(C 1-4 alkylene) -N(C 1-4 alkyl)(Ci-4alkyl), -(C1-5 alkylene)-S-(Ci-5alkyl), -(C1-5 alkylene)-SO2-(Ci-5alkyl), SO2(Ci-6alkyl), P(0)(CM alkyl)(Ci-4 alkyl), SO2NH(C 1-6 alkyl), S02N(CM alkyl)(Cw alkyl), -(C1-5 alkylene)-SO2NH-(Ci-5 alkyl), or -(C1-4 alkylene)-S02N(Ci4 alky 1 )(C 1 -4 alkyl), provided that the total number of carbons are no greater than 6, not counting any optional substituents.

[0265] In some preferred embodiments, unless otherwise specified or contrary from context, a CM heteroalkyl herein can be a CM alkoxy, NH(CI-4 alkyl), N(Ci-3 alkyl) (C 1-3 alkyl), -(C1-3 alkylene)-O-(Ci-3 alkyl), -(Ci-3 alkylene)-NH(Ci-3 alkyl), -(C1-2 alkylene) -N(C 1-2 alkyl)(Ci-2 alkyl), -(C1-3 alkylene)-S-(Ci-3 alkyl), -(C1-3 alkylene)-SO2-(Ci-3 alkyl), S02(CM alkyl), P(O)(Ci-3alkyl)(Ci-3alkyl), SO2NH(CM alkyl), SO2N(Ci-3alkyl)(Ci-3alkyl), -(C1-3 alkylene)-SO2NH-(Ci-3 alkyl), or -(C1-2 alkylene)-SO2N(Ci-2 alkyl)(Ci-2 alkyl), provided that the total number of carbons are no greater than 4, not counting any optional substituents.

[0266] “Carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non-aromatic cyclic hydrocarbon group having at least 3 carbon atoms, e.g., from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”), and zero heteroatoms in the non- aromatic ring system. The carbocyclyl group can be either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. Non-limitingexemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the carbocyclyl group defined herein.

[0267] In some embodiments, “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl. In some embodiments, the cycloalkyl can have from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" as used by itself or as part of another group refers to a divalent radical derived from a cycloalkyl group, for example,, etc.

[0268] Unless otherwise defined or contrary from context, a heteroatom herein refers to an atom selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.

[0269] “Heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3-membered or larger, such as 3- to 14-membered, non-aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. When all ring carbon atoms in a heterocyclyl as defined herein are saturated carbons, then the heterocyclyl may also be referred to as a heterocycloalkyl. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings, and the point of attachment can be on any ring. As used herein, the term "heterocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the heterocyclyl group defined herein. The heterocyclyl or heterocylylene can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.

[0270] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydro thiophenyl,pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7- membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5- membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as an example of a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6- membered heterocyclyl groups fused to an aryl ring (also referred to herein as an example of a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0271] “Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2- naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 aryl”; e.g., anthracyl). As used herein, the term "arylene" as used by itself or as part of another group refers to a divalent radical derived from the aryl group defined herein.

[0272] “Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

[0273] “Heteroaryl” as used by itself or as part of another group refers to a radical of a 5- 14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and at least one, preferably, 1-4, ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-14 membered heteroaryl”). AsO used herein, for clarity, a pyridone (e.g., a pyridin-2-one,, wherein R can be hydrogen or a nitrogen atom substituent), pyrimidinone, or the like, such as a pyridone fused to an aryl or heteroaryl (e.g., o6'" , wherein R can be hydrogen or a nitrogen atom substituent), is considered a heteroaryl ring herein. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like), the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene" as used by itself or as part of another group refers to a divalent radical derived from the heteroaryl group defined herein.

[0274] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl,isoindolyl, indazolyl, benzotri azol yl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0275] “Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0276] As used herein, unless specified or otherwise contrary, a "ring structure", "cyclic structure", or simply "ring", with a designated number of ring members, such as a "3-10 membered ring structure", a "3-12 membered ring structure", or a "5- or 6-membered ring", should be understood as encompassing any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having the designated number of ring members, which can be (1) monocyclic or polycyclic (as chemically feasible), such as a monocyclic ring or a bicyclic or tricyclic ring (including fused, spiro, and bridged bicyclic or tricyclic ring, and those ring systems where two monocyclic rings are connected through a single or double bond); (2) aromatic, partially unsaturated, or fully saturated; and in the case of a polycyclic structure, each ring can be independently aromatic, partially unsaturated, or fully saturated; and (3) containing no heteroatom (i.e., all ring members are carbon atoms) or 1-4 heteroatoms; or in the case of a polycyclic structure, each ring can independently have no ring heteroatom or 1-4 ring heteroatoms (e.g., O, N, S, etc.). When a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom can be optionally oxidized. One or more ring carbon atoms in a ring structure can be present as C(=O). A fully saturated ring refers to a ring in which none of the ring carbon atom(s) and any present ring heteroatom(s) (e.g., nitrogen) forms a double bond or triple bond with any other atom. The ring structure can be optionally substituted with one or more substituents described herein. The substituents of a ring structure herein can also have a cyclic structure, and in some cases, two substituents of a ring structure may be said to be joined to form a cyclic structure.

[0277] As commonly understood in the art, for clarity, when a structure can be characterized in multiple ways, as long as one such characterization falls within the scope of the definition of a variable herein, it can be said that the structure is a suitable definition forthe variable. For example, when a monovalent variable is defined as an optionally substituted6-membered ring, the variable encompasses, among other structures, (a) the structure ofwhich can be viewed as a 6-membered monocyclic or bicyclic ring substituted with a phenyl group; and (b) the structure of, which can be viewed as a 6-membered ring, wherein two substituents are joined to form a cyclopropyl ring(unless the optional substituents for the 6-membered ring are specified and do not include this as an option); but the variable would not encompassbecause the attaching ring is not a 6-membered ring under any characterization of the structure. To further explain, when the variable is instead defined as an optionally substituted monocyclic 6-membered ring, then the variable does not encompass, but encompasses the structure of(unless the optional substituents for the 6-membered ring are specified and do not include this as an option). And if the variable is defined as a 6-membered ring optionally substituted with halogen, then the variable can encompass structures such as,as each of which can be viewed as a 6-membered ring that is unsubstituted or substituted with 1 or two fluorine atoms.

[0278] As commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to thecorresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalky], carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.

[0279] An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable, each of which can be optionally isotopically labeled, such as deuterated. Two of the optional substituents can join to form a ring structure, such as an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle. Typically, substitution herein does not result in an O-O, O-N, S-S, S-N (except SO2-N bond), heteroatom-halogen, or -C(O)-S bond or three or more consecutive heteroatoms, with the exception of O-SO2-O, O-SO2-N, and N-SO2-N, except that some of such bonds or connections may be allowed if in a stable aromatic system.

[0280] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate.

[0281] Exemplary substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, - alkynylene-heteroaryl, — OH, hydroxyalkyl, haloalkyl, — O-alkyl, — O-haloalkyl, -alkylene- O-alkyl, — O-aryl, — O-alkylene-aryl, — O-heteroaryl, — O-alkylene-heteroaryl, — O- cycloalkyl, — O-heterocycloalkyl, acyl, — C(O)-alkyl, — C(O)-haloalkyl, — C(O)-aryl, — C(O)-alkylene-aryl, — C(O)-heteroaryl, — C(O)-alkylene-heteroaryl, — C(O)-cycloalkyl, — C(O)-heterocycloalkyl, halo, — NO2, — CN, — SF5, — C(O)OH, — C(O)O-alkyl, — C(O)O- aryl, — C(O)O — alkylene-aryl, — S(O)-alkyl, — S(O)2-alkyl, — S(O) -haloalkyl, — S(O)2- haloalkyl, — S(O)-aryl, — S(O)2-aryl, — S(O)-heteroaryl, — S(O)2-heteroaryl, — S-alkyl, — S- aryl, — S-heteroaryl, — S-alkylene-aryl, — S-alkylene-heteroaryl, — S(O)2-alkylene-aryl, — S(O)2-alkylene-heteroaryl, — S-cycloalkyl, — S-heterocycloalkyl, — S(O)-cycloalkyl, — S(O)-heterocycloalkyl, — S(O)2-cycloalkyl, — S(O)2-heterocycloalkyl, — S(O)(=NH)-alkyl, — S(O)(— NH)-haloalkyl, — S(O)(— NH)-aryl, — S(O)(— NH)-alkylene-aryl, — S(O)(— NH)- heteroaryl, — S(O)(=NH)-alkylene-heteroaryl, — S(O)(=NH)-cycloalkyl, — S(O)(=NH)- heterocycloalkyl, — S(O)(=Nalkyl)-alkyl, — S(O)(=Nalkyl)-haloalkyl, — S(O)(=Nalkyl)- aryl, — S(O)(=Nalkyl)-alkylene-aryl, — S(O)(=Nalkyl)-heteroaryl, — S(O)(=Nalkyl)- alkylene-heteroaryl, — S(O)(=Nalkyl)-cycloalkyl, — S(O)(=Nalkyl)-heterocycloalkyl, cycloalkyl, heterocycloalkyl, — O — C(O)-alkyl, — O — C(O)-aryl, — O — C(O)-cycloalkyl, — C(=N— CN)— NH2, — C(=NH)— NH2, — C(=NH)— NH(alkyl), — N(YI)(Y2), -alkylene- N(Yi)(Y2), — C(O)N(Y 1XY2) and — S(O)2N(YI)(Y2), wherein Y 1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, and Y 1 and Y2 with the nitrogen they linked can form a heterocyclic ring.

[0282] Some examples of suitable substituents include, but not limited to, (Ci-Cs)alkyl groups, (C2-C8)alkenyl groups, (C2-Cs)alkynyl groups, (C3-Cio)cycloalkyl groups, halogen(F, Cl, Br or I), halogenated (Ci-C8)alkyl groups (for example but not limited to — CF3), — O — (Ci-C8)alkyl groups, — OH, — S — (Ci-Cs)alkyl groups, — SH, — NH(Ci-C8)alkyl groups, — N((Ci-Cs)alky 1)2 groups, — NH2, — C(0)NH2, — C(O)NH(Ci-C8)alkyl groups, — C(O)N((Ci-C8)alkyl)2, — NHC(O)H, — NHC(O)(Ci-C8)alkyl groups, — NHC(O)(C3- C8)cycloalkyl groups, — N((Ci-C8)alkyl)C(O)H, — N((Ci-C8)alkyl)C(O)(Ci-Cs)alkyl groups, — NHC(O)NH2, — NHC(O)NH(Ci-C8)alkyl groups, -N((Ci-C8)alkyl)C(O)NH2groups, — NHC(O)N((Ci-C8)alkyl)2 groups, — N((Ci-C8)alkyl)C(O)N((Ci-C8)alkyl)2groups, — N((Ci- C8)alkyl)C(O)NH((Ci-C8)alkyl), — C(O)H, — C(O)(Ci-C8)alkyl groups, — CN, — NO2, — S(O)(Ci-C8)alkyl groups, — S(O)2(Ci-C8)alkyl groups, — S(O)2N((Ci-C8)alkyl)2 groups, — S(O)2NH(Ci-C8)alkyl groups, — S(O)2NH(C3-C8)cycloalkyl groups, — S(O)2NH2 groups, — NHS(O)2(Ci-C8)alkyl groups, — N((Ci-C8)alkyl)S(O)2(Ci-C8)alkyl groups, — (Ci-C8)alkyl- O — (Ci-C8)alkyl groups, — O — (Ci-C8)alkyl-0 — (Ci-Cs)alkyl groups, — C(O)OH, — C(O)O(Ci-C8)alkyl groups, NHOH, NHO(Ci-C8)alkyl groups, — O-halogenated (Ci-Cs)alkyl groups (for example but not limited to — OCF3), — S(O)2-halogenated (Ci-Cs)alkyl groups (for example but not limited to — S(O)2CF3), — S-halogenated (Ci-C8)alkyl groups (for example but not limited to — SCF3), — (Ci-Ce) heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), — (Ci-Ce) heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, — NHC(O)O — (Ci - Ce)alkyl groups, — N((Ci-Ce)alkyl)C(O)O — (Ci-Ce)alkyl groups, — C( — NH) — (Ci-Ce)alkyl groups, — C( — NOH) — (Ci-Ce)alkyl groups, or — C( — N — O — (Ci-C6)alkyl)-(Ci-C6)alkyl groups.

[0283] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C3-io carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include F, Cl, -CN, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -NH2, -N(CI-6 alkyl)2, -NH(Ci-6alkyl), -SH, -SC1-6 alkyl, -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl), -OC(=O)(Ci-6 alkyl), -OCO2(Ci_6 alkyl), -C(=O)NH2, -C(=O)N(Ci-6 alkyl)2, -OC(=O)NH(CI_6alkyl), - NHC(=O)(CI-6alkyl), -N(CI-6alkyl)C(=O)( Ci-6alkyl), -NHCO2(CI-6 alkyl), - NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -NHSO2(CI-6alkyl), - SO2N(CI-6 alkyl)2, -SO2NH(CI-6 alkyl), -SO2NH2,-SO2CI^ alkyl, -SO2OC1-6 alkyl, -OSO2C1_6 alkyl, -SOCi-6 alkyl, Ci-6 alkyl, Ci-6 haloalky], C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents can be joined to form =0.

[0284] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, acyl groups, esters, sulfone, sulfoxide, C1-10 alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, 4thed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p- Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.

[0285] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, Ci-10 alkyl, Ci-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, 4thed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl(BOM), 2-methoxyethoxymethyl (MEM), etc., those forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc.

[0286] Unless expressly stated to the contrary, combinations of substituents and / or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0287] Unless otherwise specified or contrary from context, the optionally substituted groups as referred to herein can be (A) unsubstituted; (B) substituted with one or more substituents each independently deuterium, halogen, CN, or Q’-Q2-Q3-Q4, wherein Q1, Q2, and Q3are each independently null, O, NQ4, C(O), S, SO, SO2, S(O)(=NQ4), CM alkylene optionally substituted with deuterium, F, and / or OH, or P(O)Q4, wherein Q4at each occurrence is independently hydrogen, C1-6 alkyl optionally substituted with one or more Q10, C2-6 alkenyl optionally substituted with one or more Q10, C2-6 alkynyl optionally substituted with one or more Q10, C1-6 heteroalkyl optionally substituted with one or more Q10, or 3-14 membered ring optionally substituted with one or more Q10, wherein Q10at each occurrence is independently deuterium, halogen, oxo (as applicable), CN, or Q20-Q21-Q22-Q23, wherein Q20, Q21, and Q22are each independently null, O, NQ23, C(O), S, SO, SO2, S(O)(=NQ23), CM alkylene optionally substituted with deuterium, F, and / or OH, or P(O)Q23, wherein Q23at each occurrence is independently hydrogen, C1-6 alkyl optionally substituted with one or more Q30, C2-6 alkenyl optionally substituted with one or more Q30, C2-6 alkynyl optionally substituted with one or more Q30, C1-6 heteroalkyl optionally substituted with one or more Q30, or 3-8 membered ring optionally substituted with one or more Q30, wherein Q30at each occurrence is independently deuterium, halogen, oxo (as applicable), CN, OH, NH2, CM alkyl optionally substituted with one or more Q31, CM heteroalkyl optionally substituted with one or more Q31, or 3-5 membered ring optionally substituted with one or more Q31, wherein Q31at each occurrence is independently deuterium, F, OH, CM alkyl optionally substitutedwith deuterium and / or F, or C1-4 heteroalkyl optionally substituted with deuterium and / or F; or (C) two or more substituents of the respective optionally substituted group, and / or one of the substituents of the respective optionally substituted group and another variable herein, are joined to form a ring (e.g., a spiro ring, a fused ring, or a bridged ring), which is optionally substituted with one or more substituents as defined in (B), and any remaining substituents of the respective optionally substituted group are as defined in (B). In some preferred embodiments, the optionally substituted groups as defined in connection with a formula herein can be unsubstituted or substituted with one or more substituents as defined in (B). The combination of Q1, Q2, and Q3is not particularly limited, which can preferably be (a) a linker of O, NQ4, C(O), S, SO, SO2, or P(O)Q4, when two of Q1, Q2, and Q3are null, or (b) a linker of amide (C(O)NQ4), ester (C(O)O), sulfonamide (SO2NQ4), etc., when one of Q1, Q2, and Q3is null, or (c) a linker of carbamate (OC(O)NQ4), urea (NQ4C(O)NQ4), sulfamoylamino (NQ4SO2NQ4), etc., when none of Q1, Q2, and Q3is null. The combination of Q20, Q21, and Q22should be understood similarly.

[0288] Unless otherwise specified or contrary from context, when a group herein is defined as being optionally substituted with one or more substituents selected from a defined list or simply a defined list of substituents, the group is typically unsubstituted or substituted with 1, 2, 3, or 4 substituents as defined, although in some embodiments, the group can also be substituted with more than 4 substituents. For example, an alkyl group optionally substituted with one or more substituents independently selected from deuterium, F, and OH can be typically unsubstituted or substituted with 1-4 substituents each independently deuterium, F, or OH. Similarly, an alkyl group optionally substituted with deuterium and / or F is typically unsubstituted or substituted with 1-4 substituents each independently deuterium or F.

[0289] Unless otherwise specified or contrary from context, a 3-x membered ring herein, wherein x is an integer of 6 or greater, e.g., 3-14 membered, 3-8 membered ring, etc., can be a (i) 3-x membered carbocyclic ring, (ii) 4-x membered heterocyclic ring having 1-3 ring heteroatoms each independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized; (iii) phenyl ring, or phenyl or naphthyl ring when x is 10 or greater; (iv) a 5 or 6- membered heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N, or a 5 or 6-membered heteroaryl ring or bicyclic heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N, when x is 9 or greater.

[0290] Unless otherwise specified or contrary from context, a 3-6 membered ring herein can be a (i) 3-6 membered carbocyclic ring, e.g., cyclopropyl, cyclobutyl, etc., (ii) 4-6 membered heterocyclic ring having 1-2 ring heteroatoms each independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, e.g., oxetane, azetidine, etc.; (iii) a 5-membered heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N; (iv) a 6- membered heteroaryl ring having 1 or 2 ring nitrogen atoms; or (v) a phenyl ring.

[0291] Unless otherwise specified or contrary from context, a 3-5 membered ring herein can be a (1) 3-5 membered carbocyclic ring, e.g., cyclopropyl, cyclobutyl, etc., (ii) 4-5 membered heterocyclic ring having 1-2 ring heteroatoms each independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, e.g., oxetane, azetidine, etc.; or (iii) a 5- membered heteroaryl ring having 1-4 ring heteroatoms each independently O, S, and N.

[0292] In some embodiments, the “optionally substituted” alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, -OH, CN, protected hydroxyl, oxo (as applicable), NH2, protected amino, NH(CI-4 alkyl) or a protected derivative thereof, N(CM alkyl)(Ci-4 alkyl), CM alkyl, C24 alkenyl, C2-4 alkynyl, CM alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3- 7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, -OH, oxo (as applicable), CM alkyl, fluorosubstituted CM alkyl (e.g., CF3), CM alkoxy and fluoro-substituted CM alkoxy. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl or heteroarylene group herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, -OH, -CN, NH2, protected amino, NH(CM alkyl) or a protected derivative thereof, N(CM alkyl)(Ci-4 alkyl), -S(=0)(CM alkyl), -SO2(Ci- 4 alkyl), CM alkyl, C2-4 alkenyl, C2-4 alkynyl, CM alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 , 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1 , 2, or 3 substituents independently selected from deuterium, F, -OH, oxo (as applicable), Ci-4 alkyl, fluoro-substituted Ci-4 alkyl, Ci-4 alkoxy and fluoro-substituted Ci-4 alkoxy.

[0293] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0294] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0295] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of the tautomers depends on several factors, including for example temperature, solvent, and pH. Tautomerizations are known to those skilled in the art. Exemplary tautomerizations include keto-to-enol, amide-to- imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations .

[0296] The term “subject” (alternatively referred to herein as “patient”) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0297] The term "inhibiting", "reducing," or any variation of these terms in relation of PolQ, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of PolO activity compared to its normal activity.

[0298] The term "homologous recombination" refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA.

[0299] The term "homologous recombination (HR) deficient cancer", or any variation thereof, refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence of one or more HR-associated genes or presence of one or more mutations in one or more HR- associated genes. Examples of HR-associated genes include BRCA1 , BRCA2, RAD54, RAD51B, CtlP (Choline Transporter- Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR- associated genes) Nbs 1 (Nibnn), and genes encoding Fanconi anemia (FA) proteins or FA- like genes e.g, FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.

[0300] The term "PolO overexpression", or any variation thereof, refers to the increased expression or activity of PolO in a diseased cell, e.g., cancerous cell, relative to expression or activity of PolO in a normal cell (e.g., non-diseased cell of the same kind). The amount of PolO can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the PolO expression in a normal cell. Examples of cancers having overexpression of PolO include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers.

[0301] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0302] The term "effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, prophylaxis or treatment of diseases. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily bedetermined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells and / or tissues. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0303] As used herein, the singular form “a”, “an”, and “the”, includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.

[0304] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0305] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.Examples

[0306] Abbreviations4A MS 4A molecular sievesBINAP (S)-(-)-2,2'-bis(diphenylphosphino)-l,l'-binaphthylB2Pin2 bis(pinacolato)diboron tBuXPhos 2-di-tert-butylphosphino-2’ ,4, ,6’ -triisopropylbiphenyl cataCXium bis(adamant- 1 -yl)(butyl)phosphine cataCXium A Pd G3 methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino- 1,1'- biphenyl-2-yl)palladium(II) Gen. 3CbzCl benzyloxycarbonyl chlorideCMPI 2-chloro- 1 -methylpyridinium iodideDAST diethylaminosulfur trifluorideDCM dichloromethaneDIAD diisopropyl azodicarboxylateDIPEA N,N-diisopropylethylamineDMAP 4-dimethylaminopyridineDMF N,N-dimethylformamideDMSO dimethylsulfoxideDtbbpy dibutyl [2,2’-bipyridine]-4,4'-dicarboxylateEDCI A-(3-dimethylaminopropyl)-jV'-ethylcarbodiimide hydrochlorideFA formic acidHATU hexafluorophosphate azabenzotriazole tetramethyl uroniumHPLC high-pressure liquid chromatographyHOBT 1 -hydroxybenzotrizoleIr(ppy)3tris(2-phenylpyridine)iridium(TII) hrs hoursLCMS liquid chromatography-mass spectrometryLDA lithium diisopropylamideLiHMDS lithium bis(trimethylsilyl)amideNBS N -bromosuccinimideNiBr2(dtbbpy) [4,4’ -bis(tert-butyl)-2,2’ -bipyridine] nickel dibromideNi(DME)Ch Nickel(II) chloride ethylene glycol dimethyl ether complexNMI N -methylimidazoleNMP l-methyl-2-pyrrolidinonePd2(dba)3tris(dibenzylideneacetone)dipalladiumPd(dppf)Cl2[ 1 , l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II)PE petroleum etherSelectfluor l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis (tetrafluoroborate)SFC super critical fluidTBAI tetrabutylammonium iodideTCFH N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphateTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranXantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXantphos Pd G3 methanesulfonato[(4,5-bis(diphenylphosphino)-9,9- dimethylxanthene)-2-(2'-amino-l,l'-biphenyl)]palladium(II) Gen. 3XPhos dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphineXPhos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l’- biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II)

[0307] The various starting materials, intermediates, and compounds of embodiments herein can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. The abbreviations used in the Examples section should be understood as having their ordinary meanings in the art unless specifically indicated otherwise or obviously contrary from context. The examples are illustrative only and do not limit the claimed invention in any way.

[0308] Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra.Intermediate A6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine

[0309] To a solution of 2-bromo-4-phenyl-cyclohexanone (1.3 g, 5.14 mmol) in THF (15 mL) was added thiourea (390.9 mg, 5.14 mmol). The mixture was stirred at room temperature for 24 hrs. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was treated with water and extracted with EtOAc. The combined organic layers were washed with saturate brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the crude Intermediate A (1.3 g), which was used without further purification. LCMS (ESI, m / z): [M+H]+= 231.1.Intermediate B6-(4-chlorophenyl)-4,5,6,7-tetrahvdro-l,3-benzothiazol-2-amineStep 1: 2-bromo-4-(4-chlorophenyl) cyclohexanone (B-l)

[0310] A mixture of 4-(4-chlorophenyl) cyclohexanone (340 mg, 1.63 mmol), NBS (290 mg, 1.63 mmol) and p-toluenesulfonic acid (28.1 mg, 0.163 mmol) in CCI4 (5 mL) was stirred at 80 °C for 4 hrs. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 1-5% EtOAc in PE) to afford 2-bromo-4- (4-chlorophenyl) cyclohexanone (210 mg).]H NMR (400 MHz, DMSO-de) 5 7.43-7.30 (m, 4H), 4.63-4.57 (m, 1H), 3.43-3.33 (m, 1H), 3.22-3.12 (m, 1H), 2.68-2.58 (m, 1H), 2.34-2.18 (m, 2H), 2.09-1.93 (m, 2H).Step 2: 6-(4-chlorophenyl)-4,5,6,7-tetrahydro-l,3-benzothiazol-2-amine (B)

[0311] A solution of 2-bromo-4-(4-chlorophenyl) cyclohexanone (210 mg, 0.73 mmol) and thiourea (133 mg, 1.75 mmol) in THF (10 mL) was stirred at room temperature for 2 hrs under N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford Intermediate B (180 mg). LCMS (ESI, m / z): [M+H]+= 265.0.Intermediate C2-amino-5-(4-chlorophenyl)-6,7-dihydrothiazolo[5.4-c1pyridin-4(5H)-oneStep 1: ethyl 3-((4-chlorophenyl)amino)propanoate (C-l)

[0312] To a solution of 4-chloroaniline (13.8 g, 0.108 mol) in acetic acid (8 mL) was added ethyl acrylate (13.0 g, 0.130 mol). The mixture was stirred at 100 °C for 16 hrs. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na^SCA, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 5% EtOAc in PE) to afford ethyl 3- ((4-chlorophenyl)amino)propanoate (13 g). LCMS (ESI, m / z): [M+H]+= 228.1.Step 2: ethyl 3-((4-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate (C-2)

[0313] To a solution of ethyl 3-((4-chlorophenyl)amino)propanoate (13.0 g, 0.057 mol) in DCM (40 mL) was added DIPEA (14.7 g, 0.114 mol). After cooling to 0 °C, ethyl 3-chloro- 3-oxopropanoate (10.2 g, 0.068 mol) was added under N2. The mixture was stirred at room temperature for 18 hrs. LCMS showed the reaction was complete. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSCL, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to afford ethyl 3-((4-chlorophenyl)(3-ethoxy-3- oxopropyl)amino)-3-oxopropanoate (10.0 g). LCMS (ESI, m / z): [M+H]+= 342.2.Step 3: ethyl l-(4-chlorophenyl)-2,4-dioxopiperidine-3-carboxylate (C-3)

[0314] To a mixture of ethyl 3-((4-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-3- oxopropanoate (10.0 g, 0.029 mol) in ethanol (20 mL) was added sodium ethoxide (21% in ethanol, 19.1 g, 0.059 mol). The resulting mixture was stirred at reflux for 16 hrs under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was dispersed in chloroform, acidified to pH = 3.0 with 1 N aqueous HC1 and extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum to afford the crude product which was used without purification. LCMS (ESI, m / z): [M+H]+= 296.1.Step 4: l-(4-chlorophenyl)piperidine-2,4-dione (C-4)

[0315] To a round-bottom flask was added ethyl l-(4-chlorophenyl)-2,4-dioxopiperidine- 3-carboxylate (6.5 g, 0.022 mol), acetic acid (50 mL) and water (10 mL). The mixture was stirred at 100 °C for 4 hrs. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was dispersed with water and extractedwith EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under vacuum to afford the crude product which was used without purification. LCMS (ESI, m / z): [M+H]+= 224.0.Step 5: 3-bromo-l-(4-chlorophenyl)piperidine-2, 4-dione (C-5)

[0316] To a solution of l-(4-chlorophenyl)piperidine-2, 4-dione (1.0 g, 4.47 mmol) in CH2CI2 (25 mL) was added NBS (0.952 g, 5.34 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 18 hrs. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The crude product was used without further purification. LCMS (ESI, m / z): [M+H]+= 301.7.Step 6: 2-amino-5-(4-chlorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one (C)

[0317] To the mixture of 3-bromo-I-(4-chlorophenyl)piperidine-2, 4-dione (1.045 g, 3.45 mmol), sodium bicarbonate (320 mg, 3.81 mmol) in ethanol (20 mL) was added thiourea (291 mg, 3.82 mmol). The mixture was stirred at reflux for 2.5 hrs. LCMS showed the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was dispersed with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (0.05% NH4HCO3) to afford Intermediate C (0.45 g). LCMS (ESI, m / z): [M+H]+= 280.1.Intermediate D2-amino-5-(4-chlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one

[0318] To a solution of Intermediate C (220 mg, 0.79 mmol) in 1,4-dioxane was added 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (536 mg, 2.36 mmol) at room temperature. The mixture was stirred at 100 °C for 6 hrs. LCMS showed the reaction was complete. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified byflash column chromatography on silica gel (eluting with 5% EtOAc in PE) to afford Intermediate D (65.0 mg). LCMS (ESI, m / z): [M+H]+= 278.1.Intermediate E6-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[5,l-c1[l,41oxazin-2-amineStep 1: ethyl l-(2-(4-chlorophenyl)-2-oxoethyl)-3-nitro-lH-pyrazole-5-carboxylate (E-l)

[0319] To a solution of ethyl 3-nitro-lH-pyrazole-5-carboxylate (1.00 g, 5.40 mmol) in MeCN (60 mL) was added 2-bromo-l-(4-chlorophenyl)ethanone (1.39 g, 5.95 mmol) and K2CO3 (1.49 g, 10.8 mmol). The mixture was stirred at reflux for 5 hrs. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with 5% aqueous citric acid, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford ethyl 2-[2-(4-chlorophenyl)-2-oxo-ethyl]-5-nitro-pyrazole-3-carboxylate (1.59 g). LCMS (ESI, m / z): [M+H]+= 336.0.Step 2: l-(4-chlorophenyl)-2-(5-(hydroxymethyl)-3-nitro-lH-pyrazol-l-yl)ethan-l-ol (E-2)

[0320] To a solution of ethyl 2-[2-(4-chlorophenyl)-2-oxo-ethyl]-5-nitro-pyrazole-3- carboxylate (1.59 g, 4.71 mmol) in MeOH (59.5 mL) was added sodium borohydride (0.53 g, 14.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 hrs. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with 5% aqueous citric acid, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 20-60% EtOAc in PE) to afford l-(4- chlorophenyl)-2-[5-(hydroxymethyl)-3-nitro-pyrazol-l-yl]ethanol (861.0 mg). LCMS (ESI, m / z): [M+H]+= 296.2.Step 3: 6-(4-chlorophenyl)-2-nitro-6,7-dihydro-4H-pyrazolo[5,l-c1IT,4]oxazine (E-3)

[0321] To a degassed solution of l -(4-chlorophenyl)-2-[5-(hydroxymethyl)-3-nitro- pyrazol-l-yl]ethanol (340.0 mg, 1.14 mmol) in DCM (4 mL) was added PPhs (898.7 mg, 3.43 mmol) and DIAD (692.8 mg, 3.43 mmol) under N2. The mixture was stirred at room temperature for 3 hrs. After completion, the mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous bkoSCh, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 25% EtOAc in PE) to afford 6-(4-chlorophenyl)-2-nitro-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazine (184.0 mg). LCMS (ESI, m / z): [M+H]+= 280.1.Step 4: 6-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[5.1-ciri,41oxazin-2-amine (E)

[0322] To a solution of 6-(4-chlorophenyl)-2-nitro-6,7-dihydro-4H-pyrazolo[5,l- c][l,4]oxazine (180.0 mg, 0.64 mmol) in THF (3 mL) was added Raney nickel (37.8 mg) at room temperature under N2. Hydrazine (85% in water, 379 mg, 6.44 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 3 hrs. LCMS showed the reaction was complete. The mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (0.05% NH4HCO3) to afford Intermediate E (125.0 mg). LCMS (ESI, m / z): [M+H]+= 250.2.Intermediate F5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-amineStep 1: tert-butyl (5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (F-l)

[0323] A mixture of tert-butyl (5-bromothiazolo|5,4-b|pyridin-2-yl)carbamate (700 mg, 2.12 mmol), (4-chlorophenyl)boronic acid (497 mg, 3.18 mmol), Pd(PPli3)2C12 (298 mg, 0.424 mmol) and CS2CO3 (1.45 g, 4.45 mmol) in DMF (36 mL) and water (9 mL) was degassed and stirred at 1160C for 4 hrs under N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 10-50% EtOAc in PE) to afford ten-butyl (5-(4- chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)carbamate (450 mg). LCMS (ESI, m / z): [M+H]+= 362.1.Step 2: 5-(4-chlorophenyl)thiazolo[5,4-b1pyridin-2-amine (F)

[0324] A solution of tert-butyl (5-(4-chlorophenyl) thiazolo[5,4-b] pyridine-2-yl) carbamate_(450 mg, 1.24 mmol) and HC1 (4 M in 1,4-dioxane, 10 mL) in MeOH (10 mL) was stirred at 50 ° C for 1 hr. LCMS showed the reaction was complete. The reaction mixture was concentrated under vacuum to afford crude Intermediate F (400 mg). LCMS (ESI, m / z): [M+H]+= 261.9.Intermediate G5-(6-methoxy-3-pyridyl)thiazolo[5.4-d]pyrimidin-2-amineStep 1: tert-butyl (5-chlorothiazolo[5,4-d]pyrimidin-2-yl)carbamate (G-1)

[0325] To a solution of 5-chlorothiazolo[5,4-d]pyrimidin-2-amine (500 mg, 2.68 mmol), DMAP (33 mg, 0.27 mmol) and TEA (542 mg, 5.36 mmol) in THF (10 mL) was added BOC2O (1.75 g, 8.02 mmol). The mixture was stirred at room temperature for 8 hrs. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford tert-butyl (5-chlorothiazolo[5,4-d]pyrimidin-2-yl)carbamate (500 mg). LCMS (ESI, m / z): [M+H]+= 287.1.Step 2: tert-butyl (5-(6-methoxypyridin-3-yl)thiazolo[5.4-d]pyrimidin-2-yl)carbamate (G-2)

[0326] A mixture of tert-butyl (5-chlorothiazolo[5,4-d]pyrimidin-2-yl)carbamate (220 mg, 0.767 mmol), (6-methoxy-3-pyridyl)boronic acid (141 mg, 0.921 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was added Pd(dppf)C12'CH2C12 complex (125 mg, 0.154 mmol) and CS2CO3 (750 mg, 2.30 mmol) under N2. The mixture was degassed and stirred at 100 °C for 12 hrs under N2 atmosphere. LCMS showed the reaction was complete. The mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 20-50% EtOAc in PE) to afford tertbutyl (5-(6-methoxypyridin-3-yl)thiazolo[5,4-d]pyrimidin-2-yl)carbamate (270 mg). LCMS (ESI, m / z): [M+H]+= 360.3.Step 3: 5-(6-methoxy-3-pyridyl)thiazolo[5,4-d1pyrimidin-2-amine (G)

[0327] A solution of tert-butyl N-[5-(6-methoxy-3-pyridyl)thiazolo[5,4-d]pyrimidin-2- yl]carbamate (260 mg, 0.723 mmol) in HC1 (4 M in 1,4-dioxane, 5 mL) was stirred at 50 °C for 12 hrs. LCMS showed the reaction was complete. The mixture was concentrated under vacuum to afford crude Intermediate G, which was used without further purification. LCMS (ESI, m / z): [M+H]+= 260.1.Intermediate H6-[4-(difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazin-2-amineStep 1 butyl N-[6-r4-(difluoromethoxy)phenyl1thiazolo[4.5-b1pyrazin-2-yl]carbamate (H-l)

[0328] A solution of tert-butyl N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)carbamate (500 mg, 1.51 mmol), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (530 mg, 1.96 mmol), Pd(PPh3)2Ch (212 mg, 0.30 mmol) and CS2CO3 (984 mg, 3.02 mmol) in DMF (8 mL) and water (2 mL) was degassed and stirred at 116 °C for 4 hrs under N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc in PE) to afford tert-butyl N-[6-[4- (difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazin-2-yl]carbamate (550 mg). LCMS (ESI, m / z): [M+H]+= 394.9.Step 2: 6-[4-(difluoromethoxy)phenyl1thiazolo[4,5-b1pyrazin-2-amine (H)

[0329] To a mixture of tert-butyl N-[6-[4-(difluoromethoxy)phenyl]thiazolo[4,5- b]pyrazin-2-yl]carbamate (400 mg, 1.01 mmol) in MeOH (4 mL) was added HC1 (4.0 M in 1,4-dioxane, 4 mL). The mixture was stirred at 50 °C for 2 hrs. LCMS showed the reaction was complete. The mixture was treated with saturated aqueous NaHCOs solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude Intermediate H was used without further purification. LCMS (ESI, m / z): [M+H]+= 295.2.Intermediate I2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine1-3-carboxylic acidStep 1: methyl 2'-chloro-5'-methoxy-6-methyl-[4.4'-bipyridine]-3-carboxylate (1-1)

[0330] To a solution of methyl 4-bromo-6-methylnicotinate (10 g, 43.5 mmol) and (2- chloro-5-methoxypyridin-4-yl)boronic acid (8.96 g, 47.8 mmol) in 1,4-dioxane (100 mL) and H2O (25 mL) was added K2CO3 (18.0 g, 130.2 mmol) and Pd(dppf)C12-CH2C12 complex (3.18 g, 4.3 mmol) under N2. The mixture was degassed and stirred at 80 °C under N2 atmosphere for 2 hrs. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 10-50% EtOAc in PE) to afford methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (10.1 g). LCMS (ESI, m / z): [M+H]+= 293.3.Step 2: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (I)

[0331] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxylate (10.1 g, 34.5 mmol) in THF (50 mL) and H2O (50 mL) was added LiOH-HzO (5.79 g, 138.0 mmol). The mixture was stirred at room temperature for 2 hrs. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to remove most THF. The resulting mixture was acidified with aqueous HC1 solution (2 N) to pH = 4-5. The mixture was extracted with 10% MeOH in DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 10% MeOH in DCM) to afford Intermediate I (8.7 g). LCMS (ESI, m / z): [M+H]+= 278.9.]H NMR (400 MHz, DMSO-rfe) 5 13.05 (br s, 1H), 8.89 (s, 1H), 8.21 (s, 1H), 7.44(s, 1H), 7.30 (s, 1H), 3.78 (s, 3H), 2.56 (s, 3H).Intermediate J5'-methoxy-2',6-dimethv]-[4,4'-bipyridine1-3-carboxylic acidStep 1: methyl 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine1-3-carboxylate (J-l)

[0332] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxylate (8.0 g, 27.3 mmol) in DME (100 mL) was added 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (3.5 M in THF, 25 mL, 87.5 mmol), Pd(dppf)Ch- CH2CI2 complex (3.96 g, 5.41 mmol) and K2CO3 (11.3 g, 81.8 mmol) under N2. The mixture was degassed and stirred at reflux for 16 hrs. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 10-50% EtOAc in PE) to afford methyl 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylate (6.0 g). LCMS (ESI, m / z): [M+H]+= 273.2.Step 2: 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine1-3-carboxylic acid (J)

[0333] To a solution of methyl 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylate (6.0 g, 22.0 mmol) in THF (30 mL), methanol (10 mL) and water (10 mL) was added LiOH (1.05 g, 43.8 mmol). The mixture was stirred at room temperature for 3 hrs. LCMS showed the reaction was complete. The reaction mixture was concentrated under vacuum to remove most of the solvent. The remaining aqueous phase was acidified with aqueous HC1 solution (2 N) to pH = 4-5. The mixture was purified with prep-HPLC (0.05% FA) to afford Intermediate J (3.0 g). LCMS (ESI, m / z): [M+H]+= 259.1;!H NMR (400 MHz, CD3OD) 5 8.88 (s, 1H), 8.12 (s, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 3.84 (s, 3H), 2.63 (s, 3H), 2.54 (s, 3H).Intermediate KA-(5-chlorothiazolor5,4-d]pyrimidin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3- carboxamide

[0334] To a solution of Intermediate J (1.00 g, 3.87 mmol) in MeCN (10 mL) was added 5-chlorothiazolo[5,4-d]pyrimidin-2-amine (0.86 g, 4.61 mmol), CMPI (1.98 g, 7.75 mmol) and EtsN (1.96 g, 19.4 mmol). The mixture was stirred at 40 °C for 3 hrs under N2. LCMS showed the reaction was complete. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturate brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc and PE (2 / 1) and filtered to afford Intermediate K (0.98 g). LCMS (ESI, m / z): [M+H]+= 427.2.Intermediate LA-(5-bromothiazolo[5.4-b1pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4.4'-bipyridine1-3- carboxamide

[0335] To a stirred solution of Intermediate I (1.00 g, 3.59 mmol) and 5- bromothiazolo[5,4-b]pyridin-2-amine (2.48 g, 10.8 mmol) in DMF (40 mL) was added TCFH (3.02 g, 10.8 mmol) and NMI (1.77 g, 21.6 mmol) at room temperature. The mixture was stirred at room temperature for 16 hrs under N2. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 50-80% EA in PE) to afford Intermediate L (860 mg). LCMS (ESI, m / z): [M+H]+= 490.0.Intermediate MA-(6-bromothiazolo[4,5-b1pyridin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine1-3- carboxamide

[0336] To a solution of Intermediate J (1 g, 3.87 mmol) in MeCN (10 mL) was added 6- bromothiazolo[4,5-b]pyridin-2-amine (1.66 g, 7.21 mmol), CMPI (1.98 g, 7.75 mmol) andEi^N (1.96 g, 19.4 mmol). The mixture was stirred at 40 °C under N2 for 2 hrs. LCMS showed the reaction was complete. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NaiSCU, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to afford Intermediate M (600 mg). LCMS (ESI, m / z): [M+H]+= 470.1.Intermediate NA-(3-bromothiazolo[4,5-c]pyridazin-6-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3- carboxamideStep 1: ethyl (3-bromothiazolo[4,5-c]pyridazin-6-yl)carbamate (N-l)

[0337] To a solution of 4,6-dibromopyridazin-3-amine (2 g, 7.91 mmol) in acetone (20 mL) was added O-ethyl carbonisothiocyanatidate (9.10 g, 69.4 mmol). The mixture was stirred under N2 at reflux for 16 hrs. LCMS showed the reaction was complete. The mixture was treated with water and extracted with MeOH / DCM (1 / 3). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the crude product which was used without further purification. LCMS (ESI, m / z): [M+H]+= 303.0.Step 2: 3-bromothiazok>[4,5-c]pyridazin-6-amine (N-2)

[0338] To a solution of the crude ethyl N-(3-bromothiazolo[4,5-c]pyridazin-6- yl)carbamate from step 1 in MeOH (20 mL) was added aqueous NaOH solution (2 N, 20 mL, 40 mmol). The mixture was stirred at 100 °C for 4 hrs. LCMS showed the reaction was complete. The reaction mixture was neutralized by aqueous HC1 solution (1 N). The precipitate was collected, washed with water, and dried under vacuum to afford 3- bromothiazolo[4,5-c]pyridazin-6-amine (600 mg). LCMS (ESI, m / z): [M+H]+= 231.0.Step 3: A-(3-bromothiazolo[4,5-c]pyridazin-6-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3- carboxamide (N)

[0339] To a solution of 3-bromothiazolo[4,5-c]pyridazin-6-amine (280 mg, 1.21 mmol), Intermediate J (344 mg, 1.33 mmol) and NMI (497 mg, 6.05 mmol) in DMF (10 mL) was added TCFH (680 mg, 2.42 mmol). The mixture was stirred at 40 °C for 24 hrs. LCMS showed the reaction was complete. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to afford Intermediate N (60 mg). LCMS (ESI, m / z): [M+H]+= 471.1.Intermediate O7V-(6-chlorothiazolo[4,5-c] pyridin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3- carboxamide

[0340] To a mixture of 6-chlorothiazolo[4,5-c]pyridin-2-amine (600 mg, 3.23 mmol) and Intermediate J (557 mg, 2.16 mmol) in MeCN (15 mL) was added CMP1 (550 mg, 2.15 mmol) and TEA (218 mg, 2. 15 mmol). After stirring under N2 at room temperature for 16 hrs, LCMS showed the reaction was complete. The mixture was treated with water and extracted with DCM. The combined organic layers were dried over anhydrous NaiSCU, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with 5% MeOH in DCM) to give Intermediate O (590 mg). LCMS (ESI, m / z): [M+H]+= 426.2.Intermediate P2-(difluoromethyl)-5-methoxypyridin-4-yl trifluoromethanesulfonate

[0341] Intermediate P was synthesized following a literature reported procedure (W0202350007).Intermediate O2-bromo-4-(difluoromethyl)- 1 -methoxybenzene

[0342] To a stirred solution of 3-bromo-4-methoxy-benzaldehyde (4.3 g, 20.5 mmol) in DCM (10 mL) was added DAST (5.61 g, 4.60 mL, 34.8 mmol) at 0 °C. After stirring at room temperature for 16 hrs, the reaction mixture was quenched with saturated aqueous NaHCCh solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (20:1), to afford Intermediate Q (2.69 g). ' H NMR (400 MHz, DMSO-de) 57.70 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.57 (t, J = 56.8 Hz, 1H), 3.93 (s, 3H).Intermediate R2-chloro-5-(difluoromethoxy)-4-iodopyridine

[0343] A mixture of 6-chloro-4-iodo-pyridin-3-ol (15 g, 58.7 mmol), sodium chlorodifluoroacetate (17.9 g, 117.4 mmol) and CS2CO3 (38.3 g, 117.4 mmol) in DMF (200 mL) was stirred at 100 °C for 16 hrs. After completion, the reaction mixture was treated with saturated brine and extracted with EtOAc. The combined organic layers were dried over anhydrous NajSCU, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with PE / EtOAc (10: 1), to afford Intermediate R (12 g).!H NMR (400 MHz, DMSO-A) 8 8.31 (s, 1H), 8.24 (s, 1H), 7.40 (t, J = 72.6 Hz, 1H).Intermediate S methyl 5 -bromo- l-methyl-2-oxo- L2-dihydropyridine-4-carboxylate

[0344] To a stirred solution of methyl 5-bromo-2-oxo-l,2-dihydropyridine-4-carboxylate (2 g, 8.62 mmol) and CS2CO3 (8.44 g, 25.9 mmol) in DMF (30 mL) at 0 °C was added methyl iodide (1.84 g, 13.0 mmol) under N2 atmosphere. After stirring for 2 hrs at room temperature, the reaction mixture was treated with water and extracted with EtOAc. The combined organiclayers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford Intermediate S (1.5 g). LCMS (ESI, m / z): [M+H]+= 246.0.Intermediate T ethyl 4-chloro-6-(l -(difluoromethyl)- 177-pyrazol-4-yl)nicotinate

[0345] A mixture of ethyl 4,6-dichloronicotinate (700 mg, 3.18 mmol), 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (698 mg, 2.86 mmol), Pd(dppf)Ch (234 mg, 0.32 mmol), and CS2CO3 (2.07 g, 6.36 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was degassed and stirred at 80 °C for 2 hrs under N2 atmosphere. After completion, the reaction mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with PE / EtOAc (10: 1), to afford Intermediate T (400 mg). LCMS (ESI, m / z): [M+H]+= 301.9.Intermediate U l-bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzeneStep 1: 5-bromo-2-fluoro-4-methoxybenzaldehyde (U-l)

[0346] To a stirred solution of Br2 (10.37 g, 64.8 mmol) in MeOH (50 mL) was added 2- fluoro-4-methoxybenzaldehyde (5 g, 32.4 mmol) in MeOH (10 ml) dropwise at -20 °C. After stirring at -20 °C, the reaction mixture was quenched with saturated aqueous sodium hydrogen sulfite solution and water. The precipates were collected by filtration, washed with water, and dried under reduce pressure to give 5-bromo-2-fluoro-4-methoxybenzaldehyde (U- 1, 6 g).!H NMR (400 MHz, DMSO-d6) 5 10.02 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 12.4 Hz, 1H), 3.98 (s, 3H).Step 2: l-bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzene (U)

[0347] To a stirred solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (5.9 g, 25.3 mmol) in DCM (6 mL) at 0 °C was added DAST (8.16 g, 50.6 mmol) under N2 atmosphere. After stirring for 2 hrs at room temperature, the reaction mixture was quenched with MeOHfollowed by water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (20: 1), to afford Intermediate U (3.12 g). *H NMR (400 MHz, DMSO-J6) 8 7.82 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 12.4 Hz, 1H), 7.10 (t, J = 54.0 Hz, 1H), 3.92 (s, 3H).Intermediate V methyl 5-bromo-l-(2-(dimethylamino)-2-oxoethyl)-2-oxo-l,2-dihvdropyridine-4-carboxylate

[0348] To a stirred solution of methyl 5-bromo-2-oxo-l,2-dihydropyridine-4-carboxylate (2 g, 8.62 mmol) in DMF (20 mL) was added CS2CO3 (8.43 g, 25.9 mmol) and 2-bromo-MA- dimethylacetamide (2. 15 g, 13.0 mmol) under N2 atmosphere. After stirring for 2 hrs at room temperature, the reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum to afford Intermediate V (800 mg). LCMS (ESI, m / z): [M+H]+= 316.9.Intermediate W methyl 4-bromo-6-(dimethylcarbamoyl)nicotinateStep 1: methyl (E)-4-bromo-6-(2-(dimethylamino)vinyl)nicotinate (W-l)

[0349] A solution of methyl 4-bromo-6-methylnicotinate (2.3 g, 10 mmol) and N,N- Dimethylformamide dimethyl acetal (3.57 g, 30 mmol) in DMF (10 mL) was stirred at 120 °C for 18 hrs under N2 atmosphere. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10: 1), to afford methyl (E)-4-bromo-6-(2-(dimethylamino)vinyl)nicotinate (W-l, 1.1 g). LCMS (ESI, m / z): [M+H]+= 284.9.Step 2: 4-bromo-5-(methoxycarbonyl)picolinic acid (W-2)

[0350] To a solution of methyl (E)-4-bromo-6-(2-(dimethylamino)vinyl)nicotinate (W-l, 1 g, 3.51 mmol) and K2CO3 (969 mg, 7.01 mmol) in t-BuOH (17 mL) and water (17 mL) wasadded KM11O4 (1.66 g, 10.5 mmol) portion-wise. After stirring for 1 hr at room temperature, the reaction mixture was filtered. The filtrate was purified by reverse-phase column chromatography (0.1% FA) to afford 4-bromo-5-(methoxycarbonyl)picolinic acid (W-2, 550 mg). LCMS (ESI, m / z): [M+H]+= 260.0.Step 3: methyl 4-bromo-6-(dimethylcarbamoyl)nicotinate (W)

[0351] To a stirred solution of 4-bromo-5-(methoxycarbonyl)picolinic acid (W-2, 600 mg, 2.31 mmol) and dimethylamine hydrochloride (282 mg, 3.46 mmol) in MeCN (30 mL) was added CMPI (884 mg, 3.46 mmol) and TEA (934 mg, 1.29 mL, 9.23 mmol) under N2. After stirring at rt for 1 hr, the reaction mixture was treated with water and extracted with DCM. The combined organic layeres were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1 to 1:1), to afford Intermediate W (135 mg). LCMS (ESI, m / z): [M+H]+= 286.9.Intermediate X4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acidStep 1: methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (X-l)

[0352] A mixture of 2-bromo-4-(difluoromethyl)-l-methoxybenzene (2.68 g, 11.3 mmol), B2pin2 (4.32 g, 17.0 mmol), Pd(dppf)Ch (827 mg, 1.13 mmol) and KOAc (3.33 g, 33.9 mmol) in 1,4-dioxane (100 mL) was degassed and stirred at 100 °C for 3 hrs under N2 atmosphere. After cooling to room temperature, methyl 4-bromo-6-methylnicotinate (2.17 g, 9.43 mmol), Pd(dppf)C12 (690 mg, 0.943 mmol), CS2CO3 (6.16 g, 18.9 mmol) and water (25 mL) were added to the mixture. The resulting mixture was degassed and stirred at 80 °C for another 2 hrs under N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous NtoSCb, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10: 1 to 2:1), to afford methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6- methylnicotinate (X-l, 2 g). LCMS (ESI, m / z): [M+H]+= 308.2.Step 2: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (X)

[0353] To a stirred solution of methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6- methylnicotinate (1.8 g, 5.86 mmol) in MeOH (10 mL) and was added LiOH lTC) (1.23 g, 29.3 mmol) in water (20 mL). After stirring at room temperature for 3 hrs, the reaction mixture was concentrated under vacuum to remove most MeOH and water. The residue was acidified to pH = 5-6 with aqueous HC1 solution (1 N). The mixture was purified by reversed- phase column chromatography (0.1% FA) to afford Intermediate X (1.3 g). LCMS (ESI, m / z): [M+H]+= 294.1.

[0354] The intermediates in the table below were synthesized using conditions analogous to that used to synthesize Intermediates X, by converting appropriate aromatic halide or triflate to the corresponding boronic reagents, Suzuki coupling and hydrolysis.Intermediate AL methyl 3-(5-chloro-2-methoxyphenyl)isonicotinate

[0355] To a solution of (5-chloro-2-methoxyphenyl)boronic acid (3 g, 16.1 mmol) and methyl 3 -bromoisonicotinate (3.47 g, 16.1 mmol) in 1,4-dioxane (50 mL) and water (15 mL) was added Pd(dppf)Ch.DCM (1.29 g, 1.58 mmol) and K2CO3 (5.55 g, 40.2 mmol) under N2. The mixture was degassed and stirred at 100 °C for 4 hrs under N2 atmosphere. LCMS showed the reaction was complete. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1: 1), to afford Intermediate AL (2.5 g). LCMS (ESI, m / z): [M+H]+= 278.3.Step 1: methyl 2'-cvclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (AM-1)

[0356] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3- carboxylate (1-1, 2.2 g, 7.52 mmol) in 1,4-dioxane (40 mL), water (10 mL) was added cyclopropylboronic acid (6.46 g, 75.2 mmol), CS2CO3 (7.35 g, 22.6 mmol) and Pd(dppf)C12 (1.10 g, 1.50 mmol) under N2. The mixture was degassed and stirred at 90 °C for 6 hrs under N2 atmosphere. After completion, the reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc, to afford methyl 2’-cyclopropyl-5'- methoxy-6-methyl-|4,4'-bipyridine|-3-carboxylate (AM-1, 2 g) as a brown oil. LCMS (ESI, m / z): [M+H]+= 299.2.Step 2: 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (AM)

[0357] To a solution of methyl 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4’-bipyridine]-3- carboxylate (AM-1, 2 g, 6.70 mmol) in THF (30 mL) and water (15 mL) was added L1OH.H2O (1.41 g, 33.6 mmol). After stirring at room temperature for 16 hrs, the reaction mixture was concentrated under vacuum to remove most THF and water. The residue was acidified to pH = 5-6 with aqueous HC1 solution (1 N). The mixture was purified by reversed- phase column chromatography (0.1% FA) to afford Intermediate AL (1.6 g). LCMS (ESI, m / z): [M+H]+= 285.2.

[0358] The intermediates in the table below were synthesized using conditions analogous to that used to synthesize Intermediate AL by reacting the synthesized hetero-biaryl chloride with commercially available boronic acid derivatives, via Suzuki coupling, then hydrolysis.Intermediate AO2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-( l -methyl- lH-pyrazol-3-yl)benzoic acidStep 1: methyl 2-(2-(dilluoromethyl )-5-methoxypyridin-4-yl )-4-( l -methyl- 1 H-pyrazolA- vDhenzoate (AQ-1)

[0359] To a solution of methyl 4-bromo-2-(2-(difluoromethyl)-5-methoxypyridin-4- yl)benzoate (precusor of Intermediate AD) (100 mg, 0.27 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (84 mg, 0.40 mmol), Pd(dppf)Ch CH2C12 (24 mg, 0.029 mmol) and CS2CO3 (263 mg, 0.80 mmol) under N2. The mixture was degassed and stirred at 100 °C for 3 hrs under N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified with silica gel column chromatography, eluting with PE / EtOAc (5: 1) to afford methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(l-methyl-l / 7- pyrazol-3-yl)benzoate (AQ-1, 80 mg). LCMS (ESI, m / z): [M+H]+= 374.3.Step 2: 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4-(l-methyl-lH-pyrazol-3-yl)benzoic acid (AQ)

[0360] To a solution of methyl methyl 2-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-4- (l -methyl-lH-pyrazol-3-yl)henzoate (AQ-1, 80 mg, 0.21 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH- 1LC) (13.5 mg, 0.32 mmol). After stirring at room temperature for 12 hrs, the reaction mixture was concentrated to remove most THF. The mixture was acidified with aqueous HC1 solution (1 N) to pH = 6. The resulting precipitates were collected by filtration, washed by water, and dried under vacuum to afford Intermediate AQ (70 mg). LCMS (ESI, m / z): [M+H]+= 360.2.Intermediate ASV-(6-bromothiazolo[4,5-b1pyrazin-2-y])-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'- bipyridinel-3-carboxamide

[0361] To a solution of Intermediate AJ (180 mg, 0.61 mmol) in MeCN (2.0 mL) was added 6-bromothiazolo[4,5-b]pyrazin-2-amine (141 mg, 0.61 mmol), EtsN (257 mg, 2.54 mmol) and CMPI (258 mg, 1.01 mmol) under N2. After stirring at room temperature for 4 hrs, the reaction mixture was concentrated to dryness under vacuum. The residue was purified by prep-HPLC (0.05% NH4HCO3) to afford Intermediate AS (150 mg). LCMS (ESI, m / z): [M+H]+ = 507.2.

[0362] The Intermediates in the table below were synthesized using conditions analogous to that used to synthesize Intermediates AS from the corresponding acids, via amide coupling reaction.Intermediate AW6-(cvclopropylethynyl)thiazolo[4,5-b]pyrazin-2-amineStep 1: butyl (6-bromothiazolo[4.5-b1pyrazin-2-yl)carbamate (AW-1)

[0363] A mixture of 6-bromothiazolo[4,5-b]pyrazin-2-amine (5 g, 21 .6 mmol), (Boc)2O (7.09 g, 32.5 mmol), DMAP (794 mg, 6.5 mmol) and TEA (4.38 g, 43.3 mmol) in acetone (150 mL) was stirred at 60 °C for 4 hrs. After completion, the reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (8: 1 to 1:1), to afford tert-butyl (6- bromothiazolo[4,5-b]pyrazin-2-yl)carbamate (AW-1, 4 g). LCMS (ESI, m / z): [M+H]+= 331.0.Step 2: tert-butyl (6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (AW-2)

[0364] To a stirred mixture of tert-butyl (6-bromothiazolo[4,5-b]pyrazin-2-yl)carbamate (AW-1, 4 g, 12.1 mmol), ethynylcyclopropane (2.40 g, 36.3 mmol) and TEA (3.67 g, 36.3 mmol) in DMF (40 mL) was added Cui (230 mg, 1.21 mmol) and Pd(PPh3)4 (1.40 g, 1.21 mmol) under N2. The mixture was degassed and stirred at 90 °C for 2 hrs under N2 atmosphere. The mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1), to afford tert-butyl (6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (AW-2, 3 g). LCMS (ESI, m / z): [M+H]+= 317.2.Step 3: 6-(cvclopropylethvnyl)thiazolo[4,5-b]pyrazin-2-amine (AW)

[0365] To a stirred solution of tert-butyl (6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin- 2-yl)carbamate (AW-2, 3 g, 9.48 mmol) in DCM (25 ml) was added TFA (12.5 ml). After stirring at room temperature for 2 hrs, the reaction mixture was concentrated to dryness under vacuum. The residue was purified by trituration with the mixture of aqueous ammonia and methanol to afford Intermediate AV (1.8 g). LCMS (ESI, m / z): [M+H]+= 217.2.Intermediate AX5-(cvclopropylethvnyl)thiazolo[5,4-d]pyrimidin-2-amineStep 1: tert-butyl (5-(cyclopropylethynyl)thiazolo[5.4-d]pyrimidin-2-yl)carbamate (AX-1)

[0366] To a solution of tert-butyl (5-chlorothiazolo[5,4-d]pyrimidin-2-yl)carbamate (G-l, 200 mg, 0.70 mmol) in 1,4-dioxane (3 mL) was added 2-(cyclopropy lethynyl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (201 mg, 1.05 mmol), Pd(dppf)CL (51 mg, 0.07 mmol) andCS2CO3 (683 mg, 2.09 mmol) under N2. The mixture was degassed and stirred at 100 °C for 12 hrs under N2 atmophsere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.05% NH4HCO3) to afford tertbutyl (5-(cyclopropylethynyl)thiazolo[5,4-d]pyrimidin-2-yl)carbamate (AX-1, 50 mg). LCMS (ESI, m / z): [M+H]+= 317.2.Step 2: 5-(cyclopropylethynyl)thiazolol5,4-d1pyrimidin-2-amine (AX)

[0367] To a solution of tert-butyl (5-(cyclopropylethynyl)thiazolo[5,4-d]pyrimidin-2- yl)carbamate (AX-1, 50 mg, 0.174 mmol) in THF (2 mL) was added TFA (1 mL). After stirring at room temperature for 2 hrs, the reaction mixture was concentrated to dryness under vacuum to afford Intermediate AX which was used for the next step without purification. LCMS (ESI, m / z): [M+H]+= 217.1.Intermediate AY4-(2,2-Difluoroethyl)piperazin-2-oneStep 1: tert-butyl 4-(2,2-difluoroethyl)-2-oxopiperazine-l -carboxylate (AY-1)

[0368] 2,2-Difluoroethyl trifluoromethanesulfonate (962 mg, 4.50 mmol) andDIPEA (581 mg, 4.50 mmol) were added to a solution of tert-butyl 2-oxopiperazine-l- carboxylate (900 mg, 4.50 mmol) in DCM (5 mL) under N2. After stirring for 2 hrs at rt, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (6:4), to afford tertbutyl 4-(2,2-difluoroethyl)-2-oxopiperazine-l -carboxylate (AY-1, 560.0 mg). LCMS (ESI, m / z): [M+H]+= 265.2.Step 2: 4-(2,2-dilluoroethyl)piperazin-2-one (AY)

[0369] TFA (6 mL) was added to a solution of tert-butyl 4-(2,2-difluoroethyl)-2- oxo-piperazine-l-carboxylate (AY-1, 560 mg, 2.12 mmol) in DCM (2 mL) at rt. After stirring for 2 hrs, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by prep-HPLC (0.1 % FA) to afford Intermediate AY (287 mg). LCMS (ESI, m / z): [M+H]+= 165.1.Intermediate (AZ)(6-Bromopyridin-3-yl)(imino)(methyl)-X6-sulfanone

[0370] Ammonium acetate (378 mg, 4.90 mmol) and (diacetoxyiodo)benzene (1.58 g, 4.91 mmol) were added to a solution of 2-bromo-5-(methylthio)pyridine (500 mg, 2.45 mmol) in MeOH (2 mL) at rt. After stirring for 2hrs, the mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (0.05% FA) to afford Intermediate AZ (300 mg). LCMS (ESI, m / z): [M+H]+= 235.0.Intermediate BA(6-Bromopyridin-3-yl)(methyl)(methylimino)-?i6-sulfanone

[0371] Cupric acetate monohydrate (17.0 mg, 0.085 mmol), pyridine (33.6 mg, 0.425 mmol) and methylboronic acid (127 mg, 2.13 mmol) were added to a solution of (6- bromopyridin-3-yl)(imino)(methyl)-X6-sulfanone (AZ, 100 mg, 0.425 mmol) in 1,4-dioxane (2 mL) at rt under O2 atmosphere. After stirring for 1 hr at 100 °C, the mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (0.05% FA) to afford Intermediate BA (30 mg). LCMS (ESI, m / z): [M+H]+= 248.9.Intermediate BBStep 1: .S'-(6-chloropyridin-3-yl ) benzothioate (BB-1)

[0372] Benzothioic 5-acid (16.0 g, 0.116 mol), DIPEA (28.6 g, 0.221 mol), 1,10- phenanthroline (3.78 g, 20.9 mmol) and Cui (20.0 g, 10.5 mmol) were added to a solution of 2-chloro-5 -iodo-pyridine (20.0 g, 0.084 mol) in toluene (150 mL) under N2. The resultingmixture was degassed, stirred at 1 10 °C for 4 hrs, treated with water and extracted with EtOAc. The combined organic layers were dried (NazSO^, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (1:6), to afford S-(6-chloropyridin-3-yl) benzothioate (BB-1, 19 g). LCMS (ESI, m / z): [M+H]+= 250.1.Step 2: E2-bis(6-chloropyridin-3-yl)disulfane (BB-2)

[0373] K2CO3 (21.0 g, 0.152 mol) was added to a solution of S-(6-chloropyridin-3-yl) benzothioate (BB-1, 19.0 g, 0.076 mol) in MeOH (300 mL) at rt. After stirring for 2 hrs, the mixture was concentrated under vacuum. The residue was treated with 1 N aqueous NaOH (70 mL) and K3Fe(CN)e (75.2 g, 0.228 mol). After stirring for 2 hrs, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (NazSOA, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (1:2), to afford l,2-bis(6-chloropyri din-3 - yDdisulfane (BB-2, 8.0 g). LCMS (ESI, m / z): [M+H]+=290.2Step 3: 2-chloro-5-((difluoromethyl)thio)pyridine (BB)

[0374] (Difluoromethyl)trimethylsilane (1.37 g, 11.1 mmol) and CsF (3.36 g, 22.1 mmol) were added to a solution of l,2-bis(6-chloropyridin-3-yl)disulfane (BB-2, 800 mg, 2.77 mmol) in NMP (5 mL) under Nz. After stirring for 2 hrs, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (NazSOz), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (1:1), to afford Intermediate BB (100 mg). LCMS (ESI, m / z): [M+H]+=196.1.Intermediate BC2-Bromo-5-((trifluoromethyl)thio)pyrazine

[0375] A mixture of 2-bromo-5 -iodopyrazine (500 mg, 1.76 mmol), AgSCFz (440 mg, 2.11 mmol), Cui (335 mg, 1.76 mmol) and 2,2’-bipyridine (276 mg, 1.76 mmol) in MeCN (10 mL) was degassed and backfilled with N2. After stirring at 100 °C for 2 hrs, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (NazSCU), filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel, eluting EtOAc / PE (1 :30), to afford Intermediate BC (300 mg)ppm 8.72 (s, 1H), 8.56 (s, 1H).Intermediate BD3-Bromo-6-((trifluoromethyl)thio)pyridazine

[0376] Following conditions analogous to synthesis of BC, Intermediate BD was synthesized from 3,6-dibromopyridazine. *H NMR (400 MHz, CDCI3) 8 ppm 7.70 (d, J = 9.2 Hz, 1H), 7.57 (d, 7= 9.2 Hz, 1H).Intermediate BEMethyl 4-iodo-6-((trifluoromethyl)thio)nicotinateStep 1: methyl 4-chloro-6-((trifluoromethyl)thio)nicotinate (BE-1)

[0377] A mixture of methyl 6-bromo-4-chloronicotinate (500 mg, 2.00 mmol), AgSCFs (630 mg, 3.00 mmol), Ir(ppy)3 (26.2 mg, 0.04 mmol), 77-BU4NI (1.11 g, 3.00 mmol), Ni(DME)C12 (17.6 mg, 0.08 mmol) and dtbbpy (21.5 mg, 0.08 mmol) in THF (10 mL) was degassed and backfilled with N2. After stirring at 45 °C under irradiation (18 W blue LEDs) for 3 hrs, the mixture was treated with EtOAc, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc / PE (1:4), to afford methyl 4-chloro-6-((trifhioromethyl)thio)nicotinate (BE-1, 400 mg). LCMS (ESI, m / z): [M+H]+= 272.0.Step 2: methyl 4-iodo-6-((trifluoromethyl)thio)nicotinate (BE)

[0378] Acetyl chloride (86.4 mg, 1.10 mmol) was added to a mixture of methyl 4-chloro- 6-((trifluoromethyl)thio)nicotinate (BE-1, 200 mg, 0.736 mmol) and KI (1.22 g, 7.36 mmol) in MeCN (5.0 mL) at 0 °C under N2. After stirring at reflux for 16 hrs, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford Intermediate BE (180 mg). LCMS (ESI, m / z): [M+H]+= 364.0.Intermediate BEMethyl 2-bromo-4-((2-oxopyrrolidin- l-yl)methyl)benzoate

[0379] NaH (60% dispersion in mineral oil, 38.2 mg, 0.954 mmol) and methyl 2- bromo-4-(bromomethyl)benzoate (146 mg, 0.477 mmol) were sequentially added to a solution of pyrrolidin-2-one (40.6 mg, 0.477 mmol) in DMF (4 mL) under N2. After stirring for 1 hr at rt, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (3:7), to afford Intermediate BF (98.0 mg). LCMS (ESI, m / z): [M+H]+= 31 1.8.Intermediate BGMethyl 2-bromo-4-(( I. S',2A))-2-(di methylcarbamoyl )cyclopropyl (benzoateStep 1: -2-(3-bromo-4-(methoxycarbonyl)phenyl)cyclopropane-l-carboxylic acid (BG-1)

[0380] A mixture of cyclopropanecarboxylic acid (274 mg, 3.18 mmol), methyl 2-bromo- 4-iodobenzoate (2.17 g, 6.37 mmol), Pd(OAc)2 (72.0 mg, 0.318 mmol), (7?)-A-(2-benzyl-3- (dimethylamino)propyl)acetamide (149 mg, 0.637 mmol), Ag2COs (1.32 mg, 4.77 mmol) and Na2CO3 (506 mg, 4.77 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (5 mL) was stirred at 80 °C for 5 hrs while open to air. The resulting mixture was filtered to remove solid residue. The filtrate was treated with water, acidified to pH 5 with 1 N HC1 solution and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford (17?,2S)-2-(3-bromo-4-(methoxycarbonyl)phenyl)cyclopropane-l-carboxylic acid (BG-1, 200 mg). LCMS (ESI, m / z): [M-H]’ =297.1.Step 2: methyl 2-bromo-4-(( -2-(dimethylcarbamoyl)cyclopropyl (benzoate (BG)

[0381] EDCI (385 mg, 2.01 mmol) and HOBt (272 mg, 2.01 mmol) were added to a stirred solution of (ll?,2S)-2-(3-bromo-4-(methoxycarbonyl)phenyl)cyclopropane-l- carboxylic acid (BG-1, 200 mg, 0.669 mmol), DIPEA (1.3 g, 10 mmol) and dimethylamine hydrochloride (164 mg, 2.01 mmol) in DMF (5 mL) under N2. After stirring at rt for 3 hrs, the mixture was treated with water and extracted with EtOAc. The organic layers werewashed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was puri...

Claims

WHAT TS CLAIMED IS:

1. A compound of Formula K, or a pharmaceutically acceptable salt thereof:Formula K wherein:Ring A is a phenyl ring or 5-10-membered heteroaryl ring having 1 to 4 ring heteroatoms independently selected from N, O, and S;R1is an optionally substituted phenyl, optionally substituted naphthyl, an optionally substituted 3-10 membered carbocyclic, or an optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably, R1is ortho to the amide group (-C(O)-NH-) shown in Formula K; the subscript m is an integer of 0-4, as valency permits;R2at each occurrence is independently deuterium, halogen, OH, NH2, CN, SF5, COOH, CONH2, SO2NH2, R20, OR20, SR20, N(R20)(R21), SO2R20, S(=O)(=NR21)R20, SO2N(R20)(R21), N(R21)SO2R20, COR20, COOR20, OC(O)R20,CON(R20)(R21), or N(R2I)COR20, wherein R20at each occurrence is independently an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; and R21at each occurrence is independently hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3-6 alkenyl, an optionally substituted C3-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure; or as applicable, R20and R21together with the intervening atom (e.g., the nitrogen atom) or atoms are joined to form an optionally substituted 4-8 membered heterocyclic ring; or two instances of R2are joined to form an optionally substituted 4-7 membered ring; RJis hydrogen, halogen, optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure;L is CM alkylene, C2-4 alkenylene, C2-4 alkynylene, or C1-4 heteroalkylene, each of which is optionally substituted with deuterium and / or F, andRKis hydrogen, deuterium, an optionally substituted C1-6 alkyl, an optionally substituted C1-6 heteroalkyl, or an optionally substituted 3-10 membered ring structure.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K- 1 :Formula K-l.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-2:Formula K-2.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-3:Formula K-3.

5. The compound of any of claims 1 -4, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-4:Formula K-4.

6. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-5:Formula K-5.

7. The compound of any of claims 1-3 or 6, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-6:Formula K-6.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is C2-4 alkylene,9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein RKis an optionally substituted C3-8 cycloalkyl.

10. The compound of any of claims 1 -9, or a pharmaceutically acceptable salt thereof, wherein RKis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one or more, e.g., 1-5, substituents independently selected from deuterium, F, OH, CN, CM alkyl optionally substituted with F, CM heteroalkyl optionally substituted with F, or 3-6 membered ring optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with F, and C 1-4 heteroalkyl optionally substituted with F.The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein RKis selected from:,12. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein RKis an optionally substituted 4-8 membered heterocyclyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein RKis 4-6 membered heterocyclyl having one or two ring heteroatoms, each independently O, S, or N, wherein the sulfur atom, if present, is optionally oxidized, wherein the 4-6 membered heterocyclyl is optionally substituted with one or more (e.g., 1-3) substituents independently selected from deuterium, F, oxo, OH, CN, CM alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (CM alkylene)-(3-6 membered ring), or (C 1-4 heteroalky lene)-(3 -6 membered ring), wherein the CM alkylene or C 1-4 heteroalkylene is optionally substituted with deuterium and / or F, and wherein each of the 3-6 membered ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, CM alkyl optionally substituted with F, and C 1-4 heteroalkyl optionally substituted with F.

14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, whereinRKis selected from.

15. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein RKis an optionally substituted 5 or 6-membered heteroaryl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein RKis a 5-membered heteroaryl having 1-4 ring heteroatoms, each independently O, S, or N, wherein the 5-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from F, Cl, OH, CN, Ci-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (Ci-4 alkylene)-(3-6 membered ring), or (Ci-4heteroalkylene)-(3-6 membered ring), wherein the CM alkylene or C 1-4 heteroalkylene is optionally substituted with deuterium and / or F, and wherein each of the 3-6 membered ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, C1-4 alkyl optionally substituted with F, and C 1-4 heteroalkyl optionally substituted with F.

17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein RKis a 5-membered heteroaryl selected from pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, which is optionally substituted, as valency permits, with 1-3 substituents independently selected from F, Cl, OH, CN, C1-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (C1-2 alkylene)-(3-6 membered ring), or (Ci-2heteroalkylene)-(3-6 membered ring), wherein the C1-2 alkylene or C 1-2 heteroalkylene is optionally substituted with deuterium and / or F, and wherein, preferably, the 3-6 membered ring at each occurrence is independently selected from (a) C3-6 cycloalkyl optionally substituted with methyl and / or F; or (b) 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, and wherein the 4-6 membered heterocyclyl is optionally substituted with 1-3substituents independently selected from deuterium, F, OH, oxo, CN, C1-4 alkyl optionally substituted with F, or CM heteroalkyl optionally substituted with F.

18. The compound of any of claims 15-17, or a pharmaceutically acceptable salt thereof, wherein RKiswherein: q is 0, 1, 2, or 3; andG10at each occurrence is independently F, Cl, CN, C1-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (C1-2 alkylene)- (3 -6 membered ring), or (Ci-2heteroalkylene)-(3-6 membered ring), wherein the C1-2 alkylene or C 1-2 heteroalkylene is optionally substituted with deuterium and / or F, and wherein, preferably, the 3-6 membered ring at each occurrence is independently selected from (a) C3-6 cycloalkyl optionally substituted with methyl and / or F; or (b) 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, and wherein the 4-6 membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from deuterium, F, OH, oxo, CN, C1-4 alkyl optionally substituted with F, or CM heteroalkyl optionally substituted with F.

19. The compound of claim 1 or 18, or a pharmaceutically acceptable salt thereof, whereinRKis selected from:wherein:G10Aat each occurrence is independently CM alkyl optionally substituted with deuterium and / or F, 3-6 membered ring, or (C1-2 alkylene)-(3-6 membered ring), wherein the C1-2 alkylene or C 1-2 heteroalkylene is optionally substituted with deuterium and / or F, and wherein, preferably, the 3-6 membered ring at each occurrence is independently selected from (a) C3-6 cycloalkyl optionally substituted with methyl and / or F; or (b) 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, and wherein the 4-6 membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from deuterium, F, OH, oxo, CN, C 1-4 alkyl optionally substituted with F, or C1 1 heteroalkyl optionally substituted with F; andG10Bat each occurrence is independently F, Cl, CN, or G10A.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein G10Aat each occurrence is independently CM alkyl (e.g., methyl) optionally substituted with deuterium and / or F, cyclopropyl, cyclobutyl, (C1-2 alkylene)-(cyclopropyl) or (C1-2 alkylene) - (cyclobutyl) .

21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein G10Bat each occurrence is independently F, Cl, C1-4 alkyl (e.g., methyl) optionally substituted with deuterium and / or F, cyclopropyl, cyclobutyl, (C1-2 alkylene)- (cyclopropyl) or (C1-2 alkylene)-(cyclobutyl).

22. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, whereinRKis selected from:

23. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein RKis a 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, e.g., pyridyl, pyrimidyl, etc., wherein the 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from F, Cl, OH, CN, Ci-4 alkyl optionally substituted with deuterium and / or F, C 1-4 heteroalkyl optionally substituted with deuterium and / or F, 3-6 membered ring, (Ci-4 alkylene)-(3-6 membered ring), or (Ci-4heteroalkylene)-(3-6 membered ring), wherein the C1-4 alkylene or C 1-4 heteroalkylene is optionally substituted with deuterium and / or F, and wherein each of the 3-6 membered ring is optionally substituted with one or more substituents independently selected from deuterium, halogen, CN, OH, oxo, C1-4 alkyl optionally substituted with F, and C 1-4 heteroalkyl optionally substituted with F,24. The compound of any of claims 1 , 2, and 8-23, or a pharmaceutically acceptable salt thereof, wherein RJis hydrogen.

25. The compound of any of claims 1-3 and 8-24, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring or a 5 or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as pyridine ring.

26. The compound of any of claims 1-3 and 8-24, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl, pyridinyl, pyrimidinyl, or imidazo[l,2-a]pyridinyl ring, preferably, a phenyl or pyridinyl ring.

27. The compound of any of claims 1-3 and 8-24, or a pharmaceutically acceptable salt thereof, wherein the moietyin Formula K is selected from:

28. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 , or 2, and R2at each occurrence is independently deuterium, halogen, CN, OH, (CM alkylene)-CN, GA, or Xa-Xb-GA, wherein: at each occurrence is independently null, CM alkylene, or C 1-4 heteroalkylene;Xbat each occurrence is independently null,O, NH, N(GB), C(O), C(O)O, C(O)NH, C(O)N(GB), NHC(O), N(GB)C(O), SO2, S(=O)(=NH), S(=O)(=NGB), SO2NH, or SO2N(GB); andGAat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, C(O)-NH(CM alkyl), C(O)- N(CM alkyl)(CM alkyl), or a 3-6 membered ring;(ii) Ci -6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, oxo, CM alkyl, CM alkoxy, or a 3-6 membered ring;(iii) a 3-8 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, CM alkyl, CM alkoxy, C(0)NH2, C(O)-NH(Ci-O4 alkyl), C(0)-N(CI-4 alkyl )(Ci4 alkyl),, wherein the nitrogen containing Ring E is a 4-8 membered heterocyclic ring, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, CM alkyl, Ci -4 alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring),wherein each of the CM alkyl or C1-4 alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) or Ring E is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F;GBat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F, or when applicable, GAand GBare joined to form a 4-8 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein m is 0.

30. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein m is 1.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the32. The compound of any of claims 1-27, 30 and 31, or a pharmaceutically acceptable salt thereof, wherein R2at each occurrence is independently (i) a CM alkyl optionallysubstituted with deuterium, F, and / or OH, e.g., methyl, difluoromethyl, or hydroxymethyl; (ii) a 5 or 6-membered heteroaryl, which is optionally substituted with 1- 3 substituents each independently halogen, OH, CN, CM alkyl, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein the CM alkyl or CM alkoxy is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen (e.g., F), OH, CM alkoxy, or a 3-5 membered carbocyclic or heterocyclic ring, wherein each of the 3-5 membered carbocyclic or heterocyclic ring, when present, is independently optionally substituted with deuterium, F, OH, and / or methyl; or (iii) -(Ci-4alkylene)-C(O)NHGA, -(Ci-4alkylene)-C(O)N(GA)(GB) or -(CM alkylene)-CN, for example, GAand GBare each independently a CM alkyl optionally substituted with deuterium, F and / or OH, or GAand GB, together with the nitrogen atom they are both attached to, are joined to form a 4-8 membered heterocyclic ring, which is optionally substituted.

33. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R2is CN, halogen, SCF3, CM alkyl optionally substituted with 1-3 substituents each independently CN, OH, F, or C 1.3 alkoxy optionally substituted with F, for example, R2is CN, CH2-CN, CH2-OCH3, CH2-OCF3, methyl, difluoromethyl, SCF3, or Cl.

34. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R2is -(CM alkylene)-GA1, wherein GA1is C(0)NH2, C(O)OH,OC(O)NH(CM alkyl), C(O)N(CM alkyl)(Ci-4alkyl),wherein the nitrogen containing Ring E is a 4-8 membered heterocyclic ring, wherein each of the CM alkyl in C(O)NH(CM alkyl) or C(O)N(CM alkyl)(Ci-4alkyl) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, wherein the 3-4 membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; andwherein each of the Ring E is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F; for example, R2is selected from the following:

35. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R2is a 5-membered heteroaryl having 2-4 ring heteroatoms, such as pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, etc., which is optionally substituted, for example, with 1 or 2 substituents, as valency permits, each independently deuterium, halogen, OH, CN, CM alkyl, C 1-4 heteroalkyl (such as CM alkoxy), a 3-6 membered carbocyclic or heterocyclic ring, (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring); or (CM heteroalkylene)-(3-6 membered carbocyclic or heterocyclic ring); wherein the CM alkyl, CM alkylene, CM heteroalkyl, or C 1-4 heteroalkylene is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen (e.g., F) or OH; and wherein each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F, for example, R2is selected from the following:

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein m is 1 , and R2is a pyrazolyl optionally substituted with one or two substituents, with one substituent being (i) a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (CM alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and the other substituent, if present, is halogen, OH, CN, or CM alkyl optionally substituted1-3 substituents each independently deuterium, F, or OH; for example, R2is37. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein m is 1, and R2is a 5-membered or 6-membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N, O, or S, wherein the 5 -membered or 6-membered heterocyclic ring contains one or two ring carbon atoms in the form of C(=O), or the 5- membered or 6-membered heterocyclic ring contains a ring sulfur atom in the form of SO2, wherein the 5-membered or 6-membered heterocyclic ring is optionally substituted with one or more (e.g., 1, 2, or 3) substituents: (i) each independently deuterium, halogen, OH, CN, C1-4 alkyl, C(O)-Ci-4 alkyl, CM heteroalkyl (such as CM alkoxy), 3-6 membered carbocyclic or heterocyclic ring, (CM alkylene)-(3-6 membered carbocyclic or heterocyclic ring), or (CM heteroalkylene)-(3-6 membered carbocyclic or heterocyclic ring); or (ii) two optional substituents, together with the ring atom(s) they are attached to, are joined to form a 3-6 membered carbocyclic or heterocyclic ring, and any remaining substituent(s) is as defined in (i); wherein the CM alkyl, CM alkylene, CM heteroalkyl, or C 1-4 heteroalkylene is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen (e.g., F) or OH; and each of the 3-6 membered carbocyclic or heterocyclic ring is optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN,Ci-4 alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F; for example, R2is selected from the following:

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R2is a 6-membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N or O, wherein the 6-membered heterocyclic ring contains one ring carbon atom in the form of C(=O), wherein the 6-membered heterocyclic ring is optionally substituted with 1-3 (e.g., 1 or 2) substituents each independently (i) a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) C(O)-Ci-4 alkyl, wherein the CM alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iii) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (Ci-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R2is a 6-membered heterocyclic ring having 1 or 2 ring heteroatoms each independently N or O, wherein the 6-membered heterocyclic ring contains one ring carbon atom in the form of C(=O), wherein two gem substituents of the 6-membered heterocyclic ring are joined to form a spiro cyclopropyl ring, which is unsubstituted or substituted with 1 or 2 substituents each independently F or methyl, wherein the 6-membered heterocyclic ring is optionally further substituted with one or more (e.g., 1 or 2) substituents eachindependently (i) a C1-4 alkyl optionally substituted with one or more (e.g., 1 -3) substituents each independently deuterium, F, or OH; (ii) C(O)-Ci-4 alkyl, wherein the Ci- 4 alkyl is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (iii) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy, for example, R2is selected from the following:

40. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof,L_ — GA2wherein m is 1, and R2is GA2or ' , wherein GA2is a 3-6 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1- 3) substituents each independently deuterium, halogen, oxo, OH, CN, C1-4 alkyl, C1-4O alkoxy, C(O)NH2, C(O)-NH(CI-4alkyl), C(0)-N(CM alkyl)(Ci-4alkyl), orwherein the nitrogen containing Ring E is a 4-8 membered heterocyclic ring; wherein each of the CM alkyl or C 1-4 alkoxy is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, C1-4 alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, wherein the 3-4 membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and wherein Ring E is independently optionally substituted with one or more (e.g., 1-3) substituents each independently oxo, deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the following:

42. The compound of any of claims 33-41 , or a pharmaceutically acceptable salt thereof,R1wherein the moiety ofin Formula K is43. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein m is 2, and one R2is as defined in any of claims 28 and 32-41, and the other R2is F or Cl.

44. The compound of any of claims 1-7 and 9-27, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-7a or K-7b:Formula K-7a, wherein:R100is selected from(i) hydrogen; (ii) a C1-4 alkyl optionally substituted with one or more (e.g., 1 -3) substituents each independently deuterium, F, or OH; (iii) a 3-4 membered carbocyclic or heterocyclic ring; or (iv) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (iii) or (iv) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; R101and RI02are each independently halogen, CN, or (i)-(iv) as defined for R100.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein (i) R101is hydrogen; (ii) R102is hydrogen; or (iii) both R101and R102are hydrogen.

46. The compound of claim 44 or 45, or a pharmaceutically acceptable salt thereof, wherein R100is CM alkyl optionally substituted with deuterium or F, for example, R100is methyl, CD3, ethyl, fluorine-substituted methyl (e.g., difluoromethyl or trifluoromethyl), or fluorine-substituted ethyl, such as 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc.

47. The compound of claim 44 or 45, or a pharmaceutically acceptable salt thereof, wherein R100is cyclopropyl optionally substituted with 1 or 2 substituents, each independently F or methyl.

48. The compound of any of claims 1-7 and 9-27, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-8a or K-8b:Formula K-8b, wherein:Z is O, NH, or NR113, pl is 0, 1, or 2;R110and Rn iare each independently hydrogen or C 1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; or R110and R111, together with the carbon atom they are both attached to, are joined to form a 3-4 membered ring, preferably, a cyclopropyl ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy;R112at each occurrence is independently a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; or when applicable, two R112, together with the carbon atom they are both attached to, are joined to form C(=O), or a 3-4 membered ring, preferably, a cyclopropyl ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; and R113is (i) a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein Z is O.

50. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein Z is NH or NR113.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R113is C1-4 alkyl optionally substituted with deuterium or F, for example, methyl, CD3, ethyl, fluorine-substituted methyl (e.g., difluoromethyl or trifluoromethyl), or fluorinesubstituted ethyl, such as 2,2-difluoroethyl, 2,2,2-trifluoroethyl etc.

52. The compound of any of claims 48-51, or a pharmaceutically acceptable salt thereof, wherein R110and R111are each independently hydrogen or methyl.

53. The compound of any of claims 48-51 , or a pharmaceutically acceptable salt thereof, wherein R110and R111, together with the carbon atom they are both attached to, are joined to form a cyclopropyl ring.

54. The compound of any of claims 48-53, or a pharmaceutically acceptable salt thereof, wherein pl is 0.

55. The compound of any of claims 48-53, or a pharmaceutically acceptable salt thereof, wherein pl is 1 or 2, and R112at each occurrence is methyl.

56. The compound of any of claims 48-53, or a pharmaceutically acceptable salt thereof, wherein pl is 2, and two R112are attached to the same ring carbon, and the two R112, together with to the ring carbon they are both attached to, are joined to form a cyclopropyl ring.

57. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein the moiety of58. The compound of any of claims 1-7 and 9-27, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula K-9a or K-9b:Formula K-9a,Formula K-9b, wherein:W is O, NH, C(R121)(R122), or NR123, p2 is 0, 1, or 2;R120at each occurrence is independently a Ci-4 alkyl optionally substituted with one or more (e.g., 1 -3) substituents each independently deuterium, F, or OH; or when applicable, two R120, together with the carbon atom they are both attached to, are joined to form C(=O) or a 3-4 membered spiro or fused ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; R121and R122are each independently hydrogen or C 1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; or R121and R122, together with the carbon atom they are both attached to, are joined to form a 3-4 membered ring, preferably, a cyclopropyl ring, which is optionally substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy; andR123is (i) a C1-4 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, F, or OH; (ii) a 3-4 membered carbocyclic or heterocyclic ring; or (iii) (C1-4 alkylene)-(3-4 membered carbocyclic or heterocyclic ring); wherein the 3-4 membered carbocyclic or heterocyclic ring in (ii) or (iii) is unsubstituted or substituted with 1 or 2 substituents each independently F, OH, methyl, or methoxy.

59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein W is O.

60. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein W is NH or NR123.61 . The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein R123is Ci-4 alkyl optionally substituted with deuterium or F, for example, methyl, CD3, ethyl, fluorine-substituted methyl (e.g., difluoromethyl or trifluoromethyl), or fluorinesubstituted ethyl, such as 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc.

62. The compound of of claim 58, or a pharmaceutically acceptable salt thereof, wherein W is C(R121)(R122), wherein R121and R122are each independently hydrogen or methyl.

63. The compound of any of claims 58-62, or a pharmaceutically acceptable salt thereof, wherein p2 is 0.

64. The compound of any of claims 58-62, or a pharmaceutically acceptable salt thereof, wherein p2 is 1 or 2, and R120at each occurrence is methyl.

65. The compound of any of claims 58-62, or a pharmaceutically acceptable salt thereof, wherein p2 is 2, and two gem R120, and the same ring carbon they are both attached to, together represent C(=O).

66. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein the moiety of67. The compound of any of claims 1-66, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl, pyridinyl, pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[l,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4- b]pyridinyl, thiazolo[4,5-b]pyridinyl, benzo [d] thiazole, indazolyl, [l,2,4]triazolo[l,5- a]pyrimidinyl, [l,2,4]triazolo[l,5-b]pyridazinyl, or tetrazolo[l,5-a]pyridinyl, each of which is optionally substituted.

68. The compound of any of claims 1 -66, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with 1-3 substituents independently selected from: deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C1-4 alkylene)-CN, Gc, or Xc-Xd-Gc, wherein:Xcat each occurrence is independently null, CM alkylene, or C 1-4 heteroalkylene;Xdat each occurrence is independently null, O, NH, N(GD), C(O), C(O)O, C(O)NH, C(O)N(GD), NHC(O), N(GD)C(O), P(O)(GD), SO2, SO2NH, or SO2N(GD); and Gcat each occurrence is independently:(i) C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-6 membered ring;(ii) C 1-6 heteroalkyl optionally substituted with one or more (e.g., 1-3) substituents independently deuterium, halogen, CM alkyl, CM alkoxy, or a 3-6 membered ring;(iii) a 3-7 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, oxo, OH, CN, CM alkyl, CM alkoxy, or a 3-6 membered ring; or(iv) a 5 or 6-membered heteroaryl, which is optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CN, CM alkyl, CM alkoxy, or a 3-6 membered ring (preferably carbocyclic or heterocyclic ring), wherein the CM alkyl or CM alkoxy in each of (i)-(iv) is independently optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy, or a 3-4 membered carbocyclic or heterocyclic ring, and wherein each of the 3-6 membered ring in each of (i)-(iv) is independently optionally substituted with oxo, deuterium, halogen, OH, CN, CM alkyl optionally substituted with deuterium or F, or CM alkoxy optionally substituted with deuterium or F;GDat each occurrence is independently C1-6 alkyl optionally substituted with one or more (e.g., 1-3) substituents each independently deuterium, halogen, OH, CM alkoxy optionally substituted with deuterium or F, or a 3-6 membered ring optionally substituted with oxo,deuterium, halogen, OH, CN, C1-4 alkyl optionally substituted with deuterium or F, or C1-4 alkoxy optionally substituted with deuterium or F, or when applicable, Gcand GDtogether with the heteroatom they are both attached to are joined to form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more (e.g., 1-3) substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with deuterium or F, or C 1-4 alkoxy optionally substituted with deuterium or F.

69. The compound of any of claims 1-66, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen, C1-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, C1-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)(Ci4 alkyl).

70. The compound of any of claims 1-66, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen, CM alkyl optionally substituted with deuterium, F and / or OH, C1-4 alkoxy optionally substituted with deuterium or F, C3-4 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-3 alkyl), or N(CI-3 alkyl)(Ci-3 alkyl).

71. The compound of any of claims 1-66, or a pharmaceutically acceptable salt thereof, wherein R1is a phenyl or pyridinyl, each of which is optionally substituted with 1-3 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1 -hydroxy ethyl, preferably, the substituents are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

72. The compound of any of claims 1-66, or a pharmaceutically acceptable salt thereof, wherein R1iswherein Rlaand Rlbare each independently halogen, Ci-6 alkyl optionally substituted with deuterium, F, CN, and / or OH, Ci-6 alkoxy optionally substituted with deuterium, F, CN, and / or OH, C3-6 cycloalkyl optionally substituted with deuterium, F, CN, methyl, and / or OH, NH2, NH(CI-4 alkyl), or N(CI_4alkyl)(Ci_4alkyl).

73. The compound of claim 72, or a pharmaceutically acceptable salt thereof, wherein Rlbis Ci-4 alkoxy optionally substituted with 1-3 deuterium or F, for example, methoxy, ethoxy, or difluoromethoxy.

74. The compound of claim 72 or 73, or a pharmaceutically acceptable salt thereof, wherein Rlais (i) halogen (e.g., F or Cl); (ii) C1-4 alkyl optionally substituted with 1-3 deuterium or F, e.g., methyl, trifluoromethyl, difluoromethyl, etc.; or (iii) cyclopropyl or cyclobutyl, optionally substituted with methyl and / or F.

75. A compound selected from Table 1, or Examples 1-266, or a pharmaceutically acceptable salt thereof.

76. A pharmaceutical composition comprising the compound of any of claims 1-75, or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

77. A method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by overexpression of Pol0, the method comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-75, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 76.

78. The method of claim 77, wherein the disease or disorder is cancer.

79. A method of treating a homologous recombination (HR) deficient cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-75, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 76.

80. A method for treating a cancer in a subject in need thereof, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRCA gene, and / or reduced function of BRCA protein, the method comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-75, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 76.

81. The method of any one of claims 78-80, wherein the cancer is selected from lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer.

82. The method of any one of claims 77-81, further comprising administering to the subject one or more additional therapeutic agents selected from a PARP inhibitor, a signal transduction inhibitor, a chemotherapeutic agent, and / or an immune checkpoint inhibitor.

83. A method for treating a cancer in a subject in need thereof, wherein the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy, the method comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-75, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 76.

84. The method of claim 83, wherein the cancer is breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, or colorectal cancer.

85. The method of claim 83 or 84, further comprising administering to the subject a PARP inhibitor.