NZ615960B2 - (alpha- substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5 -triazinyl benzimidazoles, pharmaceutical compositions containing them, and these compounds for use in treating proliferative diseases - Google Patents

Abstract

The disclosure relates to (alpha-substituted aralkylamino or heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles (figure (I)), and their pharmaceutical compositions, preparation, and use as agents or drugs for treating PI3K-mediated diseases. Example compounds include: 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyrrolidin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-lH-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4'-methoxybiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-bromophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-IH-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyrrolidin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine. romethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyrrolidin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-lH-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4'-methoxybiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-bromophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-IH-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine, 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyrrolidin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine.

Description

(ALPHA- SUBSTITUTED ARALKYLAMINO AND HETEROARYLALKYLAMINO) PYRIMIDINYL AND 1,3,5 -TRIAZINYL BENZIMIDAZOLES , PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THESE COMPOUNDS FOR USE IN TREATING PROLIFERATIVE DISEASES CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the priority ofUS. Provisional Application Nos. 61/468,502, filed March 28, 2011; 61/530,859, filed September 2, 2011; and 61/560,699, filed November 16, 2011; the sure of each of which is orated herein by reference in its entirety.

FIELD Provided herein are (alpha-substituted aralkylamino or arylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, and their ceutical compositions, preparation, and use as agents or drugs for treating proliferative es.

OUND Phosphoinositidekinases (PI3Ks) are a group of lipid kinases, which phosphorylate the 3-hydroxyl of phosphoinositides. They are classified into at least three classes (classes I, II, and III) and play an ant role in cellular signaling (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357). Class I enzymes are fiarther classified into classes Ia and lb based on their mechanism of activation. Class Ia PI3Ks are heterodimeric structures consisting of a catalytic subunit (p1100t, p110B, or p1108) in complex with a regulatory p85 subunit, while class-Ib PI3K (p110y) is structurally similar but lacks the p85 regulatory subunit, and instead is ted by By subunits of heterotrimeric G-proteins (Walker et al., M01.Cell. 2000, 6, 909).

PI3Ks play a variety of roles in normal tissue physiology (Foukas & Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, I83, 3), with p1100t having a specific role in cancer growth, p110B in thrombus ion mediated by integrin (11103 (Jackson et al., Nat. Med. 2005, 11, 507), and p1 10y in inflammation, rheumatoid arthritis, and other chronic inflammation states (Barber et al. Nat. Med. 2005, I I , , 933; Camps et al., Nat. Med. 2005, II, 936; Rommel et al., Nat. Rev. 2007, 7, 191; and Ito, et al., J. Pharm. Exp. Themp. 2007, 321, 1). Therefore, there is a need for PI3K inhibitors for treating cancer and/or atory diseases.

SUMMARY OF THE DISCLOSURE Provided herein is a compound of a 1: R2\/\ N / NkR6 KAY RSd R56 (\AN i 5 C \Z NWR o RSaRSb \/\J or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y, and Z are each independently N or CRX, with the o that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; R1 and R2 are each ndently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, R1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, (O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked together to form a bond, C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) en or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, WO 35160 C340 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, R1bR1°, a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NRle1°, 1°, —NR1aC(O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, (O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, (O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5f and ng are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or cyclyl; or (c) 1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, (O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one ence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 cycloalkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; m is 0 or 1; and nis 0, l, 2, 3, or 4; wherein each alkyl, ne, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, R4, R6, RX, R”, Rlb, R”, R“, R52 RSb, R5“, RSd, R53, R“, and R5g is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther ally substituted with one or more, in one ment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, )NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is filrther ally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc er with the N atom to which they are attached form heterocyclyl, which is r optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRng, )NRng, —0Re, —OC(O)Re, ORe, —OC(O)NRng, —OC(=NRe)NRng, —OS(O)Re, —OS(O)2Re, NRng, 2NRng, —NRng, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRng, —NReC(=NRh)NRng, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRng, —NReS(O)2NRng, —SRe, e, —S(O)2Re, —S(O)NRng, and —S(O)2NRng; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

In one embodiment, m is 0; and R581 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, R1a, —C(O)NR1bR1°, a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°.

Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a e of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; and one or more pharmaceutically acceptable excipients.

Furthermore, provided herein is a method for treating, ting, or ameliorating one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, comprising administering to the t a eutically ive amount of a compound disclosed herein, e.g., a compound of Formula I, or an omer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a PI3K8—mediated disorder, disease, or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a therapeutically ive amount of a compound disclosed herein, e.g., a compound of Formula I, or an enantiomer, a mixture of omers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof [0010A] Furthermore, provided herein is a use of compound disclosed herein, e.g., a compound of Formula I, or a ceutical composition comprising such a compound, in the manufacture of a medicament for the treatment, prevention, or amelioration of one or more symptoms of a PI3K-mediated disorder, disease, or ion in a t. [0010B] Provided herein is a use of compound disclosed herein, e.g., a compound of Formula I, or a pharmaceutical composition comprising such a compound, in the manufacture of a medicament for modulating PI3K enzymatic activity. 5A (Followed by page 6) Provided herein is a method for modulating PI3K activity, comprising contacting a PI3K with an effective amount of a compound disclosed herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, e, hydrate, or prodrug thereof.

Provided herein is a method for modulating PI3K5 activity, comprising contacting PI3K8 with an ive amount of a compound disclosed , e.g., a compound of Formula I, or an enantiomer, a mixture of omers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, e, hydrate, or g thereof Provided herein is a method for selectively modulating PI3K8 activity, comprising contacting PI3K8 with an effective amount of a nd disclosed herein, e.g., a nd of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

DETAILED DESCRIPTION To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this sure belongs.

The term ct” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms ct” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to include alleViating or ting a disorder, disease, or condition, or one or more of the symptoms associated with the er, disease, or condition; or alleviating or ating the cause(s) of the disorder, disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a er, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is ient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a ical le (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier, 3, CCpharmaceutically acceptable excipient,3, “physiologically acceptable carrier,” or “physiologically able excipient” refers to a pharmaceutically-acceptable al, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with other ingredients of a ceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 2lst n, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical ents, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook maceutical Additives, 3rd n, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformalation and Formalation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ry skill in the art, which depends in part on how the value is measured or ined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% ofa given value or range.

The terms “active ingredient” and “active nce” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically able excipients, to a subject for ng, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition. As used herein, “active ingredient” and “active nce” may be an lly active isomer of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is stered to a subject for ng, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.

The term “naturally occurring” or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not manipulated by man. Similarly, “non-naturally occurring” or “non-native” refers to a material that is not found in nature or that has been structurally modified or synthesized by man.

The term “PI3K” refers to a phosphoinositide 3-kinase or variant thereof, which is e of phosphorylating the inositol ring of PI in the D-3 position. The term “PI3K variant” is intended to include proteins ntially homologous to a native PI3K, z'.e., proteins having one or more naturally or turally occurring amino acid deletions, insertions, or substitutions (e.g., PI3K derivatives, homologs, and fragments), as compared to the amino acid sequence of a native PI3K. The amino acid sequence of a PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K. Examples of PI3K include, but are not limited to, p1100t, p110[3, p1108, p110y, 2u, PI3K-C2B, PI3K-C2y, Vps34, mTOR, ATM, ATR, and . See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell.

Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ks are classified into at least four classes. Class I includes , p110B, p1108, and p110y. Class II includes PI3K-C2u, PI3K-C2B, and PI3K-C2y. Class III includes Vps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is p1100t, p110[3, p1108, or p110y. In certain embodiments, the PI3K WO 35160 is a variant of a Class I kinase. In certain embodiments, the PI3K is a p1100t mutant.

Examples of p1 10d mutants include, but are not limited to, R3 8H, GlO6V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, 1800L, T102SS, M10431, M1043V, , H1047R, and H1047Y (Ikenoue et al., Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al., Proc. Natl. Acad. S612, 2007, 104, 5569-5574).

In n embodiments, the PI3K is a Class II kinase. In certain ments, the PI3K is PI3K-C20L, PI3K-C2B, or PI3K-C2y. In certain embodiments, the PI3K is a Class III kinase.

In certain embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK.

The terms “PI3K-mediated er, disease, or condition” and “a disorder, disease, or ion mediated by PI3K” refer to a disorder, disease, or condition characterized by abnormal or dysregulated, e.g. less than or greater than normal, PI3K activity. al PI3K fianctional activity might arise as the result of PI3K overexpression in cells, expression of PI3K in cells which normally do not express PI3K, or dysregulation due to constitutive activation, caused, for example, by a on in PI3K. A ediated disorder, e, or condition may be completely or partially mediated by abnormal PI3K activity. In particular, PI3K-mediated disorder, disease, or condition is one in which modulation of a PI3K activity results in some effect on the underlying disorder, disease, or condition, e.g., a PI3K inhibitor results in some improvement in at least some of patients being treated.

The terms “pl 105-mediated disorder, disease, or condition, 33 CC a disorder, disease, or condition mediated by pl 105,” “PI3K5-mediated disorder, disease, or condition,” and “a disorder, disease, or condition ed by PI3K5” refer to a disorder, disease, or condition characterized by abnormal or dysregulated, e.g., less than or greater than normal, p1105 activity. Abnormal p1105 fianctional activity might arise as the result of pl 105 overexpression in cells, expression of pl 105 in cells which normally do not express p1105, or dysregulation due to constitutive activation, caused, for example, by a mutation in p1105. A mediated disorder, disease, or condition may be completely or partially ed by abnormal p1105 activity. In particular, mediated disorder, disease, or condition is one in which modulation of a p1105 activity results in some effect on the underlying disorder, disease, or condition, e.g., a p1105 inhibitor results in some improvement in at least some of patients being treated.

The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be tuted with one or more substituents Q as described herein. The term “alkyl” also encompasses both linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 ), l to 15 (C145), 1 to 10 (C140), or 1 to 6 (C1_6) carbon atoms, or branched saturated monovalent hydrocarbon radical of3 to 20 (€3-20), 3 to 15 (€3-15), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. As used herein, linear C1_6 and branched C3_6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t—butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C1_6 alkyl refers to a linear saturated monovalent hydrocarbon radical of l to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “alkylene” refers to a linear or branched ted nt hydrocarbon radical, wherein the alkylene may optionally be tuted with one or more substituents Q as described herein. The term “alkylene” encompasses both linear and ed alkylene, unless otherwise specified. In certain embodiments, the alkylene is a linear saturated nt hydrocarbon radical that has 1 to 20 (Ci—20), l to 15 (C145), 1 to 10 (C140), or 1 to 6 (C1_6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C340), 3 to 15 (C345), 3 to 10 , or 3 to 6 (C3_6) carbon atoms. As used herein, linear C1_6 and branched C3_6 alkylene groups are also referred as “lower ne.” Examples of alkylene groups e, but are not limited to, methylene, ne, propylene (including all isomeric , n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t—butylene, pentylene (including all isomeric forms), and ne ding all isomeric . For example, C1_6 alkylene refers to a linear saturated divalent hydrocarbon radical of l to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. [003 0] The term “heteroalkylene” refers to a linear or ed saturated divalent hydrocarbon radical that contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. For example, C1_6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of l to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated nt hydrocarbon l that has 1 to 20 (C1_20), l to 15 (C145), 1 to 10 (C140), or 1 to 6 (C1_6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (€3-20), 3 to 15 (€3-15), 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. As used , linear C1_6 and branched C3_6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, —CHzO—, —CH20CH2—, zO—, —CH2NH—, —CH2NHCH2—, —CH2CH2NH—, —CHZS—, —CHZSCH2—, and —CH2CHZS—. In n embodiments, heteroalkylene may also be optionally substituted with one or more substituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent arbon radical, which contains one or more, in one ment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s). The alkenyl may be optionally substituted with one or more substituents Q as described herein. The term “alkenyl” also embraces radicals having “cis” and “trans” configurations, or alternatively, “Z” and “E” configurations, as appreciated by those of ordinary skill in the art. As used herein, the term “alkenyl” encompasses both linear and branched alkenyl, unless otherwise specified. For example, C2_6 l refers to a linear rated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the l is a linear monovalent hydrocarbon radical of 2 to 20 (Cue), 2 to 15 (C245), 2 to 10 (C240), or 2 to 6 (C26) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C345), 3 to 10 (C340), or 3 to 6 (C3_6) carbon atoms. Examples of alkenyl groups include, but are not limited to, l, propen-l-yl, propenyl, allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched nt hydrocarbon radical, which ns one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s). The alkenylene may be optionally substituted with one or more substituents Q as described . Similarly, the term “alkenylene” also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations. As used , the term “alkenylene” encompasses both linear and branched alkenylene, unless otherwise specified. For example, C2_6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C245), 2 to 10 (C240), or 2 to 6 (C2_6) carbon atoms, or a branched divalent arbon radical of 3 to 20 (C340), 3 to 15 (C345), 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. es of alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4- methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalent arbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected fiom O, S, and N in the hydrocarbon chain.

The heteroalkenylene may be ally substituted with one or more substituents Q as described herein. The term “heteroalkenylene” es radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2_6 alkenylene refers to a linear unsaturated divalent arbon radical of 2 to 6 carbon atoms or a branched rated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (Cue), 2 to 15 , 2 to 10 (C240), or 2 to 6 (C26) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (€3-20), 3 to 15 , 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, O—, —CH=CHOCH2—, —CH=CHCHzO—, —CH=CHS—, —CH=CHSCH2—, —CH=CHCHZS—, or —CH=CHCH2NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon triple ). The alkynyl may be optionally tuted with one or more substituents Q as described herein. The term “alkynyl” also encompasses both linear and ed alkynyl, unless otherwise specified. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_20), 2 to (C245), 2 to 10 (C240), or 2 to 6 (C2_6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (€3-20), 3 to 15 (C345), 3 to 10 (€3-10), or 3 to 6 (C3_6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—CECH) and propargyl (—CHZCECH). For example, C2_6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “cycloalkyl” refers to a cyclic ted bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (€3-20), from 3 to 15 (C345), from 3 to 10 ), or from 3 to 7 (C34) carbon atoms.

Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2. l . l]hexyl, o[2.2. l ]heptyl, decalinyl, and tyl. [003 6] The term “cycloalkenyl” refers to a cyclic unsaturated, nonaromatic bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkenyl has from 3 to 20 (€3-20), from 3 to 15 (€3-15), from 3 to 10 (C340), or from 3 to 7 (Cs—7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, exenyl, or cycloheptenyl, [003 7] The term “aryl” refers to a clic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6_20), from 6 to 15 (C645), or from 6 to 10 (C640) ring atoms. es of aryl groups e, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or ydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted with one or more substituents Q as described herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the l has from 7 to (€7-30), from 7 to 20 (C740), or from 7 to 16 (€7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, the aralkyl are ally substituted with one or more substituents Q as described herein. [003 9] The term oaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic ic group that contain at least one ic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N, and P in the ring. A heteroaryl group is bonded to the rest of a molecule through its ic ring. Each ring of a heteroaryl group can contain one or two 0 atoms, one or two S atoms, one to four N atoms, and/or one or two P atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, yl, thiadiazolyl, thiazolyl, thienyl, olyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, riazolyl, benzoxazolyl, ridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, azolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, l, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and pyridyl. es of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl may also be optionally substituted with one or more substituents Q as described herein as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, N, and P; and the ing ring atoms are carbon atoms.

In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. A heterocyclyl group is bonded to the rest of a molecule through its non-aromatic ring. In certain embodiments, the heterocyclyl is a clic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, fused, or d, and in which en or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quatemized, and some rings may be partially or fillly saturated, or aromatic. The cyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofilranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, B-carbolinyl, chromanyl, chromonyl, cinnolinyl, inyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, opyridinyl, dihydropyrimidinyl, dihydropyrrolyl, anyl, l,4-dithianyl, nyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, olidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and l,3,5-trithianyl. In certain ments, the heterocyclyl may also be optionally substituted with one or more substituents Q as described herein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine, bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, alkylene, alkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl-C1_6 alkyl, and heterocyclyl group, may be substituted with one or more substituents Q, each of which is independently selected from, e.g., (a) oxo (=0), halo, cyano (—CN), and nitro (—N02); (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, and heterocyclyl, each of which is fidrther ally substituted with one or more, in one embodiment, one, two, three, four, or five, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —P(O)RaRd, —P(O)(ORa)Rd, —P(O)(ORa)(ORd), —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and NRbR°, wherein each Ra, Rb, R“, and Rd is independently (i) hydrogen; (ii) c1.6 alkyl, c2.6 l, c2.6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are ed form heteroaryl or heterocyclyl, optionally substituted with one or more, in one ment, one, two, three, or four, substituents Qa. As used , all groups that can be substituted are “optionally substituted,” unless otherwise ed.

In one embodiment, each substituent Qa is independently selected from the group ting of (a) oxo, cyano, halo, and nitro; and (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRng, —C(NRe)NRng, —0Re, —OC(O)Re, —OC(O)ORe, —OC(O)NRng, —OC(=NRB)NRng, —OS(O)Re, —OS(O)2Re, —OS(O)NRng, 2NRng, —NRng, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRng, —NReC(=NRh)NRng, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRng, —NReS(O)2NRng, —P(O)ReRh, —P(O)(ORe)Rh, —P(O)(ORe)(ORh), —SRe, —S(O)Re, —S(O)2Re, —S(O)NRng, and NRng; wherein each Re, Rf, Rg, and Rh is independently (i) en, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl; or (ii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.

In certain embodiments, “optically active” and ”enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound ses about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the le about its chiral center(s). The (+) and (-) are used to denote the l rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.

The term “isotopic t” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an “isotopic variant” of a compound contains unnatural tions of one or more isotopes, including, but not limited to, hydrogen (1H), ium (2H), tritium (3H), carbon-ll (11C), carbon-12 (12C), carbon-l3 (13C), carbon-l4 (14C), en-l3 (EN), nitrogen- l 4 (MN), nitrogen-15 (UN), - 1 4 (140), oxygen-15 (150), oxygen- 1 6 (160), oxygen- 1 7 (170), oxygen- 1 8 (180), fluorine- l 7 (17F), fluorine- l 8 (18F), phosphorus-31 (3 1P), phosphorus-32 (32F), orus-33 (33P), sulfur-32 (32S), sulfur-33 (33 S), sulfur-34 (34S), sulfur-35 (35$), sulfur-36 (36S), chlorine-35 (”Cl), chlorine-36 (36Cl), chlorine-37 (37c1), bromine-79 (79130, bromine-8l (81130, iodine-123 (1231), iodine-125 (1251), iodine-127 (1271), iodine-129 (1291), and iodine-l3l (1311). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. In certain embodiments, an “isotopic variant” of a compound contains ral proportions of one or more isotopes, including, but not limited to, hydrogen (1H), ium (2H), carbon-12 (12C), carbon-l3 (13C), nitrogen- 14 (MN), nitrogen-15 (UN), oxygen- 1 6 (160), oxygen- 1 7 (170), oxygen- 1 8 (180), fluorine- l 7 (17F), phosphorus-31 (31F), sulfur-32 (32$), sulfur-33 (33S), sulfur—34 (34S), sulfur-36 (36S), chlorine-35 (35Cl), ne-37 (37Cl), bromine-79 (79Br), bromine-8l , and iodine-127 (1271). In certain embodiments, an “isotopic variant” of a compound is in an unstable form, that is, radioactive. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), -ll (11C), carbon-l4 (14C), nitrogen-l3 (EN), oxygen-l4 (140), oxygen-15 (150), fluorine-l8 (18F), phosphorus-32 (32F), phosphorus-33 (33P), sulfiJr-35 (35S), chlorine-36 (36c1), iodine-123 (1231), iodine-125 , iodine-129 (1291), and -131 . It will be understood that, in a compound as provided herein, any hydrogen can be 2H, for example, or any carbon can be 13C, for example, or any nitrogen can be 15N, for example, or any oxygen can be 180, for example, Where le according to the judgment of one of skill. In certain ments, an “isotopic variant” of a compound contains unnatural proportions of deuterium (D).

The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided , and one or more molecules of a solvent, which present in a stoichiometric or non-stoichiometric . Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not d to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an ic variant f; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “an enantiomer, a mixture of omers, a mixture of two or more reomers, or an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt, e, hydrate, or g of the nd referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or g of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein.” Compounds In one embodiment, provided herein is a compound of Formula I: R2\’/ \ N / NkR6 KAY RSd R56 r\’\N i 5 C \Z NMR \J H 0 R521 R5b or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, (O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 lkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are ed form cyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked er to form a bond, C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —C(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NRle1°, —OS(O)2NRle1°, —NR1bR1°, (O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, (O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R50 is R5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5f and ng are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 lkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 cycloalkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; m is 0 or 1; and nis 0,1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, l, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, R4, R6, RX, R”, Rlb, R”, R“, R52 RSb, R5“, RSd, R53, R“, and R5g is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, , —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and NRbR°, wherein each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is fiarther ally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is ndently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, Re, —C(O)NRng, —C(NRe)NRng, —0Re, —OC(O)Re, —OC(O)ORe, —OC(O)NRng, —OC(=NRe)NRng, —OS(O)Re, —OS(O)2Re, —OS(O)NRng, —OS(O)2NRng, —NRng, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRng, =NRh)NRng, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRng, —NReS(O)2NRng, —SRe, e, —S(O)2Re, Rng, and —S(O)2NRng; wherein each Re, Rf, Rg, and Rh is independently (i) en; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 l, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

In one embodiment, in Formula I, X, Y, and Z are each independently N or CRX’ with the proviso that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; R1 and R2 are each ndently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, or heterocyclyl; or (c) —C(O)R1a, R1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0Rla, —OC(O)R1a, OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked together to form a bond, C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2012/030640 —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 l, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, (O)Rld, (O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) 1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or NR1bR1°; R5f and ng are each ndently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or cyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, 2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 cycloalkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; n1 is 0 or 1; and nis 0, l,2,3,or4; with the proviso that the compound is neither 4-(2-(difluoromethyl)—lH— d]imidazol- l -yl)morpholino-N-(2-phenyl(pyrrolidin- l -yl)ethyl)- l ,3 ,5 -triazin amine nor 6-(2-(difluoromethyl)- 1H-benzo[d]imidazol- l -yl)-N-( l -(4-((R)-3 - (methoxymethyl)morpholino)phenyl)ethyl)morpholinopyrimidinamine; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, lkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q as defined herein.

In another embodiment, in Formula I, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) en; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, aryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are ed form cyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked together to form a bond, C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, 2012/030640 C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, (O)Rld, —NR1aS(O)2R1d, (O)NR1bR1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, R1bR1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or R5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5f and ng are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, or heterocyclyl; or (c) —C(O)R1a, R1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng er with the carbon atom to which they are attached form a C340 cycloalkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; n1 is 0 or 1; and nis 0,1, 2, 3, or 4; with the proviso that, when X, Y, and Z are N, and R5&1 is hydrogen, R5b is not idinyl; and when X and Z are N, Y is CH, and R5&1 is hydrogen, R5b is not 4-((R) (methoxyniethyl)niorpholino)phenyl; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, aryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q as defined .

In yet another embodiment, in Formula I, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; R1 and R2 are each ndently (a) en, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, (O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 l, heteroaryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked together to form a bond, C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, R1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, aryl, or heterocyclyl; or (c) —C(O)R1a, R1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) 1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, (O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5f and ng are each ndently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, (O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, 1a, —S(O)2R1a, —S(O)NR1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 cycloalkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; m is 0 or 1; and nis 0,1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, alkenyl, lene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and cyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q as defined herein.

In still another embodiment, in Formula I, X, Y, and Z are N; R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, WO 35160 —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked together to form a bond, C1_6 alkylene, C1_6 alkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 lkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, 2R1a, —OS(O)NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, (O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 l, or heteroaryl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NRle1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d,—NR1aC(O)NRle1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NRle1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5f and ng are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, (O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, (O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 lkyl or cyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; m is 0 or 1; and nis 0,1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q as defined herein.

In one embodiment, the compound of Formula I has the ure of Formula R2\/ \ N R3 X JY\ R5d R56 \r\’\N 5C \z NPNR OV\J H RSa R“) (13) or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSC, RSd, R53, m, X, Y, and Z are each as defined . In one embodiment, m is 0. In another embodiment, m is l.

In another embodiment, the compound of Formula I has the structure of Formula Ib: R2\/ \ N (lb) or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSC, RSd, R53, m, X, Y, and Z are each as defined herein. In one embodiment, m is 0. In another embodiment, m is l.

In one embodiment, provided herein is a compound of Formula I, la, or 1b as described herein, or an enantiomer, a e of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein m is 0; R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, R5“, R6, X, Y, Z, R”, Rlb, R1“, and R1d are defined herein elsewhere.

In yet another embodiment, provided herein is a compound of Formula II: R2\// \ N / »\R6 (11) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0Rla, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or cyclyl; or (iii) R1b and R10 together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked er to form a bond, C1_6 ne, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 heteroalkenylene; R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, R1bR1°, a)NR1bR1°, —0R1a, —OC(O)R1a, OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, R1bR1°, a)NR1bR1°,—OR1a, R1a, —OC(O)OR1a, NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, (O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5f and ng are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, R1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 cycloalkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; and nis 0,1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, l, alkenylene, heteroalkenylene, l, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, RflRflRKRVJFERKREinRfiRfiindekmommmMymmmmmdeNmem more, in one embodiment, one, two, three, or four, substituents Q, n each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl, each of which is fiarther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, , —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, R°, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is further optionally tuted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Q21 is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, Rng, —C(NRe)NRng, —0Re, —OC(O)Re, —OC(O)ORe, —OC(O)NRng, Re)NRng, —OS(O)Re, 2Re, —OS(O)NRng, —OS(O)2NRng, —NRng, —NReC(O)Rh, O)ORh, —NReC(O)NRng, —NReC(=NRh)NRng, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRng, —NReS(O)2NRng, —SRe, e, —S(O)2Re, —S(O)NRng, and —S(O)2NRng; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

In yet another embodiment, ed herein is a compound of Formula II: R2\Il \ N / »\R6 (11) or an enantiomer, a mixture of enantiomers, a e of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where RX is hydrogen or C1_6 alkyl; 2012/030640 R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0Rla, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; wherein each R”, Rlb, R”, and R1d is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R10 together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1_6 alkyl; or R3 and R4 are linked together to form a bond, C1_6 alkylene, C1_6 heteroalkylene, C2_6 alkenylene, or C2_6 alkenylene; R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or cyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, R1a, OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, R1bR1°, or —S(O)2NR1bR1°; R50 is C644 aryl or aryl; and R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; wherein each alkyl, alkylene, alkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, RaRaRXJfliijyiRMinRfigdekmophdestfimmdwfihmwormmfifln one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, aryl, and heterocyclyl, each of which is fiarther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, Ra, —OC(O)ORa, —OC(O)NRbR°, Ra)NRbR°, —OS(O)Ra, —OS(O)2Ra, NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbR°, —NRaS(O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, wherein each Ra, Rb, R°, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is further ally substituted with one or more, in one embodiment, one, two, three, or four, tuents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Q21 is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 l, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRng, —C(NRe)NRng, —0Re, —OC(O)Re, —OC(O)ORe, —OC(O)NRng, —OC(=NRe)NRng, —OS(O)Re, —OS(O)2Re, —OS(O)NRng, —OS(O)2NRng, —NRng, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRng, —NReC(=NRh)NRng, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRng, —NReS(O)2NRng, —SRe, e, —S(O)2Re, —S(O)NRng, and —S(O)2NRng; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

In one embodiment, the compound of Formula II has the structure of a IIa: R2\II \ N (Ila) or an isotopic variant thereof; or a ceutically acceptable salt, solvate, hydrate, or prodrug f; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSC, X, Y, and Z are each as defined herein.

In another embodiment, the compound of Formula II has the structure of Formula IIb: R2\II \ N (IIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSC, X, Y, and Z are each as defined herein.

In one embodiment, provided herein is a compound of Formula II, IIa, or IIb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; n R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 l, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0Rla, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, R5“, R6, X, Y, Z, R”, Rlb, R1“, and R1d are defined herein ere.

In yet another embodiment, provided herein is a compound of Formula III: R2\/ \ N r N N E m oV\J R5a R“) (111) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an ic t f; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; where1n R- 1 2 3 4 6 5 5b 5 R R R R R a, R R c, R“, R53, and m are each as defined here1n.- , , , , , , In one embodiment, m is 0. In another embodiment, m is l.

In one embodiment, the compound of Formula 111 has the structure of Formula IIIa: R2\/ \ N R3 N (\ANkNkNPQMR5 C o\/\/l H R5a R“) (IIIa) or an isotopic variant thereof; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSC, RSd, R53, and m are each as defined herein. In one embodiment, m is 0. In another embodiment, m is l.

In another embodiment, the compound of Formula III has the structure of a IIIb: R2\I/ \ N R3 N J}: R5d R56 (\AN 5C \N R N m oV\J H RSa R5b (IIIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSC, RSd, R53, and m are each as defined herein. In one embodiment, m is 0. In another embodiment, m is l.

In one embodiment, provided herein is a compound of Formula 111, IIIa, or IIIb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more reomers, or an isotopic variant thereof; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof; wherein m is 0; R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, (O)R1d, (O)OR1du —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, RSC, R6, Rla, Rlb, R”, and R1d are defined herein elsewhere.

In yet another embodiment, provided herein is a compound of Formula IV: / »\R6 R3 r i><\ r\/\N N RSC oV\J (IV) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, and R50 are each as defined herein.

In one embodiment, the compound of Formula IV has the ure of Formula IVa: R2\l/ \ N (IVa) or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug f; n R1, R2, R3, R4, R6, Rsa, RSb, and R50 are each as defined herein.

In r embodiment, the compound of Formula IV has the ure of Formula IVb: R2\I \ I N / N»\R6 NAN R521 R5b | ”' o\,\/' (IVb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, e, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, and R50 are each as defined herein.

In one embodiment, provided herein is a compound of Formula IV, IVa, or IVb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 l, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0Rla, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, RSC, R6, Rla, Rlb, R”, and R1d are defined herein elsewhere.

In yet another ment, provided herein is a compound of a V: R2\// \ N R3 X IY (\AN \ZANARSC oVJ H or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug f; wherein R1, R2, R3, R4, R6, RSb, RSC, X, Y, and Z are each as defined herein.

In one embodiment, the compound of Formula V has the structure of Formula R2\’/ \ N R3 X IY RSb (\“N \ZAN/kR“ oV\J H (Va) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, RSC, X, Y, and Z are each as defined herein.

In another embodiment, the compound of Formula V has the structure of Formula Vb: R2\II \ N R3 X Y 35b r\/\N \ k AZ N RSC oVJ H (Vb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, RSC, X, Y, and Z are each as defined herein.

In yet another embodiment, provided herein is a nd of Formula V1: (V1) or an omer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, and R50 are each as defined herein.

In one embodiment, the compound of Formula VI has the structure of a VIa: R2\Il \ a / \ R3 N ?\/\NJ\\NJ\N/LR5C| oVJ H (VIa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, and R50 are each as defined herein.

In r embodiment, the compound of Formula VI has the structure of a VIb: R2\’/ \ N R3 N N 85b \/\ \ J\ A r N N N RSC o\/ J (VIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, and R50 are each as defined herein.

In yet another embodiment, provided herein is a nd of Formula VII: R2\Il \ N \/\ I \ R7b l’ N Z E O\/ ’l R76 R7C R4 R7d (VII) or an enantiomer, a mixture of omers, a mixture of two or more diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein: R”, R71), R7°, RM, and R7‘3 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; two of R781, R713, RR, R“, and R7‘3 that are adjacent to each other form C340 cycloalkenyl, C644 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R”, Rlb, R”, R“, R52 RSb, X, Y, and z are each as defined herein.

In one embodiment, the compound of Formula VII has the structure of Formula VIIa: (VIIa) or an isotopic variant thereof; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7a, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, the compound of Formula VII has the structure of Formula VIIb: (VHb) or an isotopic variant thereof; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof; n R1, R2, R3, R4, R6, Rsa, RSb, R7a, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula VIII: R3 N N R5a R5b R7a (\AN J\\NJ\ R7b O\/ ’l R76 R7C R4 R7d (VIII) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R- 1 2 3 4 6 5 5b 7 R R R R R , , , , , a, R R , a, R7b, R7°, RM, and R7‘3 are each as defined herein.

In one ment, the compound of Formula VIII has the structure of Formula VIIIa: R2\,’ N / »\R6 R3(\ANxNxE) | 7b n, R O\/\/’ R76 R7C R4 R7d (VIIIa) or an isotopic variant f; or a ceutically acceptable salt, solvate, e, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7a, R7b, R7°, RM, and R7‘3 are each as defined herein.

In r embodiment, the compound of Formula VIII has the structure of Formula VIIIb: (VIIIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7a, R71), RR, R“, and R7‘3 are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula IX: R3r\’\NX\ J\NNRSCIRSC O\/\J H RSa R5b 1176 (1X) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R”, R71), R7°, RM, and R7‘3 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 lkyl, C644 aryl, C745 aralkyl, aryl, or heterocyclyl, each of which is optionally tuted with one or more substituents Q; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; two of R781, R713, RR, R“, and R7‘3 that are adjacent to each other form C340 cycloalkenyl, C644 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R”, Rlb, R”, R“, RSa, RSb, RSd, R53, X, Y, and z are each as defined .

In one embodiment, the compound of Formula IX has the structure of Formula IXa: (IXa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, e, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSa, RSb, RSd, R53, R7a, R7b, R7“, R7d, R73, X, Y, and Z are each as defined herein.

In another embodiment, the compound of a IX has the structure of Formula IXb: \l/ \ N / \ XAY RSdR56R7a R7C /\ \ J\ R7d r N Z N \- O RSa R5b R7e \/\J (IXb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSa, RSb, RSd, R53, R7a, R7b, R7“, R7d, R73, X, Y, and Z are each as defined herein.

In Formula IX, IXa, or IXb, in certain ments, one of R781, R71), RR, R“, and R7‘3 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally tuted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7°, R“, and R7e is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7 and R7e is heteroaryl, e.g., ered or , R“, 6-membered heteroaryl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7°, R“, and R7e is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally tuted with one or more substituents Q; in certain embodiments, one of R781, R71), R7°, RM, and R7‘3 is phenyl, imidazolyl, pyrozolyl, nyl, piperidinyl, or piperazinyl, each optionally substituted with one or more tuents Q; in certain embodiments, one of R781, R7b, R7°, R7d, and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in n embodiments, one of R7a, R71), RR, R“, and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R781, R71), R7 and R7‘3 is , 2-fluorophenyl, 2-chlorophenyl, , RM, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, oxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin ylmethylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, oxypyridinyl, pyrimidinyl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, ropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In a IX, IXa, or IXb, in certain embodiments, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is aryl, e.g., 5-membered or 6-membered heteroaryl, ally tuted with one or more substituents Q; in certain embodiments, R7&1 is heterocyclyl, e.g., ered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in certain embodiments, R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally tuted with one or more substituents Q; in n embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol- l -yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, nyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and in certain embodiments, R7&1 is phenyl, ophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, oxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol- 4-yl, l-methyl-pyrozolyl, 2-methylpyrozolyl, nyl, pyridinyl, pyridinyl, 2-fluoropyridin-3 -yl, 2-methylpyridinyl, ethylpiperazin- l ridinyl, 2-methoxypyridinyl, pyrimidin-S-yl, pyrrolidin-3 -yl, l-methylpyrrolidinyl, piperidin yl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l -acetylpiperidinyl, l -methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In one embodiment, in Formula IX, IXa, or IXb, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each ndently hydrogen, halo, C1_6 alkyl, optionally substituted with one or more substituents Q; R5d and RS‘3 are each independently C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally WO 35160 substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or C1_6 alkyl, optionally substituted with one or more substituents Q.

In r embodiment, in Formula IX, IXa, or IXb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R581 and R5b are hydrogen; R5d and RS‘3 are each independently C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each ndently N or CH.

In yet another embodiment, in Formula IX, IXa, or IXb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R7&1 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula IX, IXa, or IXb, R1 is hydrogen or y; R2 is hydrogen; R3 and R4 are hydrogen; WO 35160 R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula IX, IXa, or IXb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each ndently N or CH.

In still another embodiment, in Formula IX, IXa, or IXb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R7&1 is phenyl, imidazolyl, lyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another embodiment, provided herein is a nd of Formula X: \II \ N N R7b 7 7 RC 3 NAN RSdRSCRa R\/\ \ J\ 7d r N N N R O \J H RSa R5b 117e or an enantiomer, a mixture of enantiomers, a e of two or more reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSd, R53, R781, R713, RR, R“, and R7‘3 are each as defined herein.

In one embodiment, the compound of Formula X has the structure of Formula or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSd, R53, R7a, R71), R7°, RM, and R7‘3 are each as defined herein.

In another embodiment, the com ound of Formula X has the structure ofp Formula Xb: \I/ \ N / NkR6 NAN R7a R7C RSdRSC \/\ \ J\ 7d r N N N R O RSa R5b 117e \/\J (Xb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSd, R53, R7a, R71), R7°, RM, and R7‘3 are each as defined herein.

In Formula X, Xa, or Xb, in certain embodiments, one of R781, R71), R7 , RM, and R7‘3 is C644 aryl, aryl, or heterocyclyl, each of which is ally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7°, R“, and R7e is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7 and R7e is heteroaryl, e.g., 5-membered or , R“, 6-membered heteroaryl, ally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7 and R7e is heterocyclyl, e.g., 5-membered or , R“, 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R71), R7 and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, , RM, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7°, R7d, and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, one of R7a, R71), RR, R“, and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, oxyphenyl, 4-florophenyl, 4-chlorophenyl, ophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, nyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R781, R71), R7 and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, , RM, ophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, WO 35160 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, oxyphenyl, 4-florophenyl, 4-chlorophenyl, ophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, holin ylmethylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4- methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, dinyl, pyrrolidinyl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In Formula X, Xa, or Xb, in certain embodiments, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in n embodiments, R7&1 is phenyl, olyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each ally substituted with one or more substituents Q; in certain embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, ophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, ophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozol-3 -yl, pyridinyl, pyridinyl, pyridinyl, ylpyridinyl, 2-methoxypyridinyl, l-methylpiperidin- 4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, rophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, oxyphenyl, 4-methoxyphenyl, 3 -morpholinylmethylphenyl, ol- l -yl, lyl, l -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidin yl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l -methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In one embodiment, in Formula X, Xa, or Xb, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently hydrogen, halo, C1_6 alkyl, optionally tuted with one or more substituents Q; R5d and RS‘3 are each independently C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or cyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In another embodiment, in Formula X, Xa, or Xb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R581 and R5b are en; R5d and RS‘3 are each independently C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

] In yet another embodiment, in Formula X, Xa, or Xb, R1 is en or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R7&1 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is ally substituted with one or more tuents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in Formula X, Xa, or Xb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet r embodiment, in Formula X, Xa, or Xb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are methyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In still another embodiment, in Formula X, Xa, or Xb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R581 and R5b are hydrogen; R5d and RS‘3 are ; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or zinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, provided herein is a compound of Formula XI: R \I/ \2 / NkR6 R7a R7C R3 XAIY RSaRSb \\/\ \ A 3V0N z N R7d H RSf RSg R76 (X1) or an omer, a mixture of enantiomers, a mixture of two or more diastereomers, or an ic variant thereof; or a ceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R”, R71), R7 and R7‘3 are each independently (a) hydrogen, cyano, halo, or , RM, nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, (O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; two of R781, R713, RR, R“, and R7‘3 that are adjacent to each other form C340 cycloalkenyl, C644 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R”, Rlb, R”, R“, R52 RSb, RSf, ng, X, Y, and z are each as defined herein.

] In one embodiment, the compound of Formula XI has the structure of Formula XIa: (XIa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; n R1, R2, R3, R4, R6, RSa, RSb, RSf, ng, R”, R7b, R7“, R7d, R73, X, Y, and Z are each as defined herein.

] In another embodiment, the compound of Formula XI has the structure of Formula XIb: (XIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug f; wherein R1, R2, R3, R4, R6, RSa, RSb, RSf, ng, R”, R7b, R7“, R7d, R73, X, Y, and Z are each as defined herein.

In one embodiment, provided herein is a compound of Formula XI, XIa, or XIb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant f; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) 1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, (O)2R1d, (O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, RSf’ RSg’ R6, R721, R7b, R70, R7d’ R7e’ X, Y, Z, Rla’ Rlb’ R10, and R1d are defined herein ere.

In Formula XI, XIa, or XIb, in certain ments, one of R781, R71), RR, R“, and R7‘3 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7°, R“, and R7e is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7°, R“, and R7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7 and R7e is heterocyclyl, e.g., 5-membered or , R“, 6-membered heterocyclyl, optionally tuted with one or more tuents Q; in certain ments, one of R781, R71), R7 and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, , RM, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R713, RR, R“, and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain ments, one of R7a, R71), RR, R“, and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, oxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R781, R71), R7°, RM, and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, rophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, omethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin ylmethylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, pyrimidin-S-yl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, 2012/030640 l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In Formula XI, XIa, or XIb, in certain embodiments, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is heterocyclyl, e.g., ered or 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in certain embodiments, R781 is phenyl, olyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, ophenyl, 4-methoxyphenyl, imidazol- l -yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, nyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and in n embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, ylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, oxyphenyl, 4-florophenyl, rophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, oxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, l- 4-yl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidin-3 -yl, l-methylpyrrolidinyl, piperidin yl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l lpiperidinyl, l -methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In one embodiment, in Formula XI, XIa, or XIb, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally tuted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently C644 alkyl, optionally substituted with one or more substituents Q; R5f and ng are each independently hydrogen, halo, C1_6 alkyl, optionally substituted with one or more tuents Q; or R5f and ng together with the carbon atom to which they are attached form C140 cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R781 is C644 aryl, aryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or C1_6 alkyl, optionally substituted with one or more substituents Q. [001 l 1] In another embodiment, in Formula XI, XIa, or Xib, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently C644 alkyl; R5f and ng are each independently en or C1_6 alkyl; or R5f and ng together with the carbon atom to which they are attached form C140 cycloalkyl; R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is ally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each ndently N or CH.

In yet another embodiment, in Formula XI, XIa, or XIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; -6l- 2012/030640 R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R7&1 is C644 aryl, clic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each ndently N or CH. [001 13] In yet another embodiment, in Formula XI, XIa, or XIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is omethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another ment, in Formula XI, XIa, or XIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng er with the carbon atom to which they are attached form cyclopropyl, utyl, cyclpentyl, or cyclohexyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH. -62— ] In still another embodiment, in Formula XI, XIa, or XIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R7&1 is phenyl, imidazolyl, lyl, pyridinyl, piperidinyl, or zinyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet r embodiment, provided herein is a compound of Formula XII: R \I/ \2 / NkR6 NAN R7a R7C RSaRSb \r\/\N J\\NAN| R7d o\,\/' H R5f RSg R76 (XII) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug f; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSf, ng, R7a, R71), RR, R“, and R7‘3 are each as defined herein.

In one embodiment, the compound of Formula XII has the structure of Formula XIIa: (XIIa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSf, ng, R7a, R71), R7°, RM, and R7‘3 are each as defined .

In r ment, the compound of Formula XII has the structure of Formula XIIb: (XIIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, RSf, ng, R7a, R71), R7°, RM, and R7‘3 are each as defined herein.

In one embodiment, provided herein is a compound of Formula XII, XIIa, or XIIb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically able salt, solvate, e, or prodrug thereof; wherein R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, R1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, RSf’ RSg’ R6, R721, R7b, R70, R7d’ R7e’ R121, Rlb’ R10, and Rld are defined herein elsewhere.

In Formula XII, XIIa, or XIIb, in certain embodiments, one of R781, R71), RR, R“, and R7‘3 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more tuents Q; in certain embodiments, one of R7a, R71), RR, R“, and R7‘3 is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in n embodiments, one of R781, R7b, R7°, R“, and R7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R7b, R7 and R7e is heterocyclyl, e.g., 5-membered or , R“, 6-membered heterocyclyl, optionally substituted with one or more substituents Q; in certain embodiments, one of R781, R71), R7 and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, , RM, piperidinyl, or piperazinyl, each optionally substituted with one or more tuents Q; in certain embodiments, one of R781, R713, RR, R“, and R7‘3 is , imidazolyl, pyrozolyl, nyl, dinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more tuents Q; in certain embodiments, one of R7a, R71), RR, R“, and R7‘3 is , 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, ophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, ol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R781, R71), R7°, RM, and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, fluorophenyl, fluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin ylmethylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, pyrimidin-S-yl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, 1-isopropylpiperidinyl, 1-acetylpiperidinyl, ylsulfonylpiperidinyl, or 4-methylpiperaziny1.

In Formula XII, XIIa, or XIIb, in certain ments, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally tuted with one or more substituents Q; in certain embodiments, R7&1 is C644 aryl, e.g., phenyl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally tuted with one or more substituents Q; in certain ments, R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, idinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; in certain embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazolyl, pyrozolyl, 1-methyl-pyrozolyl, ylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, ylpyridinyl, 2-methoxypyridinyl, 1-methylpiperidinyl, or 4-methylpiperazinyl; and in certain embodiments, one of R781, R71), R7 and R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, , RM, ylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro methoxyphenyl, oxyphenyl, 4-methoxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozolyl, 1-methyl-pyrozolyl, 2-methylpyrozol-3 -yl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin- yridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidinyl, 1-ethylpiperidinyl, ropylpiperidinyl, 1-acetylpiperidinyl, 1-methylsulfonylpiperidinyl, or 4-methylpiperaziny1.

In one ment, in a XII, XIIa, or XIIb, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, ally tuted with one or more substituents Q; R581 and R5b are each independently C644 alkyl, optionally substituted with one or more substituents Q; R5f and ng are each independently hydrogen, halo, C1_6 alkyl, optionally substituted with one or more substituents Q; or R5f and ng together with the carbon atom to which they are attached form C140 cycloalkyl or heterocyclyl, each of which is optionally tuted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In another embodiment, in Formula XII, XIIa, or XIIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each ndently C644 alkyl; R5f and ng are each ndently hydrogen or C1_6 alkyl; or R5f and ng together with the carbon atom to which they are attached form C140 cycloalkyl; R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more tuents Q; and R7b, R7°, R“, and R7e are hydrogen.

In yet another embodiment, in Formula XII, XIIa, or XIIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R7&1 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally tuted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in Formula XII, XIIa, or XIIb, R1 is hydrogen or y; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are ed form cyclopropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are en.

, R“, In yet another embodiment, in Formula XII, XIIa, or XIIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are attached form ropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, dinyl, pyrrolidinyl, piperidinyl, or zinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In still another embodiment, in Formula XII, XIIa, or XIIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R5f and ng are hydrogen; or R5f and ng together with the carbon atom to which they are ed form cyclopropyl, cyclobutyl, cyclpentyl, or cyclohexyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, dinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In yet another ment, provided herein is a compound of Formula XIII: R3 X Y RSb R721 r\/\N A| R7b \Z E O\/ J R76 R7C R4 R7d (XIII) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein R- 1 2 3 4 6 5b 7 R R R R R R , , , , , , a, R7b, R7°, R7d, R73, X, Y, and Z are each as defined herein.

In one ment, the compound of Formula XIII has the structure of Formula XIIIa: R2\II \ N RSb R721 R3 X (\AN 7b \ JY\ R 2 E O\/ J R76 R7C R4 R7d (XIIIa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, R7a, R7b, R7°, R7d, R73, X, Y, and Z are each as defined herein. 2012/030640 In another embodiment, the compound of Formula XIII has the structure of Formula XIIIb: (XIIIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, R7a, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another ment, provided herein is a compound of Formula XIV: / »\R6 R3 N RSb R721 ?\/\N J\\NJ\N R7b O\/ J R76 R7C (XIV) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a ceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, R7a, R71), R7 and R7‘3 are each as defined herein.

, RM, In one embodiment, the compound of Formula XIV has the structure of Formula XIVa: R2\II \ N R3 N N RSb R721 r\/\N J\\NJ\N R7b O\/ J R76 R7C R4 R7d (XIVa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, RSb, R7a, R71), R7 and R7‘3 are each as , RM, defined herein.

] In another embodiment, the compound of Formula XIV has the structure of Formula XIVb: (XIVb) or an isotopic t thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein R1, R2, R3, R4, R6, RSb, R7a, R71), R7 and R7‘3 are each as , RM, defined herein.

In yet another embodiment, provided herein is a compound of Formula XV: R \l/ \2 / NkR6 A R7a R7c R3 X / IY RSa R5b r\’\N \Z N R“ O\,\’l H R76 (XV) or an omer, a e of omers, a mixture of two or more diastereomers, or an isotopic t thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7a, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XV, one of R781, R7b, R7 and R7e is €6-14 , R“, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XV, one of R781, R71), RR, R“, and R7‘3 is C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined In yet another embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined .

In yet another embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is phenyl, imidazolyl, pyrozolyl, nyl, piperidinyl, or piperazinyl, each optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, dinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

] In yet another ment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, phenyl, 4-chlorophenyl, 4-bromophenyl, oxyphenyl, 2,4-difiuorophenyl, fluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol- 4-yl, 1-methyl-pyrozolyl, ylpyrozolyl, pyridinyl, nyl, pyridinyl, 2-fiuoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazinyl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidin-3 -yl, 1-methylpyrrolidinyl, piperidin yl, 1-methylpiperidinyl, 1-ethylpiperidinyl, 1-isopropylpiperidinyl, 1-acetylpiperidinyl, 1-methylsulfonylpiperidinyl, or 4-methylpiperazinyl.

In still another embodiment, in Formula XV, one of R721, R71), R7 and R7‘3 , RM, is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, 1-methylpyrozolyl , 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridin- 4-yl, 2-methoxypyridinyl, 1-methylpiperidinyl, or 4-methylpiperazinyl; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XV, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XV, R7&1 is C644 aryl, which is optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined herein.

In yet another embodiment, in a XV, R7&1 is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, R7&1 is 5-membered or 6- membered heteroaryl, which is optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XV, R7&1 is heterocyclyl, which is optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XV, R781 is 5-membered or 6- membered heterocyclyl, which is optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, R52 RSb, R7b, R7“, R7d, R73, X, Y, and z are each as defined herein.

In yet r embodiment, in Formula XV, R7&1 is phenyl, imidazolyl, pyrozolyl, nyl, pyrozolyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, ylphenyl, 2-(3-dimethylaminopropyl)phenyl, oxyphenyl, ophenyl, rophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, oxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 -morpholinylmethylphenyl, olyl, pyrozolyl, 1 -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, nyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazinyl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, l-methylpiperidin yl, 1-ethylpiperidinyl, 1-isopropylpiperidinyl, 1-acetylpiperidinyl, 1-methylsulfonylpiperidinyl, or 4-methylpiperazinyl.

In still another embodiment, in Formula XV, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, ophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, 1-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, 1-methylpiperidinyl, or ylpiperazinyl; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7 , R7d, R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XV, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more tuents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or C1_6 alkyl, ally substituted with one or more substituents Q.

In another ment, in Formula XV, R1 is hydrogen or y; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently C644 alkyl; R781 is C644 aryl, heteroaryl, or cyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XV, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R7&1 is C644 aryl, monocyclic aryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XV, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XV, R1 is hydrogen or y; R2 is en; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more tuents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula XV, R1 is en or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or zinyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

In one embodiment, the compound of Formula XV has the ure of Formula XVa: (XVa) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7a, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVa, one of R781, R71), R7°, RM, and R7‘3 is C644 aryl, aryl, or cyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 is , RM, C644 aryl, which is optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined ] In yet another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is phenyl, olyl, pyrozolyl, pyridinyl, piperidinyl, or zinyl, each optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is phenyl, imidazolyl, lyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R781, R71), R7 and R7‘3 , RM, is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- dimethylaminopropyl)phenyl, oxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3- methoxyphenyl, oxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol yl, 1-methyl-pyrozolyl, 2-methylpyrozol-3 -yl, pyridinyl, nyl, pyridinyl, 2-fiuoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazinyl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidin-3 -yl, 1-methylpyrrolidinyl, piperidin yl, 1-methylpiperidinyl, 1-ethylpiperidinyl, 1-isopropylpiperidinyl, l-acetylpiperidinyl, 1-methylsulfonylpiperidinyl, or 4-methylpiperazinyl.

] In still r embodiment, in Formula XVa, one of R781, R71), R7 and , RM, R7‘3 is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, oxyphenyl, 4-florophenyl, 2012/030640 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, ylpyrozolyl , 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridin- 4-yl, 2-methoxypyridinyl, 1-methylpiperidinyl, or 4-methylpiperazinyl; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVa, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVa, R7&1 is C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3 , R4, R6, Rsa, RSb, R7b, R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVa, R7&1 is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined .

In yet another embodiment, in Formula XVa, R7&1 is 5-membered or 6- membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, R7&1 is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, R7&1 is 5-membered or 6- membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R52 RSb, R7b, R7“, R7d, R73, X, Y, and z are each as defined .

] In yet another embodiment, in Formula XVa, R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined .

In yet another embodiment, in a XVa, R7&1 is phenyl, imidazolyl, pyrozolyl, nyl, dinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined .

In yet another embodiment, in Formula XVa, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, oxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, omethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 -morpholinylmethylphenyl, imidazolyl, pyrozolyl, 1 -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazinyl)pyridinyl, 2-methoxypyridinyl, dinyl, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, 1-methylpiperidin yl, 1-ethylpiperidinyl, 1-isopropylpiperidinyl, 1-acetylpiperidinyl, 1-methylsulfonylpiperidinyl, or 4-methylpiperazinyl.

] In still another embodiment, in a XVa, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, 1-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, 1-methylpiperidinyl, or 4-methylpiperazinyl; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7 , R7d, R73, X, Y, and Z are each as defined .

In one embodiment, in Formula XVa, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently hydrogen or C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are en; and , RM, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or C1_6 alkyl, optionally substituted with one or more substituents Q.

In another embodiment, in Formula XVa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet r embodiment, in a XVa, R1 is en or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, -82— each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another ment, in Formula XVa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, olyl, lyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula XVa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently en or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more tuents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

] In another embodiment, the compound of Formula XV has the structure of Formula XVb: (XVb) or an isotopic variant thereof; or a pharmaceutically able salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7a, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

] In one embodiment, in Formula XVb, one of R“, R7b, R7 and R7e is , R“, C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVb, one of R781, R71), RR, R“, and R7‘3 is C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is heteroaryl, which is ally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is 5-membered or ered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined .

In yet another embodiment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is phenyl, olyl, pyrozolyl, pyridinyl, dinyl, or piperazinyl, each ally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R721, R71), R7 and R7‘3 , RM, is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, oxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, oxyphenyl, 4-florophenyl, 4-chlorophenyl, ophenyl, 4-methoxyphenyl, 2,4-difiuorophenyl, 2,6-difluorophenyl, omethoxyphenyl, 3-methoxyphenyl, oxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol- 4-yl, 1-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fiuoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazinyl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidin-3 -yl, 1-methylpyrrolidinyl, piperidin yl, 1-methylpiperidinyl, 1-ethylpiperidinyl, ropylpiperidinyl, 1-acetylpiperidinyl, 1-methylsulfonylpiperidinyl, or 4-methylpiperazinyl.

In still another embodiment, in Formula XVb, one of R721, R71), R7 and , RM, R7‘3 is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methylpyrozolyl , 2-methylpyrozolyl, nyl, nyl, pyridinyl, 2-methylpyridin- 4-yl, oxypyridinyl, l-methylpiperidinyl, or ylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVb, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVb, R7&1 is C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, R7&1 is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

] In yet another embodiment, in Formula XVb, R7&1 is 5-membered or 6- membered heteroaryl, which is optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, R7&1 is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVb, R7&1 is 5-membered or 6- membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R52 RSb, R7b, R7“, R7d, R73, X, Y, and z are each as defined herein.

In yet another embodiment, in Formula XVb, R7&1 is phenyl, imidazolyl, pyrozolyl, nyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XVb, R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined .

In yet another embodiment, in Formula XVb, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, oxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, omethoxyphenyl, 3-methoxyphenyl, oxyphenyl, 3 -morpholinylmethylphenyl, imidazol- l -yl, pyrozolyl, l -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidin yl, lpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In still another embodiment, in Formula XVb, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, oxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, lyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or ylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7 , R7d, R73, X, Y, and Z are each as defined herein.

] In one embodiment, in Formula XVb, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are en; R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently hydrogen or C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are en; and , RM, X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or C1_6 alkyl, optionally substituted with one or more substituents Q.

In another embodiment, in Formula XVb, R1 is hydrogen or y; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH. [0021 1] In yet another embodiment, in Formula XVb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each ndently hydrogen or C644 alkyl; R781 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

In yet another embodiment, in a XVb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently en or C644 alkyl; R781 is phenyl, 5- or ered heteroaryl, or 5- or 6-membered heterocyclyl, WO 35160 each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, dinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In still another ment, in Formula XVb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently en or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each ndently N or CH.

] In one embodiment, provided herein is a compound of Formula XV, XVa, or XVb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or g thereof; wherein R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, R1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or NR1bR1°; and R1, R2, R3, R4, R6, R”, R7b, R7“, R7d, R73, X, Y, z, R”, Rlb, R1“, and R1d are defined herein elsewhere.

In yet another ment, provided herein is a compound of Formula XVI: R2\I/ \ N A R7a R7C R3 N / N RSa R5b /\ J\\ A oV\J R (XVI) or an omer, a e of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R- 1 2 3 4 6 5 5b 7 R R R R R R , , , , , a, R , a, R71), R7°, RM, and R7‘3 are each as defined herein.

In one ment, in Formula XVI, one of R781, R71), R7 and R7‘3 is , RM, C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 is , RM, C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined .

] In yet another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is heterocyclyl, which is optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R7a, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or zinyl, each optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, ophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, phenyl, 4-chlorophenyl, 4-bromophenyl, oxyphenyl, 2,4-difluorophenyl, 2,6-difiuorophenyl, 4-fiuoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol- 4-yl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, dinyl, pyrrolidin-3 -yl, l-methylpyrrolidinyl, piperidin yl, l -methylpiperidinyl, l -ethylpiperidinyl, l -isopropylpiperidinyl, l -acetylpiperidinyl, l -methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In still another embodiment, in Formula XVI, one of R781, R71), R7 and R7‘3 , RM, is , 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methylpyrozolyl , 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridin- 4-yl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVI, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVI, R7&1 is C644 aryl, which is optionally tuted with one or more substituents Q; and R1, R2, R3 , R4, R6, Rsa, RSb, R7b, R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, R721 is aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XVI, R721 is 5-membered or 6-membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R52 RSb, R7b, R7“, R7d, R73, X, Y, and z are each as defined herein. [0023 1] In yet another embodiment, in Formula XVI, R721 is cyclyl, which is ally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in a XVI, R721 is 5-membered or 6-membered cyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, R721 is phenyl, imidazolyl, pyrozolyl, nyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVI, R721 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, dinyl, or piperazinyl, each optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined .

In yet r embodiment, in Formula XVI, R721 is , 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difiuorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 -morpholinylmethylphenyl, ol- l -yl, pyrozolyl, l -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, l-methylpyrrolidinyl, dinyl, l-methylpiperidin yl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, ylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl. [0023 6] In still another embodiment, in Formula XVI, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVI, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In r embodiment, in Formula XVI, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each ndently C644 alkyl; R781 is C644 aryl, aryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in a XVI, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R7&1 is C644 aryl, monocyclic heteroaryl, or monocyclic cyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in Formula XVI, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R5&1 and R5b are methyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, 2012/030640 each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, ] In yet another embodiment, in Formula XVI, R1 is en or y; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In still another embodiment, in Formula XVI, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are methyl; R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In one embodiment, the compound of Formula XVI has the structure of Formula XVIa: or an isotopic variant thereof; or a ceutically acceptable salt, solvate, hydrate, or g thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7 and R7‘3 are each as , R71), RR, R“, defined herein.

In one embodiment, in a XVIa, one of R781, R71), R7 and R7‘3 is , RM, C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the ing of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIa, one of R781, R71), RR, R“, and R7‘3 is C644 aryl, which is ally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVIa, one of R781, R71), R7°, RM, and R7‘3 is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R781, R71), R7°, RM, and R7e is 5-membered or 6-membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R781, R71), R7°, RM, and R7‘3 is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XVIa, one of R781, R71), R7°, RM, and R7e is 5-membered or ered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R781, R71), R7°, RM, and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally WO 35160 substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein. [0025 1] In yet another embodiment, in Formula XVIa, one of R781, R71), R7°, RM, and R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, dinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R781, R71), R7°, RM, and R7‘3 is phenyl, 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, imethylaminopropyl)phenyl, oxyphenyl, 3-fiuorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fiorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difiuorophenyl, 2,6-difiuorophenyl, 4-fiuoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol- 4-yl, yl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fiuoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazin- l ridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidin-3 -yl, l-methylpyrrolidinyl, piperidin yl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin-l-yl.

In still another ment, in Formula XVIa, one of R721, R71), R7 and , RM, R7‘3 is phenyl, ophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fiuorophenyl, 3-chlorophenyl, oxyphenyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl- pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, nyl, 2-methylpyridin- 4-yl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVIa, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIa, R7&1 is C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined herein.

In yet another embodiment, in a XVIa, R7&1 is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R7&1 is 5-membered or 6-membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, R52 RSb, R7b, R7“, R7d, R73, X, Y, and z are each as defined herein.

In yet another embodiment, in Formula XVIa, R7&1 is heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein. [0025 9] In yet another embodiment, in Formula XVIa, R7&1 is 5-membered or ered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R7&1 is phenyl, olyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined .

In yet r embodiment, in Formula XVIa, R7&1 is phenyl, 2-fluorophenyl, rophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, oxyphenyl, 3-fluorophenyl, rophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, oxyphenyl, 4-methoxyphenyl, 3 -morpholinylmethylphenyl, imidazol- l -yl, pyrozolyl, l -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2012/030640 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidin yl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In still another embodiment, in Formula XVIa, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, ophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7 , R7d, R73, X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVIa, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, ally substituted with one or more tuents Q; R581 and R5b are each independently hydrogen or C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more tuents Q; and R7b, R7°, R“, and R7e are hydrogen.

In another embodiment, in a XVIa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is ally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in Formula XVIa, R1 is hydrogen or y; R2 is en; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, monocyclic heteroaryl, or clic heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In yet r embodiment, in Formula XVIa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is omethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in Formula XVIa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrrolidinyl, piperidinyl, dinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are en.

, R“, In still another embodiment, in Formula XVIa, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In another embodiment, the compound of Formula XVI has the structure of Formula XVIb: (XVIb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof; wherein R1, R2, R3, R4, R6, Rsa, RSb, R7 and R7‘3 are each as , R71), RR, R“, defined herein.

In one embodiment, in Formula XVIb, one of R781, R71), R7 and R7‘3 is , RM, C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIb, one of R781, R71), R7°, RM, and R7‘3 is C644 aryl, which is optionally tuted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in a XVIb, one of R781, R71), R7 and , RM, R7‘3 is heteroaryl, which is ally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein. -lOl- In yet another embodiment, in Formula XVIb, one of R781, R71), R7 and , RM, R7e is 5-membered or ered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in a XVIb, one of R781, R71), R7 and , RM, R7‘3 is heterocyclyl, which is optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

] In yet another ment, in Formula XVIb, one of R781, R71), R7 and , RM, R7e is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7 and , RM, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R781, R71), R7 and , RM, R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVIb, one of R781, R71), R7 and , RM, R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, the ing of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R781, R71), R7 and , RM, R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fiuorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fiorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difiuorophenyl, 4-fiuoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholinylmethylphenyl, imidazol-l-yl, pyrozol- 4-yl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridin-3 -yl, ylpyridinyl, ethylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidin-3 -yl, l-methylpyrrolidinyl, piperidin yl, l -methylpiperidinyl, l -ethylpiperidinyl, l -isopropylpiperidinyl, l -acetylpiperidinyl, l -methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In still another ment, in Formula XVIb, one of R781, R71), R7 and , RM, R7‘3 is , 2-fiuorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, ophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methylpyrozolyl , ylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridin- 4-yl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, the remaining of R781, R71), R7°, RM, and R73, X, Y, and Z are each as defined herein.

In one ment, in Formula XVIb, R7&1 is C644 aryl, heteroaryl, or heterocyclyl, each of which is ally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIb, R7&1 is C644 aryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3 , R4, R6, Rsa, RSb, R7b, R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R721 is heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R7&1 is 5-membered or 6- membered heteroaryl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), RR, R“, R73, X, Y, and Z are each as defined herein.

In yet another ment, in Formula XVIb, R721 is heterocyclyl, which is optionally substituted with one or more tuents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R721 is 5-membered or ered heterocyclyl, which is optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

In yet r embodiment, in Formula XVIb, R721 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined .

In yet another embodiment, in Formula XVIb, R721 is phenyl, imidazolyl, lyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q; and R1, R2, R3, R4, R6, Rsa, RSb, R7b, R7 R7 , R“, , X, Y, and Z are each as defined .

In yet another embodiment, in Formula XVIb, R721 is phenyl, 2-fluorophenyl, rophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, fiuorophenyl, omethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3 -morpholinylmethylphenyl, imidazol- l -yl, lyl, l -methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl, pyrrolidinyl, l-methylpyrrolidinyl, dinyl, l-methylpiperidin yl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In still another embodiment, in Formula XVIb, R721 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, 2-methoxypyridinyl, l-methylpiperidinyl, or 4-methylpiperazin-l-yl; and R1, R2, R3, R4, R6, Rsa, RSb, R71), R7°, R7d, R73, X, Y, and Z are each as defined herein.

] In one embodiment, in a XVIb, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; —104— R6 is €6-14 alkyl, optionally substituted with one or more substituents Q; R581 and R5b are each independently hydrogen or C644 alkyl, optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In another embodiment, in Formula XVIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, ] In yet r embodiment, in Formula XVIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently en or C644 alkyl; R781 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are en.

In yet another embodiment, in Formula XVIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each ndently hydrogen or C644 alkyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In yet another embodiment, in Formula XVIb, R1 is en or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is omethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, lyl, pyridinyl, pyrimidinyl, idinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen.

, R“, In still r embodiment, in a XVIb, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q; and R7b, R7°, R“, and R7e are hydrogen.

In one embodiment, provided herein is a compound of Formula XVI, XVIa, or XVIb as described herein, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 l, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or cyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, 1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; and R1, R2, R3, R4, R6, R”, R7b, R7“, R7d, R73, R”, Rlb, R1“, and R1d are defined herein elsewhere.

In one ment, in any of the formulae provided herein, R1 is hydrogen or —OR1a, where R181 is C1_6 alkyl, optionally substituted with one or more substituents Q; R2 is hydrogen; R3 and R4 are hydrogen; R6 is €6-14 alkyl, ally substituted with one or more substituents Q; R581 and R5b are each independently hydrogen or C644 alkyl optionally substituted with one or more substituents Q; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CRX, with the proviso that at least two of X, Y, and Z are N; where Rx is a hydrogen or C1_6 alkyl, optionally substituted with one or more tuents Q.

In another embodiment, in any of the formulae provided herein, R1 is hydrogen or y; R2 is hydrogen; R3 and R4 are hydrogen; R6 is C644 alkyl, optionally substituted with one or more halo; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, heteroaryl, or heterocyclyl, each of which is optionally tuted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH..

In yet another embodiment, in any of the formulae provided , R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is C644 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

] In yet r embodiment, in any of the formulae provided herein, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered cyclyl, each of which is optionally substituted with one or more substituents Q; R71), R7 and R7‘3 are hydrogen; and , RM, X, Y, and Z are each independently N or CH.

In yet another embodiment, in any of the formulae provided herein, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are hydrogen; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally tuted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

In still another embodiment, in any of the formulae provided herein, R1 is hydrogen or methoxy; R2 is hydrogen; R3 and R4 are en; R6 is difluoromethyl; R5&1 and R5b are each independently hydrogen or C644 alkyl; R781 is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or zinyl, each of which is optionally substituted with one or more substituents Q; R71), R7°, RM, and R7‘3 are hydrogen; and X, Y, and Z are each independently N or CH.

The groups or variables, R1, R2, R3, R4, R6, RSa, RSb, R5“, RSd, R53, R“, RSg, R”, R71), R7°, R7d, R73, m, n, X, Y, and Z in Formulae provided herein, e.g., Formulae I to XVI, Ia to XVIa, and Ib to XVIb are filrther defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups and/or les are within the scope of this sure.

In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is cyano.

In certain embodiments, R1 is halo. In certain ments, R1 is fluoro, , bromo, or iodo. In certain embodiments, R1 is nitro. In certain embodiments, R1 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In n embodiments, R1 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C2_6 alkynyl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, R1 is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described . In certain embodiments, R1 is C644 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is C745 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is heterocyclyl, optionally substituted with one or more substituents Q as bed .

In certain embodiments, R1 is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —C(O)OR1a, wherein R1&1 is as defined herein. In certain ments, R1 is —C(O)NR1bR1°, n R1b and R10 are each as defined herein. In certain embodiments, R1 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R1 is —OR1a, wherein R1&1 is as defined . In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In n embodiments, R1 is methoxy, ethoxy, 2012/030640 propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R1 is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —OC(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is R1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n ments, R1 is —OS(O)R1a, wherein R1&1 is as defined herein. In n embodiments, R1 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —OS(O)NR1bR1°, n R1b and R10 are each as defined herein. In certain ments, R1 is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is —NRle1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined . In certain embodiments, R1 is —NR1aC(O)OR1d, n R1&1 and R1d are each as defined . In certain embodiments, R1 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R1 is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R1 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R1 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R1 is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R1 is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein.

In certain embodiments, R1 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —S(O)R1a, wherein R1&1 is as defined herein. In n embodiments, R1 is —S(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R1 is NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is cyano.

In certain embodiments, R2 is halo. In certain embodiments, R2 is fluoro, chloro, bromo, or iodo. In certain embodiments, R2 is nitro. In n ments, R2 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C2_6 l, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain ments, R2 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R2 is €6-14 aryl, optionally substituted with one or -llO- more substituents Q as described herein. In certain embodiments, R2 is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R2 is heterocyclyl, optionally substituted with one or more tuents Q as described herein.

In certain embodiments, R2 is —C(O)R1a, wherein R1&1 is as defined herein. In certain ments, R2 is —C(O)OR1a, wherein R1&1 is as defined herein. In n embodiments, R2 is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain ments, R2 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R2 is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In certain ments, R1 is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R2 is —OC(O)R1a, wherein R1&1 is as defined . In certain embodiments, R2 is —OC(O)OR1a, n R1&1 is as defined herein. In certain embodiments, R2 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In n embodiments, R2 is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined . In certain embodiments, R2 is —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R2 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R2 is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R2 is 2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R2 is —NRle1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R2 is amino (—NHZ). In certain ments, R2 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R2 is —NR1aC(O)OR1d, n R1&1 and R1d are each as defined herein. In certain embodiments, R2 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R2 is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined . In certain embodiments, R2 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain ments, R2 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In n embodiments, R2 is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R2 is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R2 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R2 is —S(O)R1a, wherein R1&1 is as defined herein. In n embodiments, R2 is —S(O)2R1a, wherein R1&1 is as defined herein. In certain -lll- 2012/030640 embodiments, R2 is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R2 is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 is hydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl).

In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R4 is hydrogen, methyl, ethyl, or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl). [003 l 1] In certain embodiments, R3 and R4 are linked together to form a bond. In certain embodiments, R3 and R4 are linked together to form C1_6 alkylene, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 and R4 are linked together to form methylene, ethylene, or ene, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 and R4 are linked er to form C1_6 heteroalkylene, optionally tuted with one or more substituents Q as described herein. In certain embodiments, R3 and R4 are linked er to form C2_6 alkenylene, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R3 and R4 are linked together to form C2_6 heteroalkenylene, optionally tuted with one or more substituents Q as described herein.

In certain embodiments, R6 is en. In certain embodiments, R6 is C1_6 alkyl, optionally tuted with one or more substituents Q as described . In n ments, R6 is C1_6 alkyl, optionally substituted with one or more, in one embodiment, one, two, or three, halo. In certain embodiments, R6 is C1_6 alkyl, optionally substituted with one or more, in one embodiment, one, two, or three, fluoro. In certain embodiments, R6 is , fluoromethyl, difluoromethyl, or trifluoromethyl. In certain embodiments, R6 is difluoromethyl. In certain ments, R6 is —S—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is —S(O)—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R6 is —SOz—C1_6 alkyl, -llZ- wherein the alkyl is optionally substituted with one or more substituents Q as described herein.

In certain ments, R5&1 is hydrogen. In certain ments, R5&1 is not hydrogen. In certain embodiments, R5&1 is halo. In certain embodiments, R5&1 is fluoro, chloro, bromo, or iodo. In certain embodiments, R5&1 is C1_6 alkyl, ally substituted with one or more substituents Q as described herein. In certain embodiments, R581 is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5&1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t—butyl.

In certain embodiments, R5&1 is methyl. In certain embodiments, R5&1 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5&1 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain ments, R581 is €3-10 cycloalkyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R581 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In n embodiments, R581 is C644 aryl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R581 is C7_1 5 aralkyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R581 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain ments, R581 is heterocyclyl, ally substituted with one or more tuents Q as described herein.

In certain embodiments, R5&1 is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is —C(O)OR1a, n R1&1 is C1_6 alkyl, optionally substituted with one or more substituents Q as described . In certain embodiments, R581 is —C(O)OCH3. In certain embodiments, R5&1 is R1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5&1 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5&1 is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is —OC(O)OR1a, n R181 is as defined herein. In n embodiments, R5&1 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5&1 is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R5&1 is —OS(O)R1a, wherein R1&1 is as defined herein. In -ll3- WO 35160 certain embodiments, R5&1 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5&1 is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5&1 is —NRle1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5&1 is amino (—NHZ). In certain embodiments, R5&1 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5&1 is (O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5&1 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R581 is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined . In certain embodiments, R5&1 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5&1 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5&1 is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5&1 is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R5&1 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is —S(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5&1 is —S(O)2R1a, wherein R1&1 is as defined herein.

In certain embodiments, R5&1 is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In n ments, R5&1 is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

] In certain embodiments, R5&1 is (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, or heteroaryl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, R1a)NR1bR1°, R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, (O)2NR1bR1°, —SR1a, 1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°. In certain embodiments, R5&1 is (a) hydrogen or halo; or (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, or heteroaryl, each of which is optionally substituted with one or more substituents Q.

In certain ments, R5b is halo. In certain embodiments, R5b is fiuoro, chloro, bromo, or iodo. In certain embodiments, R5b is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5b is methyl, ethyl, —114— propyl, or butyl, each optionally substituted with one or more tuents Q as described herein. In certain embodiments, R5b is methyl, ethyl, n-propyl, isopropyl, n-butyl, yl, or t—butyl. In certain embodiments, R5b is methyl. In certain embodiments, R5b is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In n embodiments, R5b is C2_6 l, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5b is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R5b is C3_7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5b is €6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5b is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain ments, R5b is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5b is heterocyclyl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R5b is not cyclyl.

] In certain embodiments, R5b is —C(O)R1a, wherein R181 is as defined . In certain embodiments, R5b is R1a, wherein R1&1 is as defined herein. In certain embodiments, R5b is R1a, wherein R1&1 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain ments, R5b is —C(O)OCH3. In certain embodiments, R5b is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5b is a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5b is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5b is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5b is —OC(O)OR1a, n R181 is as defined herein. In certain embodiments, R51) is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5b is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5b is —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5b is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R51) is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5b is —OS(O)2NR1bR1°, n R1b and R10 are each as defined herein.

In certain embodiments, R5b is —NRle1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5b is amino (—NHZ). In certain embodiments, R5b is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5b is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined . In certain embodiments, -llS- R5b is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5b is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R5b is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5b is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5b is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5b is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5b is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R5b is —S(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5b is —S(O)2R1a, wherein R1&1 is as defined herein.

In certain embodiments, R5b is —S(O)NR1bR1°, wherein R1b and R10 are each as defined .

In n embodiments, R5b is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R5&1 and R5b are each independently , ethyl, n- , pyl, n-butyl, isobutyl, or t—butyl, each optionally substituted with one or more substituents Q as described herein. In certain ments, R581 and R5b are each independently methyl, ethyl, n-propyl, pyl, n-butyl, isobutyl, or t—butyl, each optionally substituted with one or more halo. In n embodiments, R5&1 and R5b are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t—butyl. In certain embodiments, R5&1 and R5b are each methyl.

In n embodiments, R50 is C644 aryl, optionally substituted with one or more substituents Q as described . In certain embodiments, R5b is €6-14 aryl substituted at the 2-position with one tuent Q as described herein. In certain embodiments, RSC is phenyl or yl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R50 is phenyl, naphtha-l-yl, or naphthayl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R50 is phenyl, 4-chlorophenyl, 4-methoxyphenyl, or ayl. In certain embodiments, R50 is heteroaryl, optionally substituted with one or more tuents as described herein. In certain embodiments, R50 is moncyclic heteroaryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R50 is 5- or 6-membered aryl, optionally substituted with one or more substituents as described herein. In certain embodiments, R50 is bicyclic heteroaryl, optionally substituted with one or more substituents as described herein. -ll6- In certain embodiments, RSc is —(CR5fR5g)n—(C6_14 aryl), wherein the c6_14 aryl is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R50 is , 2-phenethyl, 3-phenylpropyl, or 4-phenylbutyl, wherein each of the phenyl moiety is optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R50 is benzyl, 2-phenethyl, 3-phenylpropyl, or 4-phenylbutyl.

In certain embodiments, R50 is benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, enzyl, methylbenzyl, or methoxylbenzyl. In certain embodiments, R50 is (naphthalen- l-yl)methyl, halenyl)methyl 2-(naphthalen-l-yl)ethyl, 2-(naphthalenyl)ethyl, 3- (naphthalen- l -yl)propyl, 3-(naphthalenyl)propyl, 4-(naphthalen- l -yl)butyl, or 4- (naphthalenyl)butyl, wherein each of the naphthyl moiety is optionally substituted with memnmmmmmmmeamhmmmdem.mcMMnmmmmmmgnEOmd.mom emmmmmmnml.momemmmmanmL234n4InwmmmmmmmmmRfim —CH2—(C6_14 aryl), wherein the C644 aryl is optionally substituted with one or more substituents Q as described herein. In certain ments, R50 is —C(CH3)2—(C6_14 aryl), wherein the C644 aryl is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R50 is —CH2—phenyl or —CH2—naphthyl, wherein the phenyl or naphthyl is each optionally substituted with one or more substituents Q as described herein, such as, e.g., optionally substituted with one or more F, Cl, Br, I, —CN, —CH3, —CF3, —OCH3, or —OCF3. In certain embodiments, R50 is —CH2—phenyl, —CH2—naphtha-l-yl, or —CH2— naphthayl, wherein the phenyl or naphthyl is each ally tuted with one or more substituents Q as described herein, such as, e. g., optionally substituted with one or more F, Cl, Br, I, —CN, —CH3, —CF3, —OCH3, or —OCF3. In certain embodiments, R50 is henyl, —CH2—naphtha-l-yl, or —CH2—naphthayl, wherein the phenyl or yl is each optionally substituted with one or more F, Cl, Br, I, —CN, —CH3, —CF3, —OCH3, —OCF3. In other embodiments, R50 is —CH2—phenyl, —CH2—naphtha-l-yl, or —CH2—naphthayl, wherein the phenyl or naphthyl is each ally substituted with one or more F, Cl, Br, I, —CN, —CH3, —CF3, —OCH3, —OCF3, _4 alkylene)—N—(C1_4 alkyl)2 (e.g., —O—CH2CH2—N(CH3)2), erocyclyl (e.g. , —O—(N—methylpiperidinyl) or —O—piperidinyl), —O—heteroaryl (e.g., —O—pyridyl), terocyclyl (e.g., —NH—(N—methylpiperidinyl), —NH—(N— methylpyrrolidinyl), —NH—piperidinyl, or rrolidinyl), —NH—heteroaryl (e.g., —NH—pyridyl), —NCH3—heterocyclyl (e.g., —NCH3—(N-methylpiperidinyl), —NCH3—(N- methylpyrrolidinyl), —NCH3—piperidinyl, or —NCH3—pyrrolidinyl), —NCH3—heteroaryl (e.g., —NCH3—pyridyl), heterocyclyl (e.g. , piperidinyl, piperazinyl, N—methylpiperidinyl, or -ll7- N—methylpiperazinyl), or heteroaryl (e.g. , pyridyl or olyl). In certain embodiments, R50 is —CH2—phenyl, —C(CH3)2—phenyl, —CH2—(2-methylphenyl), —CH2—(2-methoxylphenyl), —CH2—(2-fluorophenyl), —CH2—(2-chlorophenyl), —CH2—(2-bromophenyl), —CH2—(3- methylphenyl), —CH2—(3-methoxylphenyl), —CH2—(3-fluorophenyl), —CH2—(3-chlorophenyl), 3-bromophenyl), —CH2—(4-methylphenyl), —CH2—(4-methoxylphenyl), —CH2—(4-fluorophenyl), —CH2—(4-chlorophenyl), —CH2—(4-bromophenyl), —CH2—naphtha-lyl , or —CH2—naphthayl.

In certain ments, R50 is —(CR5fR5g)—(C6_14 aryl), wherein the C644 aryl is optionally substituted with one or more substituents Q as described herein, and wherein R5f and ng together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or cyclyl. In one embodiment, R50 is —cyclopropyl-phenyl. In one embodiment, R50 is butyl-phenyl. In one embodiment, R50 is —cyclopentyl-phenyl. In one embodiment, R50 is —cyclohexyl-phenyl.

In certain embodiments, R50 is —(CR5fR5g)n—heteroaryl, wherein the aryl is optionally substituted with one or more tuents Q as described herein, wherein n is defined herein elsewhere. In certain embodiments, R50 is —CH2—(monocyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents as described herein. In certain embodiments, R50 is —CH2—(5- or 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents as described herein. In n ments, R50 is —CH2—(bicyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more tuents as described herein.

In certain embodiments, R5d is hydrogen. In certain embodiments, R5d is halo.

In certain embodiments, R5d is fluoro, chloro, bromo, or iodo. In certain embodiments, R5d is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is methyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is . In certain embodiments, R5d is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In n embodiments, R5d is methyl, ethyl, yl, isopropyl, n-butyl, isobutyl, or t—butyl. In certain embodiments, R5d is C2_6 alkenyl, optionally substituted with one or more substituents Q as bed . In certain embodiments, R5d is C2_6 alkynyl, optionally tuted with one or more substituents Q as described herein. In certain WO 35160 embodiments, R5d is €3-10 lkyl, optionally substituted with one or more substituents Q as described herein. In certain ments, R5d is €6-14 aryl, ally substituted with one or more substituents Q as bed herein. In certain embodiments, R5d is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R5d is heteroaryl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R5d is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

] In certain embodiments, R5d is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is —C(O)OR1a, wherein R1&1 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5d is —C(O)OCH3. In certain embodiments, R5d is R1bR1°, n R1b and R10 are each as defined herein.

In certain embodiments, R5d is a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5d is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is OR1a, wherein R181 is as defined herein. In certain embodiments, R5d is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5d is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5d is —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5d is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5d is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5d is amino (—NHZ). In certain ments, R5d is (O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5d is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined . In certain embodiments, R5d is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5d is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R5d is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5d is —NR1aS(O)2R1d, n R1&1 and R1d are each as defined herein. In certain embodiments, R5d is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5d is —NR1aS(O)2NR1bR1°, wherein R. 1 a, Rlb and R1 C . In certa1n embod1ments, R5d 1s —SR1a,. . . are each as defined herein. -ll9- WO 35160 wherein R1&1 is as defined herein. In certain embodiments, R5d is —S(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5d is —S(O)2R1a, wherein R1&1 is as defined herein.

In certain ments, R5d is R1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5d is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R5‘3 is hydrogen. In n embodiments, R5‘3 is halo.

In n embodiments, R5‘3 is fluoro, chloro, bromo, or iodo. In certain embodiments, R5‘3 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5e is methyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5e is methyl. In certain embodiments, R5e is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5e is , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t—butyl. In certain embodiments, R5‘3 is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5e is C2_6 alkynyl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R5e is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5e is €6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain ments, R5e is €7-15 aralkyl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, R5e is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5e is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R5e is —C(O)R1a, wherein R181 is as defined herein. In certain embodiments, R5‘3 is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5‘3 is —C(O)OR1a, wherein R1&1 is C1_6 alkyl, optionally substituted with one or more tuents Q as described herein. In certain ments, R5e is —C(O)OCH3. In certain embodiments, R5‘3 is R1bR1°, wherein R1b and R10 are each as defined .

In certain embodiments, R5‘3 is a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R5‘3 is —OR1a, wherein R1&1 is as defined . In certain embodiments, R5‘3 is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5e is —OC(O)OR1a, wherein R181 is as defined herein. In certain embodiments, R5‘3 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5‘3 is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5‘3 is R1a, wherein R1&1 is as defined herein. In certain embodiments, R5‘3 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R5‘3 is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5‘3 is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5‘3 is —NRle1°, wherein R1b and R10 are each as defined herein. In n embodiments, R5‘3 is amino (—NHZ). In certain embodiments, R5‘3 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5‘3 is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5‘3 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5e is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R5‘3 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5‘3 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5‘3 is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5‘3 is (O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5‘3 is —SR1a, wherein R1&1 is as defined herein. In certain ments, R5‘3 is —S(O)R1a, wherein R1&1 is as defined . In certain embodiments, R5‘3 is —S(O)2R1a, wherein R1&1 is as defined herein.

In certain embodiments, R5‘3 is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5‘3 is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined ] In certain embodiments, R5f is hydrogen. In certain embodiments, R5f is halo.

In certain embodiments, R5f is fiuoro, chloro, bromo, or iodo. In n embodiments, R5f is C1_6 alkyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R5f is methyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R5f is methyl. In certain embodiments, R5f is methyl, ethyl, propyl, or butyl, each ally substituted with one or more substituents Q as described herein. In n embodiments, R5f is , ethyl, yl, isopropyl, n-butyl, yl, or t—butyl. In certain embodiments, R5f is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5f is C2_6 alkynyl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, R5f is C340 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5f is €6-14 aryl, optionally substituted with one -lZl- or more substituents Q as described . In certain embodiments, R5f is C7_1 5 aralkyl, optionally tuted with one or more substituents Q as described . In n embodiments, R5f is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain ments, R5f is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R5f is —C(O)R1a, wherein R181 is as defined herein. In certain embodiments, R5f is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5f is R1a, wherein R1&1 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R5f is —C(O)OCH3. In certain embodiments, R5f is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5f is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5f is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R5f is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R5f is —OC(O)OR1a, wherein R181 is as defined herein. In certain embodiments, R5f is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5f is —OC(=NR1a)NR1bR1°, n R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5f is —OS(O)R1a, wherein R1&1 is as defined herein. In certain ments, R5f is —OS(O)2R1a, n R1&1 is as defined herein. In certain embodiments, R5f is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5f is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5f is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R5f is amino (—NHZ). In certain embodiments, R5f is —NR1aC(O)R1d, n R1&1 and R1d are each as defined herein. In n embodiments, R5f is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5f is —NR1aC(O)NR1bR1°, n R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5f is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain ments, R5f is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined . In certain embodiments, R5f is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R5f is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5f is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R5f is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R5f is —S(O)R1a, n R1&1 is as defined . In certain embodiments, R5f is —S(O)2R1a, wherein R1&1 is as defined herein. 2012/030640 In certain embodiments, R5f is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, R5f is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain ments, ng is hydrogen. In certain ments, ng is halo.

In certain embodiments, ng is fiuoro, chloro, bromo, or iodo. In certain embodiments, ng is C1_6 alkyl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, ng is methyl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, ng is methyl. In certain embodiments, ng is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q as described herein. In certain embodiments, ng is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or l. In certain embodiments, ng is C2_6 alkenyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, ng is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, ng is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, ng is C644 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, ng is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, ng is heteroaryl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, ng is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R5g is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, ng is —C(O)OR1a, n R1&1 is as defined herein. In certain embodiments, ng is —C(O)OR1a, wherein R1&1 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain ments, ng is CH3. In certain embodiments, ng is R1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, ng is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, ng is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, ng is —OC(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, ng is —OC(O)OR1a, wherein R181 is as defined herein. In n embodiments, ng is —OC(O)NR1bR1°, n R1b and R10 are each as defined herein. In certain embodiments, ng is R1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined . In certain embodiments, ng is —OS(O)R1a, wherein R1&1 is as defined herein. In 2012/030640 n embodiments, ng is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, ng is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, ng is 2NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, ng is —NRle1°, wherein R1b and R10 are each as defined herein. In certain embodiments, ng is amino (—NHZ). In certain embodiments, ng is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, ng is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, ng is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, ng is (=NR1d)NR1bR1°, n R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, ng is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined . In certain embodiments, ng is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, ng is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, ng is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, ng is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, ng is —S(O)R1a, wherein R1&1 is as defined herein. In certain ments, ng is —S(O)2R1a, wherein R1&1 is as defined .

In certain embodiments, ng is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In certain embodiments, ng is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a C340 lkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are ed form a C3_7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In n embodiments, when one ence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a cyclopropyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are ed form a cyclobutyl, optionally substituted with one or more substituents Q as described herein. In certain embod1ments, when one occurrence ofR- 5f and one occurrence of ng are attached to the same —124— carbon atom, the R5f and ng together with the carbon atom to which they are attached form a cyclopentyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, when one ence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a exyl, optionally substituted with one or more tuents Q as described . In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are ed form a cycloheptyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a cyclopropyl.

In certain ments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng er with the carbon atom to which they are attached form a heterocyclyl, ally substituted with one or more substituents Q as described herein. In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a 3-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a ered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain ments, when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a 5-membered heterocyclyl, optionally tuted with one or more substituents Q as described herein. In certain embodiments, when one occurrence of R5f and one ence of ng are attached to the same carbon atom, the R5f and ng together with the carbon atom to which they are attached form a 6-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R781 is hydrogen. In certain embodiments, R781 is cyano. In certain embodiments, R7&1 is halo. In certain embodiments, R7&1 is fluoro, chloro, bromo, or iodo. In certain embodiments, R7&1 is nitro. In certain embodiments, R7&1 is C1_6 alkyl, ally substituted with one or more substituents Q as described herein. In certain embodiments, R7&1 is C2_6 alkenyl, optionally substituted with one or more tuents Q as described herein. In n embodiments, R781 is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R781 is C3_7 cycloalkyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R7&1 is C340 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R781 is €6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R781 is , optionally substituted with one or more substituents Q as described herein. In n embodiments, R781 is phenyl, optionally tuted with one or more substituents, each of which is selected independently from the group consisting of fluoro, chloro, bromo, methyl, and y. In n embodiments, R7&1 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2- bromophenyl, 2-methylphenyl, 2-methoxyphenyl, ophenyl, 3-chlorophenyl, 3- yphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl. In certain embodiments, R7&1 is C745 aralkyl, optionally substituted with one or more substituents Q as bed . In certain embodiments, R781 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In n embodiments, R781 is monocyclic heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7&1 is 5-membered heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R781 is imidazolyl or pyrozolyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7&1 is imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, or 2-methylpyrozol- 3-yl. In certain embodiments, R7&1 is 6-membered heteroaryl, ally substituted with one or more substituents Q as described herein. In certain embodiments, R781 is pyridinyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7&1 is pyridinyl, pyridinyl, pyridinyl, 2-methylpyridinyl, or oxypyridinyl. In certain embodiments, R7&1 is heterocyclyl, optionally substituted with one or more substituents Q as described herein. In n embodiments, R781 is monocyclic heterocyclyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R7&1 is 5-membered cyclyl, optionally substituted with one or more substituents Q as described . In certain embodiments, R7&1 is 6-membered heterocyclyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7&1 is piperidinyl or piperazinyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R781 is l-methylpiperidin yl, or 4-methylpiperazin-l-yl. In certain embodiments, R7&1 is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R7&1 is —C(O)OR1a, wherein R1&1 is as defined herein.

In certain embodiments, R7&1 is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein.

In n embodiments, R7&1 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R7&1 is —OR1a, wherein R1&1 is as defined . In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as bed herein.. In certain embodiments, R1 is y, ethoxy, y, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R7&1 is —OC(O)R1a, wherein R181 is as defined herein. In certain embodiments, R7&1 is —OC(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R7&1 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7&1 is —OC(=NR1a)NR1bR1°, wherein R- 1 a, R1b and R1 C . . . . are each as defined herein. In certain embodiments, R7&1 is —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R7&1 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain ments, R7&1 is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7&1 is 2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7&1 is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R721 is amino (—NHZ).

In certain ments, R7&1 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined .

In n embodiments, R7&1 is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7&1 is —NR1aC(O)NR1bR1°, n R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7&1 is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined . In certain embodiments, R7&1 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined . In certain embodiments, R7&1 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7&1 is —NR1aS(O)NR1bR1°, n R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7&1 is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7&1 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R7&1 is —S(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R7&1 is —S(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R7&1 is —S(O)NR1bR1°, wherein R. lb and R1 C . In certain embodiments, R7&1 is. . . are each as defined herein.

—S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R7&1 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain ments, R7&1 is , 2-fluorophenyl, 2-chlorophenyl, ophenyl, ylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fiuorophenyl, 3-chlorophenyl, 3-methylphenyl, oxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difiuorophenyl, 2,6-difluorophenyl, omethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin ylmethylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, 2-fiuoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, din-S-yl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In n embodiments, R7b is hydrogen. In certain ments, R7b is cyano. In n embodiments, R7b is halo. In n embodiments, R7b is fluoro, chloro, bromo, or iodo. In certain embodiments, R7b is nitro. In certain embodiments, R7b is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is C3_7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is €6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7b is heteroaryl, optionally substituted with one or more substituents Q as described . In certain embodiments, R7b is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R7b is —C(O)R1a, wherein R1&1 is as defined . In certain ments, R7b is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R71) is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7b is a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7b is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. In certain embodiments, R1 is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethy1aminopropoxy. In certain embodiments, R7b is —OC(O)R1a, wherein R181 is as defined herein. In certain embodiments, R7b is —OC(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R7b is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In n embodiments, R7b is R1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7b is —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R7b is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R7b is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain ments, R71) is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7b is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7b is amino (—NHZ).

In certain embodiments, R7b is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein.

In certain embodiments, R7b is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7b is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7b is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R71) is —NR1aS(O)R1d, n R1&1 and R1d are each as defined herein. In certain ments, R7b is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7b is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7b is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7b is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R71) is —S(O)R1a, wherein R1&1 is as defined . In certain embodiments, R7b is —S(O)2R1a, wherein R1&1 is as defined herein. In n embodiments, R7b is R1bR1°, wherein R. 1b and R1 C . In certain embodiments, R7b 1s. . . are each as defined herein —S(O)2NR1bR1°; wherein R1b and R10 are each as defined .

In certain embodiments, R7b is phenyl, olyl, pyrozolyl, pyridinyl, pyrimidinyl, idinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more tuents Q. In n embodiments, R7b is phenyl, 2-fiuoropheny1, 2-chloropheny1, 2-bromopheny1, 2-methy1pheny1, 2-(3-dimethy1aminopropy1)pheny1, 2-methoxyphenyl, 3-fluoropheny1, 3-chloropheny1, y1pheny1, 3-methoxyphenyl, 4-fioropheny1, 4-chloropheny1, opheny1, 4-methoxypheny1, 2,4-difluoropheny1, 2,6-difiuoropheny1, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxypheny1, 3-morpholin ylphenyl, imidazol-I-yl, pyrozoly1, 1-methy1-pyrozoly1, 2-methy1pyrozoly1, pyridinyl, nyl, pyridinyl, 2-fiuoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, pyrimidin-S-yl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In certain embodiments, R70 is hydrogen. In certain embodiments, R70 is cyano. In n embodiments, R70 is halo. In certain embodiments, R70 is fiuoro, chloro, bromo, or iodo. In certain embodiments, R70 is nitro. In n embodiments, R70 is C1_6 alkyl, optionally tuted with one or more substituents Q as bed herein. In certain embodiments, R70 is C2_6 alkenyl, ally substituted with one or more substituents Q as described herein. In certain embodiments, R70 is C2_6 alkynyl, optionally tuted with one or more substituents Q as described herein. In certain ments, R70 is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R70 is C3_7 cycloalkyl, optionally substituted with one or more tuents Q as described herein. In certain embodiments, R70 is C644 aryl, optionally substituted with one or more substituents Q as bed herein. In certain embodiments, R70 is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R70 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R70 is heterocyclyl, ally substituted with one or more substituents Q as bed .

] In certain embodiments, R7° is —C(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R70 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R70 is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.. In certain embodiments, R1 is methoxy, ethoxy, propoxy, poxy, or 3-dimethylaminopropoxy. In certain embodiments, R70 is —OC(O)R1a, wherein R181 is as defined herein. In certain embodiments, R70 is OR1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R70 is —OC(=NR1a)NR1bR1°, wherein R. 1 a, Rlb and R1 C . In certain embodiments, R70 is. . . are each as defined herein. -l30- —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R70 is —OS(O)2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R70 is 1°, wherein R1b and R10 are each as defined herein. In n ments, R70 is amino (—NHZ).

In certain embodiments, R70 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein.

In certain embodiments, R70 is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R70 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R70 is —NR1aC(=NR1d)NR1bR1°, n R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R70 is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined . In certain embodiments, R70 is (O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R70 is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined . In certain embodiments, R70 is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R70 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —S(O)R1a, wherein R1&1 is as defined herein. In certain ments, R70 is —S(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R70 is —S(O)NR1bR1°, where1n R. 1b and R1 C . . . . are each as defined here1n. In certa1n embod1ments, R7c 1s —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain ments, R70 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, dinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R70 is , 2-fluoropheny1, 2-chloropheny1, 2-bromophenyl, 2-methy1pheny1, 2-(3-dimethy1aminopropy1)pheny1, oxyphenyl, 3-fiuoropheny1, 3-chloropheny1, 3-methy1pheny1, oxyphenyl, 4-floropheny1, 4-chloropheny1, 4-bromopheny1, 4-methoxypheny1, 2,4-difiuoropheny1, 2,6-difluoropheny1, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxypheny1, 3-morpholin ylmethylphenyl, imidazol-I-yl, pyrozoly1, 1-methy1-pyrozoly1, 2-methy1pyrozoly1, pyridiny1, pyridiny1, pyridiny1, 2-fiuoropyridinyl, 2-methy1pyridiny1, 2-(4-methylpiperaziny1)pyridiny1, 2-methoxypyridiny1, pyrimidin-S-yl, pyrrolidin yl, 1-methy1pyrrolidiny1, piperidinyl, 1-methy1piperidiny1, 1-ethy1piperidiny1, 1-isopropy1piperidiny1, 1-acety1piperidinyl, 1-methy1sulfonylpiperidinyl, or 4-methy1piperaziny1.

In certain embodiments, R7d is hydrogen. In n embodiments, R7d is cyano. In certain ments, R7d is halo. In certain embodiments, R7d is fiuoro, chloro, bromo, or iodo. In certain embodiments, R7d is nitro. In certain embodiments, R7d is C1_6 alkyl, ally substituted with one or more substituents Q as described herein. In certain embodiments, R7d is C2_6 alkenyl, optionally substituted with one or more substituents Q as described . In certain embodiments, R7d is C2_6 alkynyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7d is €3-10 cycloalkyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R7d is C3_7 cycloalkyl, ally substituted with one or more substituents Q as described herein. In n embodiments, R7d is €6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7d is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7d is heteroaryl, optionally tuted with one or more tuents Q as described herein. In certain embodiments, R7d is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R7d is —C(O)R1a, wherein R1&1 is as defined herein. In n embodiments, R7d is —C(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R7d is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7d is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7d is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally tuted with one or more substituents Q as described herein.. In certain embodiments, R1 is y, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy. In n embodiments, R7d is —OC(O)R1a, wherein R181 is as defined herein. In certain embodiments, R7d is —OC(O)OR1a, n R1&1 is as defined herein. In certain embodiments, R7d is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain ments, R7d is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7d is —OS(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R7d is —OS(O)2R1a, wherein R1&1 is as defined . In certain embodiments, R7d is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined . In certain embodiments, R7d is —OS(O)2NR1bR1°, n R1b and R10 are each as defined herein. In certain embodiments, R7d is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7d is amino (—NHZ).

In certain embodiments, R7d is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein. -l32- In n embodiments, R7d is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7d is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7d is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined herein. In certain embodiments, R7d is —NR1aS(O)R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7d is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7d is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined . In certain embodiments, R7d is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R7d is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R7d is —S(O)R1a, wherein R1&1 is as defined . In certain embodiments, R7d is —S(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R7d is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain ments, R7d is NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R7d is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, idinyl, piperidinyl, or piperazinyl, each optionally tuted with one or more substituents Q. In certain embodiments, R7d is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fiuorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difiuorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin ylmethylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, nyl, pyridinyl, pyridinyl, 2-fluoropyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, pyrimidin-S-yl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In certain embodiments, R7‘3 is hydrogen. In n ments, R7‘3 is cyano. In certain embodiments, R7‘3 is halo. In n embodiments, R7‘3 is fluoro, chloro, bromo, or iodo. In certain ments, R7‘3 is nitro. In certain embodiments, R7‘3 is C1_6 alkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7e is C2_6 alkenyl, optionally substituted with one or more substituents Q as described herein. In n ments, R7e is C2_6 alkynyl, optionally substituted with one -l33- or more substituents Q as described herein. In certain embodiments, R7e is €3-10 cycloalkyl, ally substituted with one or more substituents Q as described herein. In n embodiments, R7e is C3_7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7e is €6-14 aryl, optionally substituted with one or more substituents Q as described herein. In certain ments, R7e is C7_1 5 aralkyl, optionally substituted with one or more substituents Q as described herein. In n embodiments, R7e is heteroaryl, optionally substituted with one or more substituents Q as described herein. In certain embodiments, R7e is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In certain embodiments, R7e is —C(O)R1a, wherein R181 is as defined herein. In certain embodiments, R7‘3 is —C(O)OR1a, wherein R1&1 is as defined herein. In certain ments, R73 is —C(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain ments, R7‘3 is —C(NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7‘3 is —OR1a, wherein R1&1 is as defined herein. In certain embodiments, R1 is —O—C1_6 alkyl, wherein the alkyl is optionally tuted with one or more substituents Q as described herein.. In n embodiments, R1 is y, ethoxy, y, isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R7‘3 is —OC(O)R1a, wherein R181 is as defined herein. In n embodiments, R7e is —OC(O)OR1a, wherein R1&1 is as defined herein. In certain embodiments, R7‘3 is —OC(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7‘3 is —OC(=NR1a)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R7‘3 is —OS(O)R1a, wherein R1&1 is as defined . In certain embodiments, R7‘3 is —OS(O)2R1a, wherein R1&1 is as defined herein. In certain embodiments, R7‘3 is —OS(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R73 is 2NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7‘3 is —NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7‘3 is amino .

In certain embodiments, R7‘3 is —NR1aC(O)R1d, wherein R1&1 and R1d are each as defined herein.

In certain embodiments, R7‘3 is —NR1aC(O)OR1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7‘3 is —NR1aC(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7‘3 is —NR1aC(=NR1d)NR1bR1°, wherein R”, Rlb, R”, and R1d are each as defined . In certain embodiments, R73 is —NR1aS(O)R1d, n R1&1 and R1d are each as defined herein. In certain embodiments, R7‘3 is —NR1aS(O)2R1d, wherein R1&1 and R1d are each as defined herein. In certain embodiments, R7‘3 —134— is —NR1aS(O)NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In n embodiments, R7‘3 is —NR1aS(O)2NR1bR1°, wherein R”, Rlb, and R10 are each as defined herein. In certain embodiments, R7‘3 is —SR1a, wherein R1&1 is as defined herein. In certain embodiments, R73 is —S(O)R1a, wherein R1&1 is as defined herein. In certain embodiments, R7‘3 is —S(O)2R1a, wherein R1&1 is as defined . In certain ments, R7‘3 is —S(O)NR1bR1°, wherein R1b and R10 are each as defined herein. In certain embodiments, R7‘3 is —S(O)2NR1bR1°; wherein R1b and R10 are each as defined herein.

In certain embodiments, R7‘3 is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more tuents Q. In certain embodiments, R7‘3 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fiuorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difiuorophenyl, 2,6-difluorophenyl, 4-fluoromethoxyphenyl, oxyphenyl, 4-methoxyphenyl, 3-morpholin ylphenyl, imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozolyl, pyridinyl, pyridinyl, pyridinyl, opyridinyl, 2-methylpyridinyl, 2-(4-methylpiperazin-l-yl)pyridinyl, 2-methoxypyridinyl, pyrimidin-S-yl, pyrrolidin yl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.

In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form C340 cycloalkenyl, C644 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form C340 lkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R781 and R7b together with the carbon atoms to which they are attached form cyclohexenyl, optionally tuted with one or more substituents Q. In certain embodiments, R781 and R7b er with the carbon atoms to which they are attached form C644 aryl, optionally tuted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are ed form phenyl, optionally substituted with one or more substituents Q.

In n embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form heteroaryl, optionally substituted with one or more substituents Q. In certain -l35- embodiments, R7&1 and R7b together with the carbon atoms to which they are ed form monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form - or 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are ed form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In n embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form 5- or ered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R7&1 and R7b together with the carbon atoms to which they are attached form bicyclic heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form C340 cycloalkenyl, C644 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form C340 cycloalkenyl, optionally substituted with one or more tuents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form exenyl, optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 er with the carbon atoms to which they are attached form C644 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form phenyl, optionally substituted with one or more substituents Q.

In certain embodiments, R7b and R70 er with the carbon atoms to which they are attached form aryl, optionally tuted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form clic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form - or 6-membered aryl, optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form bicyclic aryl, optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 er with the carbon atoms to which they are attached form -l36- heterocyclyl, optionally tuted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are attached form monocyclic heterocycly1, optionally substituted with one or more substituents . In certain embodiments, R7b and R70 er with the carbon atoms to which they are ed form 5- or 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R7b and R70 together with the carbon atoms to which they are ed form bicyclic heterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form C340 cycloalkenyl, C644 aryl, heteroaryl, or cyclyl, each optionally substituted with one or more tuents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form C340 cycloalkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form cyclohexenyl, optionally substituted with one or more substituents Q. In certain ments, R70 and R7d together with the carbon atoms to which they are attached form C644 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form phenyl, optionally substituted with one or more substituents Q.

In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form aryl, optionally substituted with one or more substituents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q. In n embodiments, R70 and R7d together with the carbon atoms to which they are ed form - or 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form monocyclic cyclyl, optionally substituted with one or more substituents Q. In certain ments, R70 and R7d together with the carbon atoms to which they are attached form 5- or 6-membered heterocyclyl, optionally substituted with one or more tuents Q. In certain embodiments, R70 and R7d together with the carbon atoms to which they are attached form bicyclic heterocyclyl, optionally substituted with one or more substituents Q. -l37- In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form C340 cycloalkenyl, C644 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form C340 cycloalkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7e together with the carbon atoms to which they are attached form cyclohexenyl, optionally tuted with one or more substituents Q. In certain embodiments, R7d and R7e together with the carbon atoms to which they are ed form C644 aryl, optionally substituted with one or more substituents Q. In n embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form phenyl, optionally substituted with one or more substituents Q.

In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form - or 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form bicyclic heteroaryl, ally tuted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form clic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R7d and R7‘3 together with the carbon atoms to which they are attached form 5- or 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In n ments, R7d and R7‘3 er with the carbon atoms to which they are attached form bicyclic heterocyclyl, optionally substituted with one or more substituents Q. [0035 1] In certain embodiments, m is 0. In certain embodiments, m is 1.

In certain ments, n is 0. In certain embodiments, n is 1. In n ments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 0, l, or 2. In certain embodiments, n is 0, l, 2, or 3. In certain embodiments, n is l, 2, or 3. In certain embodiments, n is l or 2. -l38- 2012/030640 In certain ments, m is 0, and n is 0, 1, 2, or 3. In certain embodiments, m is 0, n is 0, 1, or 2. In certain embodiments, m is 0, n is 0 or I. In certain embodiments, m is 0, n is 0. In certain embodiments, m is 0, n is I. In certain embodiments, m is 1, n is 0, 1, 2, or 3. In certain embodiments, m is 1, n is 0, 1, or 2. In certain embodiments, m is 1, n is 0 or I. In certain embodiments, m is 1, n is 0. In certain ments, m is 1, n is I.

In specific embodiments, m is 0, n is 1, and R581 and R5b are each methyl.

In certain embodiments, X is N In certain embodiments, X is CRX, wherein Rx is as defined herein. In certain embodiments, X is CH.

In certain embodiments, Y is N In certain embodiments, Y is CRX, n Rx is as defined herein. In certain embodiments, Y is CH.

In certain embodiments, Z is N In certain embodiments, Z is CRX, wherein Rx is as defined . In certain embodiments, Z is CH.

In certain embodiments, X, Y, and Z are N. In n embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.

] In n embodiments, the compound provided herein is not 4-(2- (difluoromethy1)-1H—benzo[d]imidazoly1)morpholino-N-(2-pheny1(pyrrolidin y1)ethy1)-1,3,5-triazinamine. In certain embodiments, the compound provided herein is not 6-(2-(difluoromethy1)-1H—benzo[d]imidazoly1)-N-(1-(4-((R)—3 - (methoxymethy1)morpho1ino)pheny1)ethy1)morpho1inopyrimidinamine.

In certain embodiments, when X, Y, and Z are N, and R581 is hydrogen, R5b is not heterocyclyl. In n embodiments, when X, Y, and Z are N, and R5&1 is hydrogen, R5b is not 5-membered heterocyclyl. In certain embodiments, when X, Y, and Z are N, and R581 is hydrogen, R5b is not pyrrolidinyl. In certain embodiments, when X, Y, and Z are N, and R5&1 is hydrogen, R5b is not pyrrolidin-I-yl.

In certain embodiments, when X and Z are N, Y is CH, and R5&1 is hydrogen, R5b is morpholino-substituted pheny. In certain embodiments, when X and Z are N, Y is CH, and R5&1 is hydrogen, R5b is not 4-((R)(methoxymethy1)morpholino)pheny1.

WO 35160 H om emm..mmm pmVmedHe.m .m a cmmQp me mmd fl0H N\ N\ cHB CHF NIA\ NIA\ 2 NIAI N/ / NH IANH N MU A1 A2 N\ QN\ cHF2 CHF NIA\ NIA\ 2 NIAI N/ 1N / J N NH N NH(MU A3 A5 N\ QN\ cH H NIA\ B C F NIA\ 2 N N/ /__ HA / N J J NH NH N 00 MHV A6 A7 N\ Q NIA\ Ni Cm 2 2 EN N/ N I I N 1NN NH f N A8 A9 WO 35160 —141— WO 35160 —142— WO 35160 A35 A36 —143— WO 35160 CHE; Fz |A\ NIA\ NHA N NHA N /N NH KO /N NH N Nd m N\ \ Cm2 NIA\ |A\ NHA N NHA N /N F KOJ /N NH NH / , \ IN —144— WO 35160 —145— WO 35160 cm. CH N|A\ cm.

NHA N f0Nd /N NH / / \ IN NINV\ Aa A63 Cm2 \ NIA\ Fz NHA N NH / / KONy NH \N N @11kaN Q15N)\CHF2 N4 NAN , K OWN)\CHF2 Q—N\ NAN j: CHF2 N E 0Q JL (\N N/ N 0Q H /§\\O NH , A74 QN CF? N\ CHF2 NXCHFz NkN A N \N A i / (\N N N fN N E 0d H O\) N N/ \’ and l ; and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically able salts, solvates, hydrates, and prodrugs thereof.

The nds provided herein are intended to encompass all possible stereoisomers, unless a particular chemistry is specified. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where ural isomers are —147— interconvertible, the compound may exist as a single er or a mixture of tautomers.

This can take the form of proton tautomerism in the nd that contains, for example, an imino, keto, or oxime group; or so-called e tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a e of enantiomers, e.g. a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of skill in the art will recognize that administration of a nd in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable lly pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, tion, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of ceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptable salts e, but are not d to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)- camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, -l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, 0L- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, lactic acid, (::)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)—L-malic acid, malonic acid, (::)-DL-mandelic acid, methanesulfonic acid, alenesulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxynaphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, oric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium ide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, ry, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, ylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, amine, 1H—imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary , triethanolamine, trimethylamine, ylamine, N-methyl-D-glucamine, 2-amino(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of a I, and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to ster than the parent compound. They may, for instance, be bioavailable by oral administration s the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent nd. A prodrug may be ted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221- 294; Morozowich et al. in “Design of Biopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977; versible Carriers in Drug in Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; ti et (1]., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asghamejad in “Transport Processes in Pharmaceutical Systems,” Amidon et (11., Ed., Marcell Dekker, 185- —149— 218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; ard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, I 7, ; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; er et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem.

Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49- 59; Gangwar et al., Des. Biopharm. Prop. Prodrugs s, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, ; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63- 80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis The compound provided herein can be prepared, isolated, or obtained by any method known to one of skill in the art, and the ing examples are only representative and do not exclude other d procedures.

SchemeI NEH Rx \2 0 C1 / C1 V\ Nx\ R6 XJ§ R4 Y R3 XIJ§Y I 3— CIAZ/ C] OIRA}*ZACI \r\R4 / NkRs HZN(CRSdR5¢)mC(RSaR5bR5°) / R6 /l\ A R3 X R3 X/IY -HC1 j: R5d RSe R“ \AN \ZX \z N m r C] \r\’\N H J O \J RSa RSb OV\ \/ R4 R 14 1 2012/030640 In one embodiment, for example, a compound of Formula I can be prepared, as shown in Scheme I, via a first ic substitution reaction of a trihalo-substituted triazine or pyrimidine with compound I-1 to form compound I-2, which can subsequently be converted to nd I-4 via a second aromatic substitution reaction with compound I-3. nd I-4 can then be converted to a compound of Formula I via a third aromatic substitution reaction with NH2(CR5dRSB)mC(RsaRSbRSC).

In one embodiment, for e, a compound of Formula II can be prepared, as shown in Scheme II, via a first aromatic substitution on of a trihalo-substituted triazine or pyrimidine with compound I-1 to form compound I-2, which can subsequently be converted to nd I-4 via a second aromatic substitution reaction with compound I-3.

Compound I-4 can then be converted to a compound of Formula II via a third aromatic substitution reaction with NH2C(R5aR5bR5°).

Scheme II [\ANH C1 oV\J R4 xJ§ A A IXI\NJ\Z/J\C1 C1 2 c1 0 J N)\R6 I HZNC(R5aR5bR5°) / NkRe 3 XgY -HC1 A R\ R3 XERWa \ k [j] Z C1 ><\N \z N R5“ 0V\R4 0o\J 1-4 11 Pharmaceutical Compositions ] In one embodiment, provided herein is a ceutical composition comprising a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser. -lSl- In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable ents or rs. The pharmaceutical compositions provided herein that are formulated for oral stration may be in tablet, e, powder, or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline solution, dextrose or other ride solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be ed. A capsule may comprise a solid carrier such as gelatin.

] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, and one or more pharmaceutically able excipients or carriers. Where pharmaceutical compositions may be formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable s on, which is pyrogen-free and has a suitable pH, isotonicity, and stability. Those of relevant skill in the art are well able to prepare le solutions using, for example, isotonic vehicles, such as Sodium Chloride injection, Ringer’s injection, or Lactated Ringer’s injection. Preservatives, stabilisers, s, antioxidants, and/or other additives may be included as required.

In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a compound ed herein, and one or more pharmaceutically acceptable excipients or rs.

The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and programmed-release, and gastric retention dosage forms.

These dosage forms can be prepared according to conventional methods and techniques known to those d in the art (see, Remington: The Science and Practice ofPharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, NY, 2008).

The pharmaceutical compositions provided herein can be provided in a unit- dosage form or multiple-dosage form. A osage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each ose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unitdosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in ated unit-dosage form. Examples of a le-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or s.

The pharmaceutical compositions provided herein can be stered at once, or multiple times at als of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the dual need and the professional judgment of the person administering or ising the administration of the formulations.

] In certain embodiments, the pharmaceutical compositions provided herein r comprise one or more chemotherapeutic agents as defined herein.

A. Oral Administration The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and gual administration. le oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, les, cachets, pellets, medicated g gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, ons, ons, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, ts, non-aqueous liquids, organic acids, and sources of carbon dioxide. -lS3- [0038l] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not d to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, se, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of l husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), , larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose m, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH- l 0 l, AVICEL-PH-103, AVICEL RC-S 81, AVICEL-PH- l 05 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

The amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

The binder or filler may be present from about 50 to about 99% by weight in the ceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium ate, calcium e, lactose, sorbitol, e, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when t in sufficient quantity, can impart ties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed s can be used as chewable tablets. The amount of a t in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; linked starches; calcium carbonate; rystalline cellulose, such as sodium starch glycolate; polacrilin potassium; es, such as corn starch, potato starch, —154— tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the ceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

] Suitable lubricants e, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, ing peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl ; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., ore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

Suitable glidants include, but are not limited to, colloidal silicon e, CAB-O-SIL® (Cabot Co. of Boston, MA), and os-free talc. Suitable ng agents include, but are not limited to, any of the approved, certified, water e FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and es thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not d to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a nt taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. le suspending and sing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium ethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and -l55- alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, lene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, ol, ethyl l, and syrup. le non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not d to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium ate.

It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

The ceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple ssed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed s coated with substances that resist the action of stomach acid but dissolve or disintegrate in the ine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble al. Film coatings include, but are not limited to, yethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or ated tablets.

The tablet dosage forms can be prepared from the active ient in powdered, crystalline, or ar forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or nts. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [003 89] The pharmaceutical compositions provided herein for oral administration can be ed as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, -lS6- or calcium alginate. The hard gelatin e, also known as the dry-filled capsule (DFC), consists of two ns, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable vatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene ate, vegetable oils, or triglycerides. es containing such solutions can be prepared as described in US. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, sions, elixirs, and syrups. An emulsion is a ase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. ons may include a pharmaceutically able non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may e a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl de, e.g., dehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are trated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, l,2-dimethoxymethane, diglyme, triglyme, lyme, polyethylene glycoldimethyl ether, hylene glycoldimethyl ether, polyethylene glycoldimethyl ether, wherein 350, 550, and 750 refer to the approximate -l57- 2012/030640 average molecular weight of the polyethylene glycol. These ations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), ted hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, in, ic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulf1te, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in US. Pat. No. 6,350,458.

The pharmaceutical compositions ed herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be tituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent es or s may include diluents, sweeteners, and wetting agents.

Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

] Coloring and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, lled, targeted-, and programmed-release forms.

B. Parenteral Administration The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.

Parenteral administration, as used herein, e intravenous, intraarterial, eritoneal, hecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared ing to conventional methods -l58- known to those skilled in the art of ceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically able carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, crobial agents or preservatives against the growth of microorganisms, stabilizers, solubility ers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, xing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH ing agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and ed Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of ble , castor oil, corn oil, cottonseed oil, olive oil, peanut oil, mint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, l,3-butanediol, liquid polyethylene glycol (e.g, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methylpyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or vatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- ybenzoates, thimerosal, konium chloride (e.g. , benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium de, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulf1te. le local anesthetics include, but are not limited to, ne hydrochloride. le suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and -lS9- triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including 0t-cyclodextrin, B-cyclodextrin, hydroxypropyl-B- cyclodextrin, sulfobutylether-B-cyclodextrin, and sulfobutylether clodextrin (CAPTISOL®, CyDex, Lenexa, KS).

When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the multiple dosage parenteral formulations must n an antimicrobial agent at bacteriostatic or fiangistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteral stration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.

In yet another embodiment, the pharmaceutical itions are provided as ready-to-use sterile suspensions. In yet another embodiment, the ceutical compositions are provided as e dry insoluble products to be reconstituted with a vehicle prior to use. In still another ment, the pharmaceutical itions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for eral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein for eral administration can be formulated as a sion, solid, semi-solid, or thixotropic liquid, for stration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is ble in body fluids but allows the active ingredient in the ceutical compositions diffilse through.

Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, -l60- plasticized polyethylene terephthalate, l rubber, polyisoprene, polyisobutylene, tadiene, polyethylene, ethylene-vinyl acetate mers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed nyl acetate.

Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene mers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and ene, r polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ne/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration The pharmaceutical compositions provided herein can be stered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracomeal, intraocular, ophthalmic, auricular, transdermal, nasal, l, al, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointrnents, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, ls, irrigations, , suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical itions provided herein can also comprise liposomes, micelles, pheres, nanosystems, and mixtures thereof ceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not d to, aqueous vehicles, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, ding and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, ation enhancers, -l6l- WO 35160 cryoprotectants, lyoprotectants, thickening agents, and inert gases.

] The ceutical compositions can also be administered lly by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and TTM (Bioject Medical Technologies Inc., Tualatin, OR).

The pharmaceutical itions provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment es e oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, White petrolatum; emulsif1able or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) ons, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, ton: The Science and Practice ofPharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of atum and a fatty alcohol such as cetyl or stearyl alcohol. The s phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.

The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

Gels are lid, suspension-type systems. Single-phase gels contain organic macromolecules buted ntially uniformly throughout the liquid carrier.

Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene , polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.

The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or ginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or . These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the ceutical compositions ed herein; and antioxidants as bed herein, including bisulfite and sodium sulf1te. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl rylate, and polyacrylic acid;. Combinations of the s vehicles can also be used.

Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, sions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular s, and implants.

The pharmaceutical compositions provided herein can be administered intranasally or by tion to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or on for delivery using a rized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable lant, such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in ation with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a lant as solvent; and/or a tant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form rticles, high pressure homogenization, or spray drying.

] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as e or starch; and a mance modifier, such as l—leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, e, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a le flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.

D. Modified Release The ceutical compositions provided herein can be ated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of the active ient(s) is different from that of an ate dosage form when stered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, lled-, accelerated- and fast-, targeted-, programmed-release, and c retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be ed using a variety of modified e devices and methods known to those d in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and ations thereof. The release rate of the active ingredient(s) can also be modified by varying the le sizes and polymorphorism of the active ient(s).

Examples ofmodified release include, but are not limited to, those described in US. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 595; 5,591,767; 5,120,548; 5,073,543; 476; 5,354,556; 5,639,480; 5,733,566; ,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 350; 6,248,363; 970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 358; and 500. 1. Matrix Controlled Release Devices The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art (see, Takada et a]. in lopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, ing, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as ccharides and proteins.

Materials useful in forming an erodible matrix include, but are not limited to, chitin, an, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; en; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl ose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; rylic acid; copolymers of ylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acidglycolic acid copolymers; poly-D-(-)hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffilsion through the inert matrix once administered. Materials suitable for use as a odible matrix device include, but are not limited to, insoluble cs, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, thylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ne/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, dene chloride, ethylene and ene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl l copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, cized nylon, plasticized hylene terephthalate, natural rubber, silicone s, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, vidone, and cross- linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as camauba wax, microcrystalline wax, and triglycerides.

In a matrix controlled release system, the desired e cs can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or rs in the compositions.

The pharmaceutical compositions provided herein in a modified release -l66- dosage form can be prepared by methods known to those skilled in the art, ing direct compression, dry or wet granulation ed by compression, and melt-granulation followed by compression. 2. Osmotic Controlled e Devices The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber , asymmetric membrane technology (AMT), and extruding core system (ECS). In l, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable ne ls the influx of water to the core from an aqueous nment of use so as to cause drug e by extrusion through the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for ort of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.” Suitable swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, nyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the nding coating.

Suitable osmogens e, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, -l67- 2012/030640 potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as se, se, glucose, inositol, lactose, maltose, mannitol, raff1nose, sorbitol, sucrose, ose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fiJmaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and es thereof.

Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEMTM EZ (SP1 Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually e of the remaining amount to in the d level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients and rs as described herein to enhance the performance of the dosage form or to promote ity or processing.

Materials useful in forming the semipermeable membrane e various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of le polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, ose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl ate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar e, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- crylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, -l68- collagen, n, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane, n the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in US. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as kenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, lfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and tic waxes.

The delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by e of a r portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in US. Pat. Nos. ,612,059 and 5,698,220.

] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

The pharmaceutical compositions in an c lled-release dosage form can fiarther comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.

] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice ofPharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al. , Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric c membrane that coats a core comprising the active ingredient(s) and other pharmaceutically -l69- acceptable excipients or carriers. See, US. Pat. No. 059 and WC 7918. The AMT controlled-release dosage forms can be prepared ing to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which ses an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl ose, and other pharmaceutically acceptable excipients or carriers. 3. Multiparticulate Controlled Release Devices The pharmaceutical itions provided herein in a d release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of les, granules, or pellets, ranging from about 10 um to about 3 mm, about 50 um to about 2.5 mm, or from about 100 um to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletz'zatz'on Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting les can themselves constitute the multiparticulate device or can be coated by various rming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be fiarther processed as a capsule or a tablet. 4. Targeted Delivery The ceutical compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the t to be treated, including liposome-, resealed erythrocyte-, and antibody-based ry systems. Examples include, but are not limited to, those disclosed in US. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. 2012/030640 Methods ofUse In one embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a PI3K-mediated disorder, disease, or ion in a subject, comprising administering to the subject a therapeutically effective amount of a nd disclosed herein, e.g., a compound of Formula I, or an enantiomer, a e of omers, a mixture of two or more diastereomers, or an ic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof.

In certain embodiments, the PI3K is a Wild type PI3K. In certain embodiments, the PI3K is a PI3K variant.

In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is PI3K0L, PI3KB, PI3K5, or PI3Ky. In certain embodiments, the PI3K is pl 10a, pl 10B, pl 108, or pl 10y. In certain embodiments, the PI3K is a Wild type ofa Class I kinase.

In n embodiments, the PI3K is a variant of a Class I kinase.

In certain embodiments, the PI3K is pl 10a. In certain embodiments, the PI3K is a Wild type of pl 10a. In certain embodiments, the PI3K is a pl 10d mutant. In certain embodiments, the pl 10d mutant is R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, 1800L, T1025S, M10431, M1043V, H1047L, H1047R, or H1047Y. In certain embodiments, the p1100t mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, 1800L, T1025S, M1043I, , H1047R, or H1047Y. In certain embodiments, the p1100t mutant is C420R, E542K, E545A, E545K, Q546K, 1800L, M1043I, H1047L, or H1047Y.

In n embodiments, the PI3K is PI3Ky. In certain embodiments, the PI3K is a Wild type of PI3Ky. In certain embodiments, the PI3K is a t of PI3Ky.

In certain embodiments, the compound provided herein selectively targets PI3K5. In certain embodiments, the compound provided herein selectively targets a Wild type of PI3K8. In certain embodiments, the compound provided herein selectively targets a variant of PI3K5.

In certain ments, the compound provided herein is a selective inhibitor of PI3K5. In certain embodiments, the compound provided herein has a selectivity against 2012/030640 PI3K8 over PI3K0L ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain ments, the compound provided herein has a selectivity against PI3K8 over PI3KB ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain embodiments, the compound ed herein has a selectivity against PI3K8 over PI3Ky ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain embodiments, the compound provided herein has a selectivity against PI3K5 over mTOR ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain embodiments, the compound provided herein is a selective inhibitor of PI3KB. In certain embodiments, the compound provided herein has a selectivity against PI3KB over PI3K0L ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain embodiments, the compound provided herein has a selectivity against PI3KB over PI3K8 ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain embodiments, the compound provided herein has a ivity t PI3KB over PI3Ky ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain ments, the compound provided herein has a selectivity against PI3KB over mTOR ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain embodiments, the compound provided herein is a selective tor of PI3K5 and PI3KB. In certain embodiments, the compound provided herein has a selectivity against PI3K5 and PI3KB over PI3K0L ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain embodiments, the compound provided herein has a selectivity against PI3K5 and PI3KB over PI3Ky ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certain embodiments, the compound provided herein has a selectivity against PI3K5 -l72- and PI3KB over mTOR ranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about 1000 fold.

In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is a Wild type of a Class IV kinase. In certain embodiments, the PI3K is a variant of a Class IV kinase. In certain ments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certain embodiments, the PI3K is mTOR.

In another embodiments, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a eutically effective amount of a compound disclosed herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof [0045 7] In certain ments, the subject is a . In certain embodiments, the subject is a human. In certain embodiments, the subject is a primate other than a human, a farm animal such as cattle, a sport animal, or a pet such as a horse, dog, or cat.

In certain ments, the proliferative disease is cancer. In certain embodiments, the erative disease is hematological cancer. In certain embodiments, the proliferative disease is an inflammatory disease. In certain embodiments, the proliferative e is an immune disorder. [0045 9] The disorders, diseases, or conditions treatable with a compound provided herein, include, but are not limited to, (l) inflammatory or allergic diseases, including systemic anaphylaxis and hypersensitivity ers, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food ies ding celiac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) itis, and 's syndrome; (4) psoriasis and inflammatory oses, including dermatitis, eczema, atopic dermatitis, allergic contact itis, urticaria, viral cutaneous pathologies including those derived from human papillomavirus, HIV or RLV infection, bacterial, flugal, and other parasital ous pathologies, and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, exercise induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, -l73- hypersensitivity lung diseases, and chronic ctive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I es, myasthenia gravis, multiple sclerosis, Graves' disease, and glomerulonephritis; (7) graft ion (including allograft rejection and v-host disease), e.g., skin graft ion, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, ension, angina is, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, ry artery disease, restenosis, and vascular stenosis; (10) ovascular disorders, including traumatic brain injury, stroke, ischemic reperfiJsion injury and aneurysm; (ll) cancers of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, , oral cavity, colon and gastrointestinal tract (e.g., esophagus, h, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, connective tissue disease, and sarcoidosis, (l3) genital and reproductive ions, including erectile dysfunction; (14) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurologic disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy, sleep apnea syndrome, and Pickwick Syndrome; (l7) pain; (1 8) renal disorders; (19) ocular disorders, including glaucoma,; and (20) infectious diseases, including HIV.

In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (l) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, oleukemia leukemias and myelodysplastic me or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), kemia, and chronic myelomonocytic leukemia , (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) mas, including, but not limited to, Hodgkin's disease and non-Hodgkin's e; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, retory myeloma, osteosclerotic myeloma, plasma cell ia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, —174— 2012/030640 ing, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, arcoma (hemangiosarcoma), f1brosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, myosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast , including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, r breast cancer, papillary breast cancer, primary cancers, s disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not d to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, ary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, ing, but not limited to, insulinoma, gastrinoma, onoma, Vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) ary cancer, including, but limited to, Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not d to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and arcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine a; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, ing, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, ous carcinoma, and oat cell (small cell) oma; (24) h , including, but not limited to, adenocarcinoma, fiangating (polypoid), ulcerating, superficial spreading, ely spreading, malignant lymphoma, liposarcoma, f1brosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, , including, but not limited to, pappillary, r, and diffilse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (3 l) testicular cancer, ing, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma sac tumor); (32) te cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not d to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx , including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading ma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (3 9) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma, hypemephroma, rcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms’ tumor; (41) bladder cancer, including, but not limited to, transitional cell oma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary oma, and papillary arcinomas (See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book ofCancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

Depending on the disorder, disease, or condition to be treated, and the t’s ion, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration and can be ated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of stration.

Also provided is stration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined -l76- 2012/030640 time period.

In the ent, tion, or amelioration of one or more ms of the disorders, diseases, or conditions described , an appropriate dosage level generally is ranging from about 0.001 to 100 mg per kg subject body weight per day (mg/kg per day), from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses. Within this range, the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, or from about 1 to about 50 mg/kg per day.

For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The pharmaceutical compositions can be administered on a regimen of l to 4 times per day, including once, twice, three times, and four times per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular ion, and the host undergoing therapy.

Also provided herein are methods of modulating PI3K activity, comprising contacting a PIK3 enzyme with a compound ed herein, e.g., a compound of a I, or an enantiomer, a e of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PIK3 enzyme is inside a cell.

In certain embodiments, the PI3K is a wild type PI3K. In certain -l77- embodiments, the PI3K is a PI3K variant.

In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is PI3K0L, PI3KB, PI3K5, or PI3Ky. In n embodiments, the PI3K is p1100t, p110B, p1108, or p110y. In certain embodiments, the PI3K is a wild type ofa Class I kinase.

In certain embodiments, the PI3K is a variant of a Class I kinase.

In certain embodiments, the PI3K is pl 10d. In certain ments, the PI3K is a wild type of pl 10d. In n embodiments, the PI3K is a pl 10d mutant. In certain embodiments, the pl 10d mutant is R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, 1800L, T102358, M10431, M1043V, H1047L, H1047R, or H1047Y. In certain embodiments, the p1100t mutant is R38H, K111N, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, 1800L, T102SS, M1043I, , H1047R, or H1047Y. In certain ments, the p1100t mutant is C420R, E542K, E545A, E545K, Q546K, 1800L, M1043I, H1047L, or H1047Y.

In certain embodiments, the PI3K is PI3Ky. In certain embodiments, the PI3K is a wild type of PI3Ky. In certain embodiments, the PI3K is a variant of PI3Ky.

In n embodiments, the compound provided herein selectively targets PI3Ky. In certain embodiments, the compound provided herein selectively targets a wild type of PI3Ky. In certain embodiments, the compound provided herein selectively targets a variant of PI3Ky.

In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is a wild type of a Class IV kinase. In certain embodiments, the PI3K is a variant of a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certain embodiments, the PI3K is mTOR.

In certain embodiments, the nd ed herein, e.g., a nd of Formula I, or an enantiomer, a e of enantiomers, a mixture of two or more diastereomers, or an isotopic t thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity t a PI3K and a variant f.

In certain embodiments, the compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a wild type of a PI3K. In certain embodiments, the PI3K is PI3Ky.

In certain embodiments, the compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more reomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; shows inhibitory activity against a PI3K variant. In certain embodiments, the PI3K variant is a pl 10(1 mutant. In certain embodiments, the pl 10(1 mutant is C420R, E542K, E545A, E545K, Q546K, 1800L, , H1047L, or .

The compound provided herein, e.g., a compound of a I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, e, or prodrug thereof; can also be combined or used in combination with other agents or therapies useful in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions for which the compounds provided herein are useful, including , allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant ion, inflammatory bowel e, cancer, infectious diseases, and those pathologies noted herein.

Suitable other therapeutic agents can also include, but are not limited to, (l) alpha-adrenergic agents; (2) antiarrhythmic agents; (3) anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycins, mitomycin, omycin, and plicamycin; (5) anticancer agents and xic agents, e.g., alkylating agents, such as en mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and nes; (6) agulants, such as oumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, in, and ximelagatran; (7) anti-diabetic agents, such as biguanides (e.g., metformin), idase inhibitors (e.g., acarbose), ns, meglitinides (e.g., repaglinide), sulfonylureas (e.g., iride, glyburide, and glipizide), thiozolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8) antifungal agents, such as amorolf1ne, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofiangin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftif1ne, -l79- natamycin, nystatin, azole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole; (9) flammatories, e.g., non-steroidal anti-inflammatory agents, such as aceclofenac, acin, amoxiprin, aspirin, pazone, benorilate, nac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lomoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, cam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; (11) anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., ogrel, ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12) antiproliferatives, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) NF dies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors; (15) beta-adrenergic agents, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as questran; (17) m channel blockers, such as amlodipine te; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as azathioprine and hosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, oromethiazide, polythiazide, benzothiazide, ynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors, such as oramidon; (24) enzymes, such as L- asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors; (26) famesyl-protein transferase inhibitors; (27) fibrates; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors, such as tatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, tatin, or Visastatin); neutral endopeptidase (NEP) tors; (31) al agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants; (33) mineralocorticoid receptor antagonists, such as WO 35160 spironolactone and eplerenone; (34) microtubule-disruptor agents, such as ecteinascidins; (35) microtubule-stabilizing agents, such as pacitaxel, docetaxel, and epothilones A-F; (36) MTP Inhibitors; (37) niacin; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, and afil); (39) plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF) antagonists; (4l) platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) prenyl-protein transferase inhibitors; (44) protein tyrosine kinase tors; (45) renin inhibitors; (46) squalene tase inhibitors; (47) steroids, such as aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytic agents, such as eplase, reteplase, tenecteplase, tissue nogen activator (tPA), recombinant tPA, okinase, urokinase, prourokinase, and lated plasminogen streptokinase activator complex (APSAC); (5 l) thromboxane receptor antagonists, such as ifetroban; (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; and (54) other miscellaneous agents, such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold compounds.

In certain embodiments, the other therapies that may be used in combination with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biologic response modifiers (e.g. , interferons, eukins, and tumor is factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any e effects (e.g., antiemetics).

In certain embodiments, the other therapeutic agents that may be used in combination With the compounds provided herein include, but are not limited to, ting drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (high dose bine), and methotrexate), purine antagonists and dine nists (6- mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, bicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), and es (tamoxifen, leuprolide, flutamide, and -l8l- megestrol), ib, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer ies; See, /www.nci.nih.gov/, a list of the FDA approved oncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck , Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by nce.

In another embodiment, the method ed herein ses administration of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, together with administering one or more chemotherapeutic agents and/or therapies selected from: alkylation agents (e.g., cisplatin, latin); antimetabolites (e.g., methotrexate and 5-FU); antitumour antibiotics (e.g., adriamymycin and bleomycin); antitumour vegetable alkaloids (e.g., taxol and etoposide); antitumor hormones (e.g., dexamethasone and tamoxifen); antitumour immunological agents (e.g., interferon 0t, [3, and y); radiation therapy; and surgery. In n embodiments, the one or more chemotherapeutic agents and/or therapies are administered to the subject before, during, or after the administration of the compound provided herein.

Such other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof When a compound provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in on to the compound provided herein can be utilized, but is not required. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or eutic , in addition to a compound provided herein.

The weight ratio of a compound provided herein to the second active ingredient can be , and will depend upon the effective dose of each ingredient.

Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a NSAID, the weight ratio of the compound to the NSAID can range from about 1,000:1 to about 1:1,000, or about 200:1 to about 1:200. Combinations of a compound provided herein and other active ingredients will lly also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article of cture using ing materials well known to those of skill in the art. See, 6. g. , US.

Pat. Nos. 907; 5,052,558; and 5,033,252. Examples ofpharmaceutical ing materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and ent.

] Provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

In n embodiments, the kit includes a container comprising a dosage form of the compound provided herein, e.g., a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in a container comprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle- less ors drip bags, patches, and inhalers. The kits ed herein can also include s for administration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For e, if an active ingredient is provided in a solid form that must be reconstituted for parenteral stration, the kit can comprise a sealed ner of a le vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not -l83- limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, se and Sodium Chloride Injection, and Lactated Ringer’s Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous es, ing, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl , isopropyl myristate, and benzyl benzoate.

The disclosure will be fiarther understood by the following non-limiting EXAMPLES As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the l of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); uL (microliters); M (molar); mM (millimolar); uM (micromolar); eq. (equivalent); mmol (millimoles); Hz (Hertz); MHz (megahertz); hr or hrs (hour or hours); min (minutes); and MS (mass ometry).

For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise ted, all temperatures are expressed in 0C (degrees rade). All ons conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure. 2012/030640 Example 1 Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)morpholino-N-(1 - phenylethyl)- 1 ,3 ,5 -triazinamine A1 Q1?)\CHF2 Compound Al was prepared according to Scheme 1, where compound 1 (1-[4- chloro(4-morpholinyl)- 1 ,3 ,5 -tianzinyl](difluoromethyl)- 1H-benzimidazole) was synthesized according to the procedure as bed in US. Pat. Appl. Publ. No. 2007/244110, the disclosure of which is incorporated herein by reference in its entirety.

Scheme 1 ixCHFZ H N2 CTNNkCHFZ N \N NJ§N (\N / N C1 JL {\N N/ N O H 1 A1 A mixture of compound 1 (184 mg, 0.502 mmol) and (x-methylbenzylamine (121 mg, 1.00 mmol) in dioxane (25 mL) was d overnight. The mixture was poured into water to precipitate a white solid, which was recrystallized from ethanol to give 185 mg (81% yield) of compound A1 as a white solid: 97.1% purity (HPLC); MS m/z: 452.2 (M+1); 1H NMR(CDC13, 500 MHz) (rotamers) 5 8.42 (d, J: 8.0 Hz, 0.5H), 8.09 (d, J: 8.0 Hz, 0.5H), .86 (m, 1H), 7.65 (t, JHF = 53.5 Hz, 0.5H), 7.44-7.28 (m, 8H), 5.59 (d, J: 6.5 Hz, 0.5H), 5.19-5.06 (m, 1H), 3.76-3.91 (m, 8H), 1.63 (d, J: 7.0 Hz, 3H) ppm.

Example 2 Synthesis of (S)(2-(difluoromethyl)— 1H-benzo [d]imidazol- l -yl)morpholino-N-( l - ethyl)- l ,3 ,5 -triazinamine A2 Compound A2 was synthesized according to the procedure for compound A1, substituting -methylbenzylamine in place of (x-methylbenzylamine to give the product in 82% yield: 90.6% purity (HPLC); MS m/z: 452.2 (M+l); 1H NMR (CDClg, 500 MHz) (rotamers) 5 8.42 (d, J: 8.0 Hz, 0.5H), 8.09 (d, J: 7.5 Hz, 0.5H), 7.91-7.85 (m, 1H), 7.65 (t, JHF = 54.0 Hz, 0.5H), .22 (m, 8H), 5.61-5.57 (m, 0.5H), 5.25-5.17 (m, 1H), 3.87-3.66 (m, 8H), 1.68-1.61 (m, 3H) ppm.

Example 3 Synthesis of (R)(2-(difluoromethyl)- 1H-benzo [d]imidazol- l -yl)morpholino-N-( l - phenylethyl)- l ,3 ,5 -triazinamine A3 Compound A3 was synthesized ing to the procedure for compound A1, substituting (R)-0L-methylbenzylamine in place of (x-methylbenzylamine to give a 68% yield ofthe product: 98.7% purity (HPLC); MS m/z: 452 (M+1); 1H NMR , 500 MHz) 5 8.41 (d, J: 8.0 Hz, 0.5H), 8.08 (d, J: 8.0 Hz, 0.5H), 7.86 (m, 1H), 7.64 (t, JHF = 54.0 Hz, 0.5H), 7.44-7.19 (m, 75H), 5.58 (d, J: 7.5 Hz, 0.5H), 5.20 (m, 1H), 3.88-3.65 (m, 8H), 1.62 (d, J: 7.0 Hz, 3H) ppm. -l86- Example 4 Synthesis of (S)(2-(difluoromethyl)— 1H-benzo [d]imidazol- l -yl)morpholino-N-( l - phenylpropyl)-l ,3 ,5 -triazinamine A5 Compound A5 was synthesized according to the ure for compound A1, substituting (S)-0L-ethylbenzylamine in place of u-methylbenzylamine to give the product in 73% yield: 96.7% purity (LCMS); MS m/z: 466.2 (M+1); 1H NMR (DMSOd6, 500 MHz) ers) 5 8.58 (d, J: 8.5 Hz, 0.6H), 8.49 (d, J: 8.0 Hz, 0.6H), 8.46 (d, J: 8.5 Hz, 0.4H), 8.11 (m, 0.4H), 7.91 (t, JHF = 53.0 Hz, 0.6H), 7.85-7.78 (m, 1H), 7.61 (t, JHF = 53.0 Hz, 0.4H), 7.49 (t, J: 7.5 Hz, 0.5H), .38 (m, 3H), 7.38-7.31 (m, 2H), 7.27-7.20 (m, 1H), 4.90 (m, 1H), .55 (m, 8H), 1.95-1.65 (m, 1H), 0.93 (m, 3H) ppm.

Example 5 Synthesis of (R)(2-(difluoromethyl)- 1H-benzo [d]imidazol- l -yl)morpholino-N-( l - phenylpropyl)-l ,3 ,5 -triazinamine A6 Compound A6 was sized according to the procedure for compound A1, substituting (R)-oL-ethylbenzylamine in place of u-methylbenzylamine to give a 62% yield of product: 96.2% purity (HPLC); MS m/z: 466.2 (M+l); 1H NMR(CDC13, 500 MHz) (rotamers) 8.41 (d, J: 8.0 Hz, 0.4H), 8.11 (d, J: 8.0 Hz, 0.6H), 7.89 (d, J: 8.0 Hz, 0.4H), 7.86 (d, J = 7.5 Hz, 0.6H), 7.65 (t, JHF = 53.5 Hz, 0.6H), 7.46-7.25 (m, 7.4H), 5.62 (m, 0.5H), 4.99 (m, 0.5H), 4.92 (m, 0.5H), 3.87-3.65 (m, 8H), 2.02-1.89 (m, 2H), 1.04-0.98 (m, 3H) ppm. -l87- Example 6 Synthesis of (R)-methyl 2-((4-(2-(difluoromethyl)- 1H-benzo dazolyl)morpholino- 1 ,3 ,5 -triazinyl)amino)phenylacetate A1 1 Saturated aqueous sodium bicarbonate was added dropwise to a solution of (R)phenylglycine methyl ester hydrochloride (83 mg, 0.41 mmol) in water (4 mL) at 0 0C until pH = 8. Then the mixture was ted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was added to a mixture of compound 1 (50 mg, 0.14 mmol) in dioxane (5 mL) and the resulting mixture was refluxed for 4 hrs.

After the volatiles were removed in vacuo, the e was taken up in water and ethyl acetate. The organic extracts were dried over anhydrous sodium e and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/5) to give 44 mg (65% yield) of compound A11 as a yellow solid: 98.71% purity (LCMS); MS m/z: 496.1 (M+1); 1H NMR (CDClg, 500 MHz) (rotamers) 5 8.43 (d, J: 8.0 Hz, 0.5H), 8.11 (d, J: 8.0 Hz, 0.5H), 7.88 (m, 1H), 7.64 (t, JHF = 53.5 Hz, 0.5H), 7.52-7.35 (m, 7.5H), 6.33 and 6.25 (2d, J: 6.5 and 6.0 Hz, 1H), 5.69 and 5.60 (2d, J: 6.5 and 6.0 Hz, 1H), 3.89-3.70 (m, 11H) ppm.

Example 7 Synthesis of (S)-methyl 2-((4-(2-(difluoromethyl)- 1H-benzo[d]imidazolyl)morpholino- 1 ,3 ,5-triazinyl)amino)phenylacetate A12 Compound A12 was synthesized according to the procedure for compound A11, substituting phenylglycine methyl ester hydrochloride in place of (R) phenylglycine methyl ester hydrochloride to give the product in 67% yield: 95.5% purity (HPLC); MS m/z: 496.1 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.45 (d, J: 8.5 Hz, 0.5H), 8.13 (d, J: 8.0 Hz, 0.5H), 7.89 (m, 1H), 7.64 (t, JHF = 53.5 Hz, 0.5H), 7.52-7.36 (m, 7.5H), 6.32 and 6.25 (2d, J: 6.0 and 5.5 Hz, 1H), 5.69 and 5.60 (2d, J: 6.5 and 6.0 Hz, 1H), 3.89- 3.62 (m, 11H) ppm.

Example 8 Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)morpholino-N-(2- phenylpropanyl)- 1 ,3 ,5 inamine A7 A mixture of compound 1 (184 mg, 0.502 mmol) and 2-phenylpropanamine (170 mg, 1.26 mmol) in dioxane (5 mL) was refluxed overnight. The volatiles were removed in vacuo and the residue was separated by ethyl e and water. The organic extracts were washed sequentially with aq. sodium hydroxide (1 N), water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography % ethyl acetate in petroleum ether) to give 148 mg (63% yield) as a white solid: 99.6% purity ; MS m/z: 466.2 (M+1); 1H NMR(CDC13, 500 MHz) (rotamers) 5 8.45 (d, J: 8.0 Hz, 0.5H), 7.90 (d, J: 7.5 Hz, 0.5H), 7.79 (d, J: 8.0 Hz, 0.5H), 7.66 (t, JHF = 53.5 Hz, 0.5H), 7.50 (d, J: 8.0 Hz, 1H), 7.47-7.38 (m, 3.5H), 7.35-7.26 (m, 2H), 7.22 (t, J: 7.5 Hz, 0.5H), 7.13 (t, J: 7.5 Hz, 0.5H), 6.82 (t, JHF = 53.5 Hz, 0.5H), 5.82 (s, 1H), 3.87 (m, 2H), 3.81 (m, 2H), 3.74 (m, 1H), 3.67 (m, 1H), 3.41 (m, 1H), 3.31 (m, 1H), 1.80 and 1.78 (2s, 6H) ppm.

Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)morpholino-N-(2- (naphthalenyl)propanyl)-1 ,3 ,5 -triazinamine A13 Methylmagnesium bromide (3.6 mL, 3.0 M in tetrahydrofuran, 10.5 mmol) was added to a solution of naphthalenecarbonitrile (459 mg, 3.0 mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated in a microwave at 100 0C for 10 min. The resulting mixture was added titanium sopropanolate (0.9 mL, 3.0 mmol) and then irradiated with ave at 50 0C for 1 hr. The mixture was poured into water and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product, which was triturated by the dropwise addition of hydrochloric acid in ether (1 N) to precipitate 2-(naphthalenyl)propanamine as its hydrochloric acid salt (600 mg, 90%) as a yellow solid: 84.7% purity (LCMS); MS m/z: 171 (M+1).

The crude 2-(naphthalenyl)propanamine hydrochloride (246 mg, 1.09 mmol), compound 1 (200 mg, 0.550 mmol), and potassium carbonate (377 mg, 2.73 mmol) were suspended in dioxane (25 mL) and the mixture was refluxed ght. The mixture was diluted with water and extracted with ethyl e. The organic extracts were dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was d by preparative-HPLC to give 150 mg (53% yield) of compound A13 as a white solid: 98.5% purity (HPLC); MS m/z: 516.2 (M+1); 1H NMR (CDClg, 500 MHz) 5 8.43 (d, J: 8.0 Hz, 0.6H), 7.98-7.36 (m, 10H), .87 (m, 1H), 6.26 (t, J: 8.0 Hz, 0.4H), 5.88 and 5.83 (2s, 1H), 3.87-2.89 (m, 8H), 1.89 and 1.86 (2s, 6H) ppm.

Example 10 Synthesis ofN—(2-(4-chlorophenyl)propanyl)(2-(difluoromethyl)- 1H—benzo[d]imidazol- 1-yl)morpholino- 1 ,3 ,5 -triazinamine A8 r/\N N/ O\V/J E Compound A8 was synthesized in two steps according to the ure for compound A13, substituting 4-chlorobenzonitrile in place of naphthalenecarbonitrile. The crude product was d by preparative HPLC to give 125 mg (41% yield for 2 steps) of compound A8 as a white solid: 99.5% purity (HPLC); MS m/z: 500.2 (M+1); 1H NMR (CDClg, 500 MHz) 5 8.44 (d, J: 8.0 Hz, 0.6H), 7.90 (d, J: 7.5 Hz, 0.6H), 7.80 (d, J: 8.0 Hz, 0.4H), 7.65 (t, JHF = 54.0 Hz, 0.6H), 7.49-7.33 (m, 4H), 7.33-7.27 (m, 2H), 7.15-6.87 (m, 0.8H), 5.75 and 5.72 (2s, 1H), 3.86 (m, 2H), 3.81 (m, 2H), 3.76 (m, 1H), 3.69 (m, 1H), 3.46 (m, 1H), 3.30 (m, 1H), 1.79 and 1.76 (2s, 6H) ppm Example 11 sis of 4-(2-(difluoromethyl)- 1H-benzo[d]imidazolyl)-N-(2-(4- methoxyphenyl)propanyl)morpholino- 1 ,3 ,5 -triazinamine A9 OCH3 ] Compound A9 was synthesized in two steps according to the procedure for compound A13, substituting 4-methoxybenzonitrile in place of naphthalenecarbonitrile.

The crude compound A9 was purified by preparative HPLC to give 150 mg (50% yield for 2 steps) of product as a white solid: 98.0% purity (LCMS), MS m/z: 496.2 (M+1); 1H NMR (CDClg, 500 MHz) 5 8.44 (d, J: 8.5 Hz, 0.5H), 7.90 (d, J: 8.0 Hz, 0.5H), 7.80 (d, J: 8.0 Hz, 0.5H), 7.65 (t, JHF = 53.5 Hz, 0.5H), 7.53 (d, .1: 8.5 Hz, 0.5H), 7.47—7.33 (m, 3H), 7.31 (t, .1: 7.5 Hz, 0.5H), 7.16 (t, .1: 7.5 Hz, 0.5H), 6.95 (d, .1: 9.0 Hz, 1H), 6.85 (d, .1: 9.0 Hz, 1H), 6.85 (t, JHF = 53.0 Hz, 0.5H), 5.77 (d, .1: 8.5 Hz, 1H), 3.87 (m, 2H), 3.81 (m, 5H), 3.76 (m, 1H), 3.69 (m, 1H), 3.48 (m, 1H), 3.40 (m, 1H), 1.79 and 1.75 (2s, 6H) ppm.

Example 12 sis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(4-fluorophenyl) methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A22 A mixture of 1-(4-fluorophenyl)methylpropanamine (125 mg, 0.748 mmol) and compound 1 (183 mg, 0.499 mmol) in dioxane (15 mL) was refluxed overnight.

The volatiles were removed in vacuo and the residue was purified by prep-HPLC to give 4- (2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-( 1 orophenyl)methylpropanyl)- 6-morpholino-1,3,5-triazinamine (35 mg, 14% yield) as a white solid: 98.1% purity (HPLC); MS m/z: 498.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.37 (d, J: 7.5 Hz, 1H), 7.88 (d, J: 7.5 Hz, 1H), 7.63 (t, JHF = 54.0 Hz, 1H), 7.41 (m, 2H), 7.04 (t, J: 8.0 Hz, 2H), 6.96 (t, J: 8.5 Hz, 2H), 5.10 (s, 1H), 4.00-3.72 (m, 8H), 3.18 (s, 2H), 1.45 (s, 6H) ppm.

Example 1 3 Synthesis of 4-(2-(difluoromethyl)- 1H-benzo [d]imidazolyl)-N-(2-methylphenylpropan- 2-yl)—6-morpholino- 1 ,3 ,5 -triazinamine A14 To a mixture of 2-methylphenylpropanol (1.5 g, 10 mmol) and acetonitrile (3 mL) in acetic acid (15 mL) was added concentrated SlllfilI'lC acid (3 mL) dropwise at room ature. The mixture was stirred at 65 0C for 3 hours and then poured into ice-water (ca. 200 mL). The aqueous solution was d with saturated s sodium hydroxide until pH > 11. The suspension was stirred for further 0.5 hour, and then the precipitated solid was filtered and washed with water. The white solid was air-dried to give N—(2-methylphenylpropanyl) acetamide (1.5 g, 78% yield), which was used for the next step without further purification.

A mixture of N—(2-methylphenylpropanyl) acetamide (191 mg, 1.00 mmol) and potassium hydroxide (1 g) in ethylene glycol (10 mL) was refluxed for 8 hours.

The mixture was diluted with ice-water and extracted with ethyl e. The combined organic fractions were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 2-methylphenylpropan-amine (200 mg) as a brown oil, which was used for the next step without filrther purification. nd A14 was synthesized according to the ure for compound A22, substituting the crude 2-methylphenylpropan-amine in place of 1-(4-fiuorophenyl) methylpropanamine. The t was purified by preparative HPLC to give compound A14 (30 mg, 13% yield for 2 steps) as a white solid: 96.4% purity (HPLC); MS m/z: 480.3 (M+1); 1H NMR(CDC13, 500 MHz) 8 8.39 (d, J: 7.5 Hz, 1H), 7.90 (d, J: 7.5 Hz, 1H), 7.65 (t, JHF = 54.0 Hz, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.16-7.10 (m, 2H), 5.15 (s, 1H), 4.01-3.75 (m, 8H), 3.22 (s, 2H), 1.49 (s, 6H) ppm.

Example 14 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2-chlorophenyl) methylpropanyl)morpholino-1 ,3 ,5 -triazinamine A16 ] A mixture of 1-(2-chlorophenyl)methylpropanamine hydrochloride (165 mg, 0.750 mmol), compound 1 (184 mg, 0.502 mmol) and potassium carbonate (138 mg, 2012/030640 1.00 mmol) in dioxane (15 mL) was refluxed for 12 hours. The volatiles were removed in vacuo and the residue was d by reverse phase flash chromatography (0 to 80% acetonitrile in aq. 0.5% ammonium bicarbonate) to give 4-(2-(difluoromethyl)-1H- benzo[d]imidazolyl)-N-(1-(2-chlorophenyl)methylpropanyl)morpholino-1 ,3 ,5 - triazinamine (65 mg, 25% yield) as a white solid: 99.2% purity (HPLC); MS m/z: 514.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.41 (d, J: 8.0 Hz, 1H), 7.90 (d, J: 7.0 Hz, 1H), 7.66 (t, JHF = 53.5 Hz, 1H), 7.50-7.36 (m, 3H), 7.24-7.05 (m, 3H), 5.34 (s, 1H), 4.05-3.70 (m, 8H), 3.43 (s, 2H), 1.53 (s, 6H) ppm.

Example 1 5 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(4-methoxyphenyl) methylpropanyl)morpholino-1 ,3 ,5 -triazinamine A25 A mixture of 4-(hydroxymethyl)phenol (1.0 g, 8.1 mmol) and opropane (4.0 g, 45 mmol) in diglyme (50 mL) was cooled in an ice bath. Potassium tert—butoxide (0.45 g, 4.0 mmol) was added in portions, then the reaction mixture was heated to reflux overnight. After g, the mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give 4-(2-methyl nitropropyl)phenol (1.3 g, 83% yield) as a light yellow solid. thane (0.12 mL, 1.3 mmol) was added to a mixture of 4-(2-methyl nitropropyl)phenol (300 mg, 1.5 mmol) and potassium carbonate (425 mg, 3.1 mmol) in tetrahydrofuran (20 mL) and methylformamide (1 mL). After refluxing overnight, the mixture was cooled and concentrated under vacuum. The e was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated to provide crude 1-methoxy(2-methylnitropropyl)benzene (200 mg, 62% yield) as yellow oil which was used directly in the next step.

The crude 1-methoxy(2-methylnitropropyl)benzene (200 mg, 0.96 mmol) —194— WO 35160 was combined with palladium on carbon (40 mg) in methanol (30 mL). The suspension was vigorously stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through Celite and the filtrate was trated to give 1-(4-methoxyphenyl) methylpropanamine (150 mg, 88% yield) as a yellow oil which was used t r purification. (MS m/z: 180 (M+l)).

A e of the 1-(4-methoxyphenyl)methylpropanamine (73 mg, 0.41 mmol) and compound 1 (100 mg, 0.27 mmol) in dioxane (25 mL) was refluxed overnight.

The volatiles were removed under vacuum and the residue was purified by prep-HPLC to give compound A25 (40 mg, 29% yield) as a white solid: > 99.5% purity (HPLC); MS m/z: 510.2 (M+1); 1H NMR(CDC13, 500 MHz) 8 8.38 (d, J: 8.0 Hz, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.64 (t, JHF = 54.0 Hz, 1H), 7.41 (m, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.82 (d, J: 8.0 Hz, 2H), 5.10 (s, 1H), 3.93 (m, 3H), 3.83 (m, 5H), 3.77 (s, 3H), 3.13 (s, 2H), 1.45 (s, 6H) ppm.

Example 1 6 Synthesis of 4-(2-(difiuoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(2-methoxyphenyl) methylpropanyl)morpholino-1 ,3 ,5 inamine A19 Compound A19 was synthesized according to the procedure for compound A16, substituting 1-(2-methoxyphenyl)methylpropanamine in place of 1-(2- chlorophenyl)methylpropanamine hydrochloride. The product was purified by reverse phase flash chromatography (0 to 80% acetonitrile in water) to give compound A19 (66 mg, 81% yield) as a white solid: > 99.5% purity (HPLC); MS m/Z: 510.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.42 (dd, J: 7.5 Hz and 1.5 Hz, 1H), 7.88 (dd, J: 6.5 Hz and 2.5 Hz, 1H), 7.67 (t, JHF = 53.5 Hz, 1H), 7.39 (m, 2H), 7.26 (m, 2H), 7.12 (dd, J: 7.5 Hz and 1.5 Hz, 1H), 6.95 (m, 2H), 6.68 (s, 1H), 3.97 (s, 3H), 3.93-3.74 (m, 8H), 3.04 (s, 2H), 1.56 (s, 6H) ppm.

Example 1 7 Synthesis ofN—( 1 -(4-bromophenyl)methylpropanyl)(2-(difluoromethyl)- 1H- benzo[d]imidazolyl)morpholino-1 ,3 ,5 -triazinamine A24 Compound A24 was synthesized according to the procedure for compound A16, substituting 1-(4-bromophenyl)methylpropanamine hloride in place of 1- (2-chlorophenyl)methylpropanamine hydrochloride. The product was purified by reverse phase flash chromatography (0 to 80% acetonitrile in water) which yielded nd A24 (110 mg, 39% yield) as a white solid: 98.6% purity (HPLC); MS m/Z: 558.2 (M+l), 560.2 (M+3); 1H NMR , 500 MHz) 5 8.38 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.65 (t, JHF = 53.5 Hz, 1H), 7.52-7.38 (m, 4H), 6.97 (d, 2H), 5.07 (s, 1H), 4.00-3.70 (m, 8H), 3.18 (s, 2H), 1.47 (s, 6H) ppm. e 1 8 Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-(2-methyl(0- tolyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A18 CHXCHFZ (\NkN/ E Compound A18 was synthesized according to the procedure for compound A16, substituting 2-methyl(0-tolyl)propanamine hydrochloride in place of 1-(2- chlorophenyl)methylpropanamine hydrochloride. The product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give nd A18 (120 mg, 89% yield) as a white solid: >99.5% purity (HPLC); MS m/z: 494.2 (M+1); 1H C13, 500 MHz) 8 8.39 (d, J: 8.0 Hz, 1H), 7.88 (d, J: 7.0 Hz, 1H), 7.64 (t, JHF = 53.5, 1H), 7.40 (m, 2H), .98 (m, 4H), 5.24 (s, 1H), 4.00-3.75 (m, 8H), 3.25 (s, 2H), 2.36 (s, 3H), 1.49 (s, 6H) ppm.

Example 1 9 Synthesis ofN—( 1 -(4-chlorophenyl)methylpropanyl)(2-(difluoromethyl)- 1H- benzo[d]imidazolyl)morpholino-1 ,3 ,5 -triazinamine A23 Methylmagnesium bromide (3 M in ether, 5.5 mL, 16.5 mmol) was added se to a solution of methyl 4-chlorophenylacetate (1.0 g, 5.4 mmol) in tetrahydrofuran (20 mL) at 0 0C under a en atmosphere. The mixture was stirred at room temperature overnight and then quenched by the addition of water (30 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated to give 1-(4-chlorophenyl) methylpropanol (1.0 g, 100% yield) as a yellow oil, which was used without filrther purification.

A solution of the crude alcohol (184 mg, 0.996 mmol) and chloroacetonitrile (150 mg, 1.99 mmol) in acetic acid (3.0 mL) was cooled to 0 oC. Concentrated sulfiaric acid (1.0 mL) was added to the solution dropwise while keeping the reaction temperature below CC. After stirring at room temperature for 1 hour, the resulting solution was poured onto ice and ed by the addition of solid potassium carbonate to pH > 8. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give 150 mg of 2-chloro-N-(1- (4-chlorophenyl)methylpropanyl)acetamide as yellow solid. The crude material was used directly in the next step.

To a mixture of 2-chloro-N-(1-(4-chlorophenyl)methylpropan tamide (259 mg, 1.00 mmol) in dioxane (5.0 mL) was added conc. hydrochloric acid (20 mL). After stirring at 105 0C for 16 hours, the reaction mixture was poured onto ice and basified by the addition of saturated aq. sodium bicarbonate to pH > 8. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was then purified by reverse phase flash chromatography (0 to 25% acetonitrile in aq. 0.01% formic acid) to give 1-(4-chlorophenyl)methylpropanamine (70 mg, 38% yield) as a white solid.

A mixture of 1-(4-chlorophenyl)methylpropanamine (70 mg, 0.38 mmol), compound 1 (93 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.50 mmol) in dioxane (10 mL) was refluxed overnight. The volatiles were removed under vacuum and the residue was purified by reverse phase flash chromatography (0 to 70% itrile in aq. 0.01% ammonium bicarbonate) to give nd A23 (57 mg, 44% yield) as a white solid: 93.1% purity (HPLC); MS m/z: 514.1 (M+1); 1H NMR (CDClg, 500 MHZ) 5 8.37 (d, J: 8.0 Hz, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.63 (t, JHF = 54.0 Hz, 1H), 7.41 (m, 2H), 7.25 (m, 2H), 7.18- 6.90 (m, 2H), 5.05 (s, 1H), 4.00-3.72 (m, 8H), 3.19 (s, 2H), 1.45 (s, 6H) ppm.

Example 20 Synthesis ofN—( 1 -(3 -chlorophenyl)methylpropanyl)(2-(difluoromethyl)- 1H- benzo[d]imidazolyl)morpholino-1 ,3 ,5 -triazinamine A20 Thionyl chloride (11 g, 100 mmol) was added dropwise to a mixture of 3- chlorophenylacetic acid (1.7 g, 10 mmol) in ol (20 mL) at 0 CC. The resulting mixture was refluxed at 80 0C for 12 hours. The volatiles were removed under vacuum and the residue was diluted with water and ted with ethyl acetate. The combined organic solution was washed with water, dried over sodium sulfate and the concentrated to give 1.5 g of methyl hlorophenyl)acetate as a yellow oil, which was used t further purification.

Compound A20 was sized in 4 steps according to the procedure for nd A23, substituting the crude methyl hlorophenyl)acetate in place of methyl 4- chlorophenylacetate. The final product was purified by reverse phase flash chromatography (0 to 70% itrile in aq. 0.01% ammonium bicarbonate) to give 19 mg of compound A20 as a white solid: >99.5% purity (HPLC); MS m/z: 514.1 (M+1); 1H NMR(CDC13, 500 MHz) 8.37 (d, J: 8.0 Hz, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.62 (t, JHF = 54.0 Hz, 1H), 7.41 (m, 2H), 7.21 (m, 2H), 7.10 (s, 1H), 6.96 (m, 1H), 5.10 (s, 1H), 4.00-3.69 (m, 8H), 3.19 (s, 2H), 1.47 (s, 6H) ppm.

Example 21 Synthesis of 4-(2-(difluoromethyl)— 1H-benzo[d]imidazolyl)-N—(1 thoxyphenyl) methylpropanyl)morpholino-1 ,3 ,5 -triazinamine A2 1 Lithium diisopropylamide (2 M in tetrahydrofuran, 2.71 mL, 5.42 mmol) was added to a mixture of ethyl yrate (600 mg, 5.17 mmol) in tetrahydrofuran (60 mL) at —78 0C and stirred at this temperature for 1 hour. 3-Methoxybenzyl chloride (1.15 g, 7.34 mmol) was added se and the reaction mixture was stirred at —78 0C for another 1 hour and then at room temperature overnight. The mixture was quenched by water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give ethyl(3-methoxyphenyl)-2,2- dimethylpropanoate (1.3 g) as a yellow oil, which was used in the next step without further purification.

The crude ethyl(3-methoxyphenyl)-2,2-dimethylpropanoate (1.00 g, 4.23 mmol) was taken up in a solution of ethanol (50 mL) and sodium hydroxide (2 N, 10 mL).

The reaction e was refluxed overnight and then concentrated under vacuum. The concentrated aqueous solution was acidified with hydrochloric acid (2 N) to pH 3—4 and extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate and ated to yield 3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (600 mg) as a brown oil, which was used ly in the next step. MS m/z: 207 (M-l).

] A mixture of 3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (200 mg, 0.96 mmol) in e (40 mL) and water (4 mL) was cooled to 0 0C. Triethyl amine (0.18 mL, 1.3 mmol) was added to the reaction mixture followed by methyl chloroformate (118 mg, 1.25 mmol). The mixture was stirred for 1 hour at 0 0C and then another solution of sodium azide (94 mg, 1.45 mmol) in water (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for another 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated to give 3-(3-methoxyphenyl)-2,2-dimethylpropanoyl azide (60 mg) as a crude yellow oil, which was used without further purification.

A mixture of the crude 3-(3-methoxyphenyl)-2,2-dimethylpropanoyl azide (160 mg, 0.69 mmol) in toluene (20 mL) was refluxed overnight. The solvent was d under vacuum to give 1,3-bis(l-(3-methoxyphenyl)methylpropanyl)urea (158 mg) as a brown oil, which was used without purification: MS m/z: 383 (M-l).

A mixture of the crude urea (80 mg, 0.21 mmol) and potassium hydroxide (32 mg, 0.57 mmol) in ethylene glycol (5 mL) was refluxed for 2 hours. The reaction e was diluted with water and extracted with ethyl e. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated to give l-(3- methoxyphenyl)methylpropanamine (75 mg) as a brown oil, which was used ly in the next step. MS m/z: 180 (M+l).

A mixture of the crude amine (63 mg, 0.35 mmol) and compound 1 (100 mg, 0.27 mmol) in dioxane (25 mL) was refluxed overnight. The volatiles were removed in vacuo and the residue was purified by prep-HPLC to give compound A21 (30 mg, 22% yield) as a white solid: >99.5% purity (HPLC); MS m/z: 510.2 (M+l); 1H NMR(CDC13, 500 MHz) 8 8.37 (d, J: 8.0 Hz, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.62 (t, JHF = 53.5 Hz, 1H), 7.40 (m, 2H), 7.20 (t, J: 7.5 Hz, 1H), 6.79 (dd, J: 8.5 Hz & 2.0 Hz, 1H), 6.69 (d, J: 7.5 Hz, 1H), 6.65 (s, 1H), 5.14 (s, 1H), 4.00-3.76 (m, 8H), 3.74 (s, 3H), 3.17 (s, 2H), 1.48 (s, 6H) ppm.

Example 22 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(2-methyl(naphthalen yl)propanyl)morpholino-1 ,3 ,5 -triazinamine A26 m bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 25.3 mL, 25.3 mmol) was added to a mixture of ethyl yrate (2.67 g, 23.0 mmol) in tetrahydrofuran (25 mL) at —78 0C. After ng for 30 m, a solution of 2-(chloromethyl)naphthalene (400 mg, 2.30 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture se. The mixture was stirred at —78 0C for another hour and then at room temperature ght. The mixture was quenched by the on of water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give ethyl 2,2-dimethyl(naphthaleneyl)propanoate (1.00 g) as a yellow oil, which was used without fiarther purification.

The crude ester (915 mg) was taken up in e (4 mL) and 20% aqueous sodium hydroxide (8 mL). After stirring at room ature for 2 hours, the reaction mixture was diluted with ethyl acetate. The aqueous fraction was acidified to pH = 2 with concentrated hydrochloric acid and was then extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated to yield 2,2-dimethyl (naphthaleneyl)propanoic acid (211 mg, 40% yield for two steps) as a white solid, which was used directly in the next step.

A mixture of the intermediate acid (211 mg, 0.920 mmol) in acetone (3 mL) and water (0.3 mL) was cooled to 0 0C . Triethyl amine (0.20 mL, 1.40 mmol) was added to the reaction mixture followed by methyl chloroformate (104 mg, 1.10 mmol). The reaction was stirred at room temperature for 30 minutes and a solution of sodium azide (120 mg, 1.84 mmol) in water (0.5 mL) was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water and extracted with petroleum ether. The combined organic fractions were washed with water, dried over sodium sulfate and evaporated to give crude 2,2-dimethyl(naphthaleneyl)propanoyl azide (117 mg, 50% yield) as a ess oil, which was used without further purification.

The crude acyl azide (1 17 mg, 0.46 mmol) was refluxed in e (3 mL) overnight to generate the intermediate isocyanate. The reaction mixture was allowed to cooled to room temperature and a solution of 10% hydrochloric acid (3 mL) was added.

After refluxing for 4 hours, the reaction e was concentrated under vacuum to give 2- methyl-l-(naphthaleneyl)propanamine (98 mg, 90% yield) as a yellow solid, which was used directly in the next step.

A mixture of the crude amine (98 mg, 0.42 mmol), compound 1 (103 mg, 0.28 mmol) and potassium carbonate (116 mg, 0.84 mmol) in dioxane (3 mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by prep- HPLC to give compound A26 (12 mg, 8% yield) as a white solid: > 99.5% purity (HPLC); MS m/z: 530.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.37 (d, J: 8.0 Hz, 1H), 7.85-7.37 (m, 10H), 5.19 (s, 1H), .75 (m, 8H), 3.37 (s, 2H), 1.53 (s, 6H) ppm.

Example 23 Synthesis of difluoromethyl)-1H—benzo[d]imidazolyl)-N—(2-methyl(naphthalen yl)propanyl)morpholino-1 ,3 ,5 -triazinamine A27 ‘N’LhN (\NAN/ E g Methylmagnesium bromide (3 M in ether, 10 mL, 30 mmol) was added dropwise to a solution of methyl naphthalene-l-acetate (2.0 g, 10 mmol) in tetrahydrofuran (20 mL) at 0 0C under a nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixtures was quenched by the on of water. The organic fraction was washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude 2- methyl(naphthaleneyl)propanol (2.0 g) as a yellow oil, which was used directly in the next step. 2012/030640 The crude alcohol (2.0 g, 10 mmol) was dissolved in acetonitrile (10 mL) and concentrated sulfuric acid (4.9 g, 50 mmol) was added dropwise at 0 0C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water and extracted with dichloromethane. The combined c ons were dried over sodium sulfate and evaporated. The residue was purified by silical gel column chromatography (petroleum ether/ethyl acetate ) to give N-(2-methyl-l-(naphthalene-l-yl)propanyl)acetamide (0.90 g, 37% yield) as a yellow solid.

Concentrated hydrochloric acid (10 mL) was added to a solution of the ediate acetamide (0.20 g, 0.83 mmol) in e (2 mL) and the resulting mixture was refluxed for 3 days. After cooling to room ature, the reaction mixture was basif1ed to pH 9 by the addition of solid sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic fractions were dried over sodium sulfate and concentrated to give crude yl-l-(naphthalene-l-yl)propanamine (0.15 g, 23% yield) as a yellow oil, which was used without further purification.

The crude amine (153 mg, 0.25 mmol), compound 1 (48 mg, 0.13 mmol) and potassium carbonate (36 mg, 0.25 mmol) were taken up in dioxane (2 mL) and heated to reflux overnight. The reaction mixture was concentrated under vacuum and the residue was purified by prep-HPLC to give compound A27 (16 mg, 23% yield) as a white solid: > 99.5% purity (HPLC); MS m/z: 530.3 (M+l); 1H NMR(CDC13, 500 MHz) 8 8.29 (d, J: 8.0 Hz, 1H), 8.15 (d, J: 7.0 Hz, 1H), 7.88 (d, J: 6.5 Hz, 2H), 7.77 (d, J: 8.0 Hz, 1H), 7.56 (t, JHF =54.0 Hz, 1H), 7.48 (m, 2H), 7.39 (m, 3H), 7.27 (d, J: 7.0 Hz, 1H), 5.29 (s, 1H), .73 (m, 8H), 3.66 (s, 2H), 1.54 (s, 6H) ppm.

Example 24 Synthesis of 4-(2-(difluoromethyl)- lH—benzo[d]imidazol- l -yl)-N—( l -(2-fluorophenyl) methylpropanyl)morpholino- l ,3 ,5 -triazinamine A15 WO 35160 ] Compound A15 was sized in 6 steps ing to the procedure for compound A21, substituting 2-fluorobenzyl e in place of 3-methoxybenzyl chloride.

The final product was purified by prep-HPLC to give compound A15 (30 mg, 22% yield) as a white solid: 99.4% purity (HPLC); MS m/z: 498.2 (M+1); 1H NMR (CDClg, 500 MHz) 5 8.39 (d, J: 8.0 Hz, 1H), 7.89 (d, J: 7.5 Hz, 1H), 7.65 (t, JHF = 53.5 Hz, 1H), 7.41 (m, 2H), 7.22 (m, 1H), 7.06 (m, 3H), 5.25 (s, 1H), 4.00-3.73 (m, 8H), 3.28 (s, 2H), 1.49 (s, 6H) ppm.

Example 25 Synthesis of 4-(2-(difluoromethyl)- 1H-benzo [d]imidazolyl)-N—(2-methylphenylpropyl)- 6-morpholino- 1 ,3 ,5 -triazinamine A29 Powdered lithium aluminum hydride (137 mg, 3.61 mmol) was added portionwise to a solution of 2-methylphenylpropanenitrile (436 mg, 3.00 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred at 80 0C overnight. The reaction was then cooled to 0 0C and water (66 uL, 3.7 mmol), 10% sodium hydroxide (1.44 g, 3.6 mmol) and water (195 uL, 10.8 mmol), respectively, were added dropwise into the reaction mixture. The suspension was filtered through anhydrous magnesium sulfate and the solution was concentrated under vacuum to give 2-methylphenylpropanamine (400 mg) as a yellow oil, which was used for the next step without filrther ation.

The crude amine (400 mg, 2.7 mmol) and compound 1 (147 mg, 0.401 mmol) were refluxed in dioxane (25 mL) for 4 hours. After cooling, the reaction mixture was concentrated under vacuum. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic ons were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by prep- HPLC to give compound A29 (75 mg, 35% yield for 2 steps) as a white solid: > 99.5% purity (HPLC); MS m/z: 480.2 (M+1); 1H NMR(CDC13, 500 MHz) (rotamers) 8 8.45 (d, J: 7.5 Hz, 0.5H), 8.33 (d, J: 8.0 Hz, 0.5H), 7.92 (d, J: 7.5 Hz, 0.5H), 7.88 (d, J: 7.5 Hz, 0.5H), 7.64 —204— and 7.60 (2t, JHF = 53.5 Hz, 1H), 7.42 (m, 6H), 7.28 (m, 1H), 5.13-5.00 (m, 1H), 4.00-3.70 (m, 10H), 1.45 and 1.44 (2s, 6H) ppm.

Example 26 Synthesis of 4-(2-(difluoromethyl)- 1H-benzo[d]imidazolyl)-N-(2-( 1 - phenylcyclopropyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A30 Methylmagnesium bromide (3.0 M in ydrofuran, 3.0 mL, 9.0 mmol) was added to a solution of 1-phenylcyclopropanecarbonitrile (429 mg, 3.0 mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 100 0C for 10 minutes in a microwave oven. Then titanium(IV) poxide (0.9 mL, 3.0 mmol) was added and the reaction mixture was heated to 50 0C for 1 hour in the microwave. After cooling, a solution of 25% aqueous ammonia (2 mL) was added se to the reaction mixture. The suspension was filtered through a Celite pad which was washed with tetrahydrofuran. The combined filtrate was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium e and concentrated under vacuum to give 2-(1-phenylcyclopropyl)propan amine (400 mg) as a crude yellow oil: MS m/z: 178 (M+1).

The crude amine (200 mg, 1.1 mmol) was combined with compound 1 (100 mg, 0.27 mmol) and potassium carbonate (150 mg, 1.1 mmol) in dioxane (20 mL) and heated to reflux overnight. The mixture was diluted with water and extracted with ethyl e.

The organic extracts were dried with anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reversed phase flash chromatography (0 to 85% acetonitrile in 0.01% ammonium bicarbonate) to give compound A30 (46 mg 34% yield) as a white solid: 94.4% purity (HPLC); MS m/z: 506.2 (M+1); 1H C13, 500 MHz) 5 8.34 (d, J: 7.5 Hz, 1H), 7.90 (d, J: 7.5 Hz, 1H), 7.61 (t, JHF = 54.0 Hz, 1H), 7.42 (m, 2H), 7.35 (m, 2H), 7.29 (m, 2H), 7.24 (m, 1H), 5.26 (s, 1H), 4.00-3.65 (m, 8H), 1.48 (s, 6H), 1.17 (m, 2H), 0.84 (m, 2H) ppm.

Example 27 Synthesis of difluoromethyl)-1H-benzo[d]imidazol- l -( l -(2-bromophenyl) methylpropanyl)-morpholino- l ,3 ,5 -triazinamine A17 Lithium diisopropylamide (2M in hexane, 1.5 mL, 3.0 mmol) was added to a solution of ethyl isobutyrate (233 mg, 2.01 mmol) in tetrahydrofuran (1 mL) at -78 0C and the reaction mixture was stirred at this temperature for 30 min. Then, a solution of 2- bromobenzyl bromide (250 mg, 1.00 mmol) in tetrahydrofuran (1 mL) was added dropwise.

The on mixture was stirred at -78 0C for another 1 hr and then at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate, and concentrated to give 482 mg of ethyl romophenyl)-2,2-dimethylpropanoate as a yellow oil. The crude intermediate was used directly in the next step.

A solution of the crude ester (482 mg) in dioxane (2 mL) was combined with aqueous sodium hydroxide (20%, 4 mL) and stirred at room temperature for 2 hrs. The reaction mixture was d with ethyl acetate and the aqueous fraction was acidified to pH 2 with cone. hydrochloric acid. After extraction with ethyl acetate, the combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give 121 mg (47% yield for two steps) of romophenyl)-2,2-dimethylpropanoic acid as a white solid. The crude carboxylic acid was used in the next step without further purification: MS m/z: 255.0 (M-l).

Triethylamine (1 12 mg, 1.11 mmol) was added to a e of the intermediate carboxylic acid (188 mg, 0.731 mmol) in acetone (8 mL) and water (1 mL). The reaction mixture was cooled to 0 0C and methyl chloroformate (84 mg, 0.88 mmol) was added. The e was stirred at room temperature for 30 min and then a solution of sodium azide (95 mg, 1.46 mmol) in water (0.5 mL) was added dropwise. After stirring at room temperature ght, the resulting mixture was diluted with water and extracted with petroleum ether. The ed c factions were washed with water, dried over sodium sulfate, and trated to give 162 mg (79% yield) of 3-(2-bromophenyl)-2,2- dimethylpropanoyl azide as a white solid, which was used directly in the next step: MS m/z: 252.9 (M-28).

A solution of the crude acyl azide (162 mg, 0.574 mmol) in toluene (3 mL) was refluxed overnight to give 1-bromo(2-isocyanatomethylpropyl)benzene. Then, the solution was cooled to room temperature and 10% aq. hydrochloric acid (3 mL) was added.

The resulting mixture was refluxed for 4 hrs. The volatiles were removed in vacuo to give 129 mg (85% yield) of 1-(2-bromophenyl)methylpropanamine hydrochloride as a white solid. The crude amine hydrochloride salt was used in the next step without fiarther purification: MS m/z: 228.1 (M+l).

A mixture ofthe amine salt (129 mg, 0.49 mmol), compound 1 (121 mg, 0.33 mmol), and potassium carbonate (183 mg, 1.33 mmol) was refluxed in dioxane (4 mL) overnight. The volatiles were removed under vacuum and the residue was purified by silical gel column tography (9% ethyl acetate in petroleum ether) to give 99 mg (54% yield) of compound A17, difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2-bromophenyl)- 2-methylpropanyl)morpholino-1,3,5-triazinamine, as a white solid: >99.5% purity (HPLC); MS m/z: 558.2 (M+1), 560.2 (M+3); 1H NMR(CDC13, 500 MHz) 5 8.42 (d, 1H), 7.91 (d, 1H), 7.67 (t, 1H), 7.60 (d, 1H), 7.48-7.37 (m, 2H), 7.22 (t, 1H), 7.11 (m, 2H), 5.32 (s, 1H), 4.01-3.76 (m, 8H), 3.46 (s, 2H), 1.54 (s, 6H) ppm.

WO 35160 Example 28 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(2-methyl(2-(pyridin yl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A33 CHN)\CHF2 1&1“ (\N N/ g 0Q / Compound A17 (200 mg, 0.358 mmol), nylboronic acid (49 mg, 0.40 mmol), sodium carbonate (114 mg, 1.08 mmol), and 1,1'-bis(diphenylphosphino)ferrocene- palladium(H)dichloride dichloromethane complex (29 mg, 0.036 mmol) were taken up in imethylformamide (4 mL) and water (1 mL) and stirred under en at 100 CC overnight. The reaction mixture was diluted with ethyl acetate and filtered through Celite.

The filtrate was washed with water and brine, dried over sodium sulfate, and concentrated.

The crude product was purified by prep-HPLC to give 18 mg (9% yield) of compound A33, 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(2-methyl(2-(pyridinyl)phenyl)- propanyl)morpholino-1,3,5-triazinamine, as a white solid: >99.5% purity (HPLC); MS m/z: 557.3 (M+1); 1H NMR(CDC13, 500 MHz) (rotamers) 5 8.53 (br s, 2H), 8.39 (d, 1H), 7.92 (d, 1H), 7.66 (t, 1H), 7.49-7.38 (m, 2H), 7.34 (m, 2H), 7.26 (m, 1H), 7.23-7.15 (m, 3H), 4.88 (s, 1H), 3.95-3.75 (m, 8H), 3.35 (s, 2H), 1.28 (s, 6H) ppm. e 29 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(biphenylyl) methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A47 Compound A17 (140 mg, 0.251 mmol), phenylboronic acid (61 mg, 0.500 mmol), sodium carbonate (80 mg, 0.755 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II)dichloride dichloromethane complex (21 mg, 0.0257 mmol) were taken up in imethylformamide (8 mL) and water (2 mL) and stirred under nitrogen at 100 0C overnight. The reaction mixture was diluted with ethyl acetate and filtered through .

The filtrate was washed with water and brine, dried over sodium sulfate, and concentrated.

The crude product was purified by chiral-SFC to give 60 mg (44% yield) of compound A47, 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(biphenylyl)methylpropan yl)morpholino-1,3,5-triazinamine, as a white solid: >99.5% purity (HPLC); MS m/z: 556.2 (M+1); 1H NMR(CDC13, 500 MHz) (rotamers) 5 8.39 (d, 1H), 7.92 (d, 1H), 7.66 (t, 1H), 7.44 (m, 2H), 7.28 (m, 7H), 7.22 (m, 2H), 4.94 (s, 1H), 3.92-3.55 (m, 8H), 3.37 (s, 2H), 1.28 (s, 6H) ppm.

Example 30 Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-( 1 -(3-fiuorophenyl) propanyl)morpholino- 1 ,3 ,5 -triazinamine A39 Compound A39 was synthesized in 6 steps according to the ure for A21, substituting 3-fiuorobenzyl bromide in place of oxybenzyl chloride. The final product was purified by prep-HPLC to give compound A39 (35 mg) as a white solid: 99% purity ; MS m/z: 498.2 (M+1); 1H NMR (DMSOd6, 500 MHz) 5 8.60 (d, 1H), 8.01 (t, 1H), 7.84 (d, 1H), 7.54 (s, 1H), 7.45 (m, 2H), 7.30 (m, 1H), 7.03 (m, 1H), 6.94 (m, 2H), 3.85 (m, 4H), 3.75 (m, 4H), 3.25 (s, 2H), 1.40 (s, 6H) ppm.

Example 3 1 sis of 4-(2-(difluoromethyl)- 1H-benzo [d]imidazolyl)-N-(2-methylm-tolylpropan- 2-yl)morpholino- 1 ,3 ,5-triazinamine A49 Compound A49 was synthesized in 6 steps according to the ure for A21, substituting 3-methylbenzyl bromide in place of 3-methoxybenzyl chloride. The final product was purified by prep-HPLC to give compound A49 (15 mg) as a white solid: 98% purity (HPLC); MS m/z: 494.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.38 (d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.48 (s, 1H), 7.42 (m, 1H), 7.19 (t, 1H), 7.10-6.88 (m, 3H), 5.17 (s, 1H), 4.10-3.80 (m, 8H), 3.16 (s, 2H), 2.31 (s, 3H), 1.49 (s, 6H) ppm.

Example 32 Synthesis of 4-(2-(difluoromethyl)- 1H-benzo [d]imidazolyl)-N-( 1 -(4-fluoro-3 - methoxyphenyl)methylpropanyl)morpholino- 1 ,3 ,5-triazinamine A50 Compound A50 was synthesized in 6 steps according to the procedure for A21, substituting 4-fiuoromethoxybenzyl in place of 3-methoxybenzyl de. The final t was purified by prep-HPLC to give nd A50 (115 mg) as a white solid: 99% purity (HPLC); MS m/z: 528.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.37 (d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.43 (m, 2H), 6.99 (m, 1H), 6.71-6.60 (m, 2H), 5.12 (s, 1H), 4.01-3.78 (m, 8H), 3.77 (s, 3H), 3.17 (s, 2H), 1.49 (s, 6H) ppm.

Example 33 Synthesis of 4-(2-(difiuoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2,4-difiuorophenyl) methylpropanyl)morpholino-1 ,3 ,5 -triazinamine A5 1 Compound A51 was synthesized in 5 steps according to the procedure for A20,substituting 2,4-difiuorophenylacetic acid in place of 3-chlorophenylacetic acid. The final product was purified by PLC to give compound A51 (60 mg) as a white solid: 99% purity (HPLC); MS m/z: 516.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.40 (d, 1H), 7.90 (d, 1H), 7.65 (t, 1H), 7.43 (m, 2H), 7.04 (m, 1H), 6.84 (m, 2H), 5.19 (s, 1H), 4.00-3.75 (m, 8H), 3.26 (s, 2H), 1.49 (s, 6H) ppm.

Example 34 Synthesis of 4-(2-(difiuoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2,6-difiuorophenyl) methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A52 WO 35160 Compound A52 was synthesized in 5 steps according to the procedure for A20, substituting 2,6-difluorophenylacetic acid in place of 3-chlorophenylacetic acid. The final product was purified by prep-HPLC to give compound A52 (38 mg) as a white solid: 98% purity (HPLC); MS m/z: 516.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.41 (d, 1H), 7.90 (d, 1H), 7.66 (t, 1H), 7.43 (m, 2H), 7.23 (m, 1H), 6.91 (t, 2H), 5.43 (s, 1H), 4.05-3.70 (m, 8H), 3.33 (s, 2H), 1.53 (s, 6H) ppm.

Example 35 sis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(2-methyl(2-(pyridin-3 - yl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A40 Compound A40 was synthesized according to the procedure for A33, substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine in place of pyridinyl c acid. The crude product was purified by prep-HPLC to give compound A40 (41 mg, 41% yield) as a white solid: 98% purity (HPLC); MS m/z: 557.3 (M+1); 1H NMR (DMSOdg, 500 MHz) 5 8.58 (d, 1H), 8.40 (s, 1H), 8.37 (dd, 1H), 8.01 (t, 1H), 7.84 (d, 1H), 7.58 (dd, 1H), 7.48 (t, 1H), 7.43 (t, 1H), 7.40-7.28 (m, 3H), 7.19 (s, 1H), 7.13 (m, 2H), 3.82-3.60 (m, 8H), 3.34 (s, 2H), 1.23 (s, 6H) ppm.

Example 36 sis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(2-(2-methoxypyridin yl)phenyl)methylpropanyl)morpholino-1 ,3 ,5 -triazinamine A4 1 CF?XCHFZ Compound A41 was synthesized according to the procedure for A33, substituting 2-methoxypyridineboronic acid in place of pyridinylboronic acid. The crude product was purified by prep-HPLC to give compound A41 (250 mg, 24% yield) as a white solid: 95% purity (HPLC); MS m/z: 587.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.40 (d, J: 8.0 Hz, 1H), 8.06 (d, 1H), 7.91 (d, 1H), 7.65 (t, 1H), 7.43 (m, 2H), 7.33 (m, 2H), 7.25 (t, 1H), 7.16 (d, 1H), 6.78 (d, 1H), 6.62 (s, 1H), 4.85 (s, 1H), 3.95-3.75 (m, 8H), 3.74 (s, 3H), 3.36 (s, 2H), 1.32 (s, 6H) ppm. e 37 Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-(2-methyl(2-(2- methylpyridinyl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A43 131“ Compound A43 was synthesized according to the procedure for A33, substituting ylpyridineboronic acid in place of nylboronic acid. The crude product was purified by prep-HPLC to give compound A43 (15 mg, 24% yield) as a white solid: 98% purity (HPLC); MS m/z: 571.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.45 (d, 1H), 8.40 (d, 1H), 7.91 (d, 1H), 7.66 (t, 1H), 7.44 (m, 2H), 7.33 (m, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 7.13-6.95 (m, 2H), 4.88 (s, 1H), 4.00-3.75 (m, 8H), 3.36 (s, 2H), 2.49 (s, 3H), 1.28 (s, 6H) ppm.

Example 3 8 Synthesis of difluoromethyl)- 1H-benzo [d]imidazolyl)-N-( 1 -(2-(1H-pyrazol yl)phenyl)methylpropanyl)morpholino-1 ,3 ,5 -triazinamine A44 HN-N Compound A44 was synthesized according to the procedure for bstituting 1-Boc-pyrazoleboronic acid pinacol ester in place of pyridinylboronic acid. The crude product was d by prep-HPLC to give compound A44 (15 mg, 31% yield) as a White solid: 99% purity (HPLC); MS m/z: 546.3 (M+l); 1H NMR (DMSOd6, 500 MHz) 5 12.84 (s, 1H), 8.59 (d, 1H), 8.00 (t, 1H), 7.84 (d, 1H), 7.74 (br s, 1H), 7.50 (br s, 1H), 7.48 (t, 1H), 7.42 (t, 1H), 7.37 (s, 1H), 7.20 (m, 4H), 3.85-3.42 (m, 8H), 3.42 (s, 2H), 1.21 (s, 6H) ppm. —214— Example 39 Synthesis of 4-(2-(difluoromethyl)-1H-benzo [d]imidazolyl)-N-(2-methyl(2-(1 -methyl- 1H-pyrazolyl)phenyl)propanyl)morpholino- 1 ,3 ,5 -triazinamine A45 191“ (\N N/ E 0Q / Compound A45 was synthesized ing to the procedure for A33, substituting 1-methyl-1H—pyrazoleboronic acid pinacol ester in place of pyridinyl boronic acid. The crude product was purified by prep-HPLC to give compound A45 (35 mg, 12% yield) as a white solid: 98% purity (HPLC); MS m/z: 560.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.38 (d, 1H), 7.91 (d, 1H), 7.65 (t, 1H), 7.51 (s, 1H), .37 (m, 2H), 7.34 (s, 1H), 7.28-7.17 (m, 4H), 5.04 (s, 1H), .78 (m, 11H), 3.40 (s, 2H), 1.35 (s, 6H) ppm.

Example 40 Synthesis of difluoromethyl)-1H—benzo[d]imidazolyl)-N—(2-methyl(2-(1-methyl- 1H-pyrazolyl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A46 < IN\ CHF2 nd A46 was synthesized according to the procedure for A33, substituting 1-methyl-1H—pyrazoleboronic acid pinacol ester in place of pyridinyl boronic acid. The crude product was purified by prep-HPLC to give compound A46 (7 mg, 4% yield) as a white solid: 98% purity (HPLC); MS m/z: 560.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.40 (d, 1H), 7.91 (d, 1H), 7.67 (t, 1H), 7.50—7.30 (m, 5H), 7.24 (t, 2H), 6.21 (s, 1H), .03 (s, 1H), 3.96-3.75 (m, 8H), 3.65 (s, 3H), 3.21 (s, 2H), 1.32 (s, 6H) ppm.

Example 41 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2'-fluorobiphenylyl)- 2-methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A59 Compound A59 was synthesized according to the ure for A33_1 substituting 2-fluorophenylboronic acid in place of pyridinylboronic acid. The crude product was purified by PLC to give nd A59 (73 mg, 71% yield) as a white solid: 99% purity (HPLC); MS m/z: 574.2 (M+1); 1H NMR (DMSOd6, 500 MHz) 5 8.61 (d, 1H), 8.02 (t, 1H), 7.84 (d, 1H), 7.48 (t, 1H), 7.43 (t, 1H), 7.39-7.22 (m, 5H), 7.22 (t, 1H), 7.14 (m, 2H), 6.97 (t, 1H), 3.74 (m, 8H), 3.30 (d, 1H), 3.14 (d, 1H), 1.20 (s, 3H), 1.17 (s, 3H) ppm.

Example 42 Synthesis of 4-(2-(difluoromethyl)— 1H-benzo[d]imidazolyl)-N-(2-methyl(2'- methylbiphenylyl)propanyl)morpholino- 1 ,3 ,5 -triazinamine A60 Compound A60 was synthesized according to the procedure for A33, substituting 2-methylphenylboronic acid in place of pyridinylboronic acid. The crude product was purified by prep-HPLC to give compound A60 (120 mg, 47% yield) as a white solid: 99% purity ; MS m/z: 570.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.42 (d, 1H), 7.92 (d, 1H), 7.68 (t, 1H), 7.44 (m, 2H), 7.35-6.95 (m, 8H), 5.01 (s, 1H), 4.10-3.70 (m, 8H), 3.30 (d, 1H), 2.99 (d, 1H), 2.06 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H) ppm.

Example 43 sis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(6'-chlorobiphenylyl)- 2-methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A6 1 Compound A61 was synthesized according to the procedure for A33: substituting 2-chlorophenylboronic acid in place of pyridinylboronic acid. The crude product was purified by prep-HPLC to give compound A61 (88 mg, 55% yield) as a white solid: 99% purity (HPLC); MS m/z: 590.2 (M+1); 1H NMR(CDC13, 500 MHz) 5 7.92 (d, 1H), 7.67 (t, 1H), 7.44 (m, 2H), 7.33 (m, 3H), 7.27-7.00 (m, 5H), 4.96 (s, 1H), 4.00-3.75 (m, 8H), 3.24 (d, 2H), 1.33 (s, 6H) ppm.

Example 44 Synthesis of difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(6'-chlorobiphenylyl)- 2-methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A62 Compound A62 was sized according to the procedure for A33: substituting opyridinylboronic acid in place of pyridinylboronic acid. The crude product was purified by PLC to give compound A62 (134 mg, 65% yield) as a white solid: 96% purity (HPLC); MS m/z: 575.3 (M+l); 1H C13, 500 MHz) 5 8.38 (d, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.66 (t, 1H), 7.62 (m, 1H), 7.49-7.32 (m, 4H), 7.28 (d, 1H), 7.15 (d, 1H), 6.91 (t, 1H), 4.80 (s, 1H), 4.05-3.70 (m, 8H), 3.60 (d, 1H), 2.99 (d, 1H), 1.42 (s, 3H), 1.27 (s, 3H) ppm.

Example 45 Synthesis of 4-(2-(difluoromethyl)- lH—benzo[d]imidazol- l -yl)-N-(2-methyl- l -(2-(pyrimidinyl)phenyl)propanyl)morpholino-l ,3 ,5 -triazinamine A63 Compound A63 was synthesized according to the procedure for A33: substituting pyrimidineboronic acid pinacol ester in place of pyridinylboronic acid. The crude product was purified by prep-HPLC to give compound A63 (75 mg, 50% yield) as a white solid: 98% purity (HPLC); MS m/z: 558.3 (M+l); 1H NMR(CDC13, 500 MHz) 5 9.05 (s, 1H), 8.62 (s, 2H), 8.36 (d, 1H), 7.90 (d, 1H), 7.65 (t, 1H), 7.50-7.27 (m, 5H), 7.16 (d, 1H), 4.86 (s, 1H), 3.95-3.80 (m, 8H), 3.34 (s, 2H), 1.32 (s, 6H) ppm. -2l8- Example 46 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(2-methyl(2-(2-(4- methylpiperazinyl)pyridinyl)phenyl)propanyl)morpholino- 1 ,3 ,5 inamine Compound A64 was synthesized according to the procedure for A33: substituting 2-(4-methylpiperazinyl)pyridineboronic acid pinacol ester in place of nylboronic acid. The crude product was purified by prep-HPLC to give compound A64 (24 mg, 20% yield) as a White solid: 98% purity (HPLC); MS m/Z: 655.4 (M+1); 1H NMR (DMSOdg, 500 MHz) 5 8.58 (d, 1H), 7.99 (t, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.48 (t, 1H), 7.43 (t, 1H), 7.37 (d, 1H), 7.35-7.22 (m, 3H), 7.21 (s, 1H), 7.07 (d, 1H), 6.58 (d, 1H), 3.82-3.62 (m, 8H), 3.37 (s, 2H), 3.26 (br s, 4H), 2.25 (br s, 4H), 2.16 (s, 3H), 1.23 (s, 6H) Example 47 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(2-methyl(3'- (morpholinomethyl)biphenylyl)propanyl)morpholino- 1 ,3 ,5 -triazinamine A65 Compound A65 was synthesized according to the procedure for A33: substituting 3-(morpholinomethyl)phenylboronic acid pinacol ester in place of pyridinyl boronic acid. The crude product was purified by prep-HPLC to give compound A65 (40 mg, 17% yield) as a white solid: 99% purity (HPLC); MS m/z: 655.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.39 (d, 1H), 7.91 (d, 1H), 7.64 (t, 1H), 7.43 (m, 2H), 7.35-7.10 (m, 8H), 4.97 (s, 1H), 3.93-3.74 (m, 8H), 3.68 (m, 4H), 3.50-3.32 (m, 4H), 2.38 (m, 4H), 1.23 (s, 6H) ppm. e 48 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(3'-methoxybiphenyl yl)methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A66 < :Z»N\ CHF2 Compound A66 was sized according to the procedure for A33: substituting 3-methoxyphenylboronic acid in place of nylboronic acid. The crude product was purified by prep-HPLC to give compound A66 (18 mg, 11% yield) as a white solid: 99% purity (HPLC); MS m/z: 586.3 (M+1); 1H NMR(CDC13, 500 MHz) 8 8.39 (d, 1H), 7.91 (d, 1H), 7.65 (t, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.27-7.17 (m, 3H), 6.88-6.70 (m, 3H), 4.90 (s, 1H), 3.95-3.75 (m, 8H), 3.55 (s, 1H) 3.38 (s, 2H), 1.32 (s, 6H) ppm.

Example 49 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(1-(4'-methoxybiphenyl yl)methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A67 Compound A67 was synthesized according to the procedure for A33, substituting 4-methoxyphenylboronic acid in place of nylboronic acid. The crude product was purified by prep-HPLC to give compound A67 (83 mg, 39% yield) as a white solid: 99% purity (HPLC); MS m/z: 586.2 (M+1); 1H NMR (DMSOdg, 500 MHz) 5 8.61 (d, 1H), 7.85 (t, 1H), 7.84 (d, 1H), 7.49 (t, 1H), 7.43 (t, 1H), 7.30-7.19 (m, 4H), 7.08-7.02 (m, 3H), 6.73 (d, 2H), 3.82-3.63 (m, 8H), 3.62 (s, 3H), 3.34 (s, 2H), 1.21 (s, 6H) ppm.

Example 50 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N—(2-methyl(2-(piperidin- 4-yl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A68 terthutyl 4—(2{24(4"(Z—(difluoromethyl)—1H—benzo{ailimidazoln 1 —yl)—6~ morpho l ino— 1 ,3 ,5 wtri azin-Z-yl)ami metby}propyl)phenyl)~5 ,{éwdihydropyridine—1(2H)— carboxylate was synthesized ing to the ure for A33J substituting N-Boc-1,2,5,6- tetrahydropyridineboronic acid pinacol ester in place of pyridinylboronic acid. The crude product was purified by flash chromatography to give tert—butyl 4-(2-(2-((4-(2- (difiuoromethyl)-1H-benzo[d]imidazolmorpholino- 1 ,3 ,5 -triazinyl)amino) methylpropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (270 mg, 81% yield) as a white solid: MS m/z: 586.2 (M+l).

A mixture of the Boc-protected dihydropyridine (215 mg, 0.325 mmol) and 10% palladium/carbon (22 mg) in methanol was stirred under a hydrogen atmosphere at 50 0C for 3 hrs. The reaction mixture was filtered h Celite. The filtrate was then concentrated and the residue was purified by flash chromatography to give 70 mg (33% yield) of tert—butyl 4-(2-(2-((4-(2-(difiuoromethyl)- 1H-benzo dazolyl)morpholino- 1 ,3 ,5 -triazin yl)amino)methylpropyl)phenyl)piperidinecarboxylate as a white solid. MS m/z: 663 (M+l).

A mixture of the Boc-piperidine intermediate (65 mg, 0.098 mmol) and roacetic acid (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 2 hrs. The volatiles were removed under reduced pressure. The residue was diluted with water and basified at 0 0C with 1M sodium hydroxide to pH ~ 8 and extracted with romethane. The combined extracts were dried over sodium sulfate and trated.

The crude product was purified by prep-HPLC to give compound A68 (12 mg, 22% yield) as a white solid: 98% purity (HPLC); MS m/z: 563.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.37 (d, 1H), 7.89 (d, 1H), 7.66 (t, 1H), 7.41 (m, 2H), 7.33 (d, 1H), 7.28 (t, 1H), 7.16 (t, 1H), 7.07 (d, 1H), 5.16 (s, 1H), 4.00-3.70 (m, 8H), 3.37 (m, 2H), 3.23 (s, 2H), 3.04 (m, 2H), 2.76 (m, 2H), 2.03 (m, 2H), 1.80 (m, 2H), 1.52 (s, 6H) ppm.

Example 51 Synthesis of 4—(2—(di fluoromcthyI)—l oMimidazol-l -yi)-N-(2-meihyl- 1-(2—( lmethylpiperidin —4—yl)phenyl)propanyl)~6-morpholino— 1 ,3,5-triaziu—2-amine A35 i ‘ N 0\/' A e of compound A68 (80 mg, 0.14 mmol), aq. formaldehyde (37%, 23 mg), and sodium cyanoborohydride (11 mg, OJ 7 mmol) in methanol (2 mL) was stirred at room temperature for 1 hr. The crude product was purified by PLC to give compound A35 (11 mg, 13% yield) as a white solid: 99% purity (HPLC); MS m/z: 577.3 (MM ); 'H NMR(CDC13, 500 MHZ) 0' 8.37 (d. 1H), 7.90 (d, 1H), 7.64 (I, 1H), 7.42 (m, 2H), 7.32 (d, 1H), 7.24 (t, 1H), 7.13 (t: IH), 7.07 (d, 1H), 5.15 (s, 1H), 4.00-3.70 (m, 8H), 3.28 (s, 2H), 2.94 (m, 2H), 2.78 (m, 2H), 2.28 (s. 3H), 1.89-1.60 (m, 6H), 1.53 (s, 6H) ppm.

Example 52 Synthesis of4~(2-(difluoromethyl)-lH-bcnzoMimidazol-l -yl)-N-(I -(2»( l-ethylpipcridiu—4~ prhenyD-Z-metbylpropanyl)morpholino-l ,3.5-triazin—2~amine A70 A mixture ofcompound A68 (0.14 g. 0.25 mmol), sodium cyannhnmhydride RECTIFIED SHEET (RULE 91) (19 mg, 0.30 mmol), 40% aq. acetaldehyde (2 mL), and ropylethylamine (0.16 g, 1.2 mmol) in acetonitrile (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under vacuum and the residue was d by prep-HPLC to give compound A70 (35 mg, 24% yield) as a white solid: 99% purity (HPLC); MS m/z: 591.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.37 (d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.41 (m, 2H), 7.35 (d, 1H), 7.24 (t, 1H), 7.13 (t, 1H), 7.07 (d, 1H), 5.17 (s, 1H), 4.00-3.71 (m, 8H), 3.28 (s, 2H), 3.08 (m, 2H), 2.85 (m, 1H), 2.46 (m, 2H), 1.91 (m, 4H), 1.70 (m, 2H), 1.53 (s, 6H), 1.11 (t, 3H) ppm.

Example 53 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2-(1-isopropylpiperidin- 4-yl)phenyl)methylpropanyl)morpholino- 1 ,3 ,5 -triazinamine A71 i \ N (\N N/ N 0Q H A mixture of nd A68 (70 mg, 0.12 mmol), acetone (2 mL), panol (2 mL), and glacial acetic acid (38 mg, 0.62 mmol) in a sealed vial was stirred at 120 0C for 2 hrs. After the mixture was cooled to room temperature, sodium borohydride (24 mg, 0.62 mmol) was added and the sealed vial was stirred at 80 0C for another 3 hrs. The reaction mixture was basified with saturated aqueous sodium bicarbonate to pH 8. The volatiles were removed under reduced pressure and the residue was purified by prep-HPLC to give compound A70 (40 mg, 53% yield) as a white solid: 97% purity ; MS m/z: 605.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.38 (d, 1H), 7.91 (d, 1H), 7.64 (t, 1H), 7.49-7.35 (m, 3H), 7.24 (t, 1H), 7.13 (t, 1H), 7.07 (d, 1H), 5.15 (s, 1H), 4.01-3.73 (m, 8H), 3.28 (s, 2H), 2.97 (m, 2H), 2.80 (m, 2H), 2.05 (m, 2H), 1.78 (m, 2H), 1.70 (m, 2H), 1.53 (s, 6H), 1.04 (s, 6H) ppm. —224— Example 54 sis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-(2-methyl(2-(1 - acetylpiperidinyl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A72 1S1“ (\N N/ N 0Q H ] A mixture of compound A68 (50 mg, 0.089 mmol), acetyl bromide (22 mg, 0.18 mmol), and triethylamine (27 mg, 0.27 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hrs. The volatiles were removed under vacuum and the e was purified by prep-HPLC to give compound A72 (26 mg, 48% yield) as a white solid: 99% purity (HPLC); MS m/z: 605.3 (M+1); 1H NMR (CDC13, 500 MHz) 5 8.36 (d, 1H), 7.91 (d, 1H), 7.64 (t, 1H), 7.42 (m, 2H), 7.28-7.20 (m, 2H), 7.15 (t, 1H), 7.08 (d, 1H), 5.15 (s, 1H), 4.78 (m, 1H), 4.00-3.74 (m, 9H), 3.42 (d, 1H), 3.20 (d, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.48 (m, 1H), 2.10 (s, 3H), 1.79-1.58 (m, 4H), 1.57 (s, 3H), 1.50 (s, 3H) ppm.

Example 55 Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-(2-methyl(2-(1 - (methylsulfonyl) piperidinyl)phenyl)propanyl)morpholino-1,3 ,5-triazinamine A73 (\NAN/ N 0Q H /§\\O A mixture of compound A68 (50 mg, 0.089 mmol), methanesulfonyl chloride (51 mg, 0.44 mmol), and triethylamine (90 mg, 0.89 mmol) in dichloromethane (4 mL) was stirred at room temperature for 1 hr. The volatiles were removed under vacuum and the residue was purified by prep-HPLC to give compound A73 (22 mg, 38% yield) as a white solid: 99% purity (HPLC); MS m/z: 641.3 (M+l); 1H NMR(CDC13, 500 MHz) 5 8.37 (d, 1H), 7.91 (d, 1H), 7.63 (t, 1H), 7.42 (m, 2H), 7.27 (m, 2H), 7.17 (m, 1H), 7.08 (d, 1H), 5.18 (s, 1H), 3.97-3.71 (m, 10H), 3.29 (s, 2H), 2.92 (m, 1H), 2.76 (s, 3H), 2.59 (m, 2H), 1.90-1.74 (m, 4H), 1.52 (s, 6H) ppm.

Example 56 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(2-methyl(2-(pyrrolidinyl)phenyl)propanyl)morpholino-1 ,3 ,5 -triazinamine A74 < :Z—N\ N CHF2 |/\N N/ N 0Q H nd A74 was synthesized ing to the procedure for compound A68, substituting N-Boc-2,5-dihydropyrroleboronic acid pinacol ester in place ofN-Boc- l,2,5,6-tetrahydropyridineboronic acid pinacol ester. The crude t was purified by prep-HPLC to give compound A74 (13 mg) as a white solid: 92% purity (HPLC); MS m/z: 549 (M+l); 1H NMR (CDC13, 500 MHz) 5 8.39 (d, 1H), 7.90 (d, 1H), 7.67 (t, 1H), 7.42 (m, 2H), 7.35 (d, 1H), 7.27 (t, 1H), 7.14 (t, 1H), 7.05 (d, 1H), 5.23 (s, 1H), 3.97-3.74 (m, 8H), 3.68 (m, 1H), 3.47-3.25 (m, 4H), 3.17 (m, 1H), 2.93 (m, 1H), 2.25 (m, 1H), 1.92 (m, 1H), 1.51 (s, 6H) ppm.

Example 57 sis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazolyl)-N-(2-methyl(2-(1 - methylpyrrolidinyl)phenyl)propanyl)morpholino- 1 ,3 ,5 -triazinamine A75 N CHF2 (\NAN/ N 0Q H Compound A75 was synthesized according to the procedure for compound A69, substituting A74 in place of nd A68. The crude product was purified by prep- HPLC to give compound A75 (21 mg) as a White solid: 98% purity (HPLC); MS m/z: 563.4 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.40 (d, J: 7.5 Hz, 1H), 7.91 (d, J: 7.5 Hz, 1H), 7.65 (t, JHF = 53.5 Hz, 1H), 7.50-7.38 (m, 3H), 7.26 (t, J: 7.0 Hz, 1H), 7.11 (t, J: 7.5 Hz, 1H), 7.01 (d, J: 7.5 Hz, 1H), 5.19 (s, 1H), 3.97-3.70 (m, 9H), 3.32 (s, 2H), 2.98 (m, 1H), 2.85 (m, 1H), 2.72 (m, 1H), 2.48 (m, 1H), 2.43 (s, 3H), 2.34 (m, 1H), 1.88 (m, 1H), 1.51 (s, 3H), 1.48 (s, 3H) ppm.

Example 5 8 Synthesis of 4-(2-(difluoromethyl)-1H—benzo[d]imidazolyl)-N-(1-(2-(3 - (dimethylamino)propyl)phenyl)methylpropanyl)morpholino-1 ,3 ,5-triazinamine ] A solution of compound A17 (0.30 g, 0.54 mmol), 1-dimethylamino propyne (0.13 g, 1.6 mmol), bis(triphenylphosphine)palladium(H) chloride (76 mg, 0.11 mmol), and cuprous iodide (21 mg, 0.11 mmol) in N,N’-dicyclohexylmethylamine (12 mL) was stirred at 150 0C for 24 hrs. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate, and concentrated under vacuum to give crude 4-(2_ {difluoromethyl}1H“benzo [ti]imidazoln l nyl)nN~( l “(243{dimethyla.mino)propw l nyn— 1 ~ yl)phenyl)~2~methylpropan~2~yl)~6—morpholino—l ,3,5~triazin~2—amine (200 mg) as yellow oil, which was used directly in the next step without further purification: MS m/z: 561 (M+l).

A mixture of the crude alkyne (120 mg, 0.21 mmol) and 10% Pd/C (40 mg) in methanol (30 mL) was stirred under hydrogen at room temperature overnight. The reaction mixture was ed through Celite and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC to give compound A76 (20 mg, 17% yield) as a white solid: 98% purity (HPLC); MS m/z: 565.3 (M+1); 1H NMR(CDC13, 500 MHz) 5 8.41 (d, 1H), 7.90 (d, 1H), 7.69 (t, 1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.13 (m, 1H), 7.05 (d, 1H), 5.31 (s, 1H), 3.95-3.75 (m, 8H), 3.26 (s, 2H), 2.80-2.24 (m, 10H), 1.88 (m, 2H), 1.51 (s, 6H) ppm.

Example I A luciferase-based luminescence assay PI3K catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) and ATP to atidylinositol-3,4,5-trisphosphate (PIP3) and ADP. For all assays, the reaction buffer comprised 50 mM HEPES, pH 7.5, 3 mM MgC12, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS and 2 mM DTT. Compounds for testing were ved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted 1:25 in reaction buffer.

PI3K alpha and PI3K delta enzymatic activity was determined by measuring the amount ofATP consumed ing the kinase reaction using a luciferase-based luminescence assay (Kinase Glo®, Promega Corp., Madison, WI, USA). PI3K enzyme solutions were prepared by diluting PI3K alpha (Invitrogen Corp., Carlsbad, CA, USA) or PI3K delta (Millipore, ica, MA, USA) in on buffer, to 4x the final assay concentration (final trations of enzymes were 1.65 nM and 6.86 nM for PI3K alpha and PI3K delta, respectively). A ate solution was prepared by mixing PIP2 and ATP in on buffer at 2x the final assay concentration (final concentrations were 50 uM and 25 uM for PIP2 and ATP respectively). 2.5 uL each of the compound and kinase mixtures were added to individual wells of white low volume 384-well assay plates and mixed by shaking.

The reactions were started by adding 5 uL of substrate mixture per well and shaking. The assay plates were covered and reactions were allowed to d for 1 hour (PI3K alpha) or 2 hours (PI3K delta), after which 10 uL of Kinase Glo® reagent was added. The plates were briefly centrifuged and ted for 10 s, after which luminescence was measured using a FlexStation plate reader (Molecular Devices, Sunnyvale, CA, USA). IC50 values were determined by curve fitting using Graphpad Prism software (Graphpad Software, La Jolla, CA, USA).

PI3K beta and gamma enzymatic activity was determined by measuring the amount ofADP produced following the kinase on using a luciferase-based luminescence assay (ADP Glo®, Promega Corp., Madison, WI, USA). PI3K enzyme solutions were prepared by diluting PI3K beta (Millipore, Billerica, MA, USA) or PI3K gamma (Invitrogen Corp., Carlsbad, CA, USA) in reaction , to 4x the final assay concentration (final concentrations of enzymes were 4.8 nM and 7.6 nM for PI3K beta and PI3K gamma respectively). A substrate on was prepared by mixing PIP2 and ATP in reaction buffer at 2x the final assay concentration (final concentrations were 50 uM and 25 uM for PIP2 and ATP respectively). 2.5 uL each of the compound and kinase es were added to individual wells of white low volume 384-well assay plates and mixed by shaking.

The ons were started by adding 5 uL of substrate mixture per well and shaking. The assay plates were covered and reactions were allowed to proceed for 1 hour. Then, 5 uL of reaction mix was transferred to another white low volume 384-well plate, and 5 uL ofADP- GloTM reagent was added. The plates were briefly centrifuged and incubated for 40 minutes, after which 10uL of kinase detection buffer was added. The plates then were centrifuged briefly, shaken slowly and equilibrated at room ature for 30 s, after which luminescence was measured using a FlexStation plate reader (Molecular s, Sunnyvale, CA, USA). IC50 values were determined by curve fitting using ad Prism software (Graphpad Software, La Jolla, CA, USA).

The biological results of inhibition of enzymatic activity of PI3Ks are summarized in Table 1, wherein A represents a value no greater than 100 nM, B represents a value greater than 100 nM but less than 200 nM, C represents a value no less than 200 nM but no greater than 500 nM, and D represents a value greater than 500 nM; and wherein A’ represents a ratio of greater than 20, B’ represents a ratio of no greater than 20 but no less than 10, C’ represents a ratio of no greater than 10 but no less than 5, and D’ represents a ratio of no greater than 5.

TABLE 1. Biological Activity IC50 (1/6 7/6 (1/3 ratio ratio ratio ratio 110a 1106 Ref. 1 -- :9NH -- 3232mm» OUUUUUUUUW I!“ owoo> UUU OOOUO U |D§>O>UUUW>>>W>>>>>>UU U |>wow>>>w>>>>>>oo> UUUUUUUUUUUUUUU DO WC O > DU ICso (1/6 [3/5 7/6 /I3 Compound racu0 racu0 ratio ratlo 1 1 0a m11 m11 1 1 0v0 m0R A35 A A73 DDCDCCBCCDDDDDDDDCDDDDDDDBCDD AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA DDDDDDDDDDDDDDDDDDDDDDDDDDDDDD ,A,A,A,A,A,A,A,A,A,A,A,A,C,A,A,A,A,A,A,A,A,A,A,A,A,A,A,A,A,A Innaflnnnnflnflflflnnnflflnnflflflnflnnflfln ] In Table l, the (1/8 ratio is the ratio of the IC50 value of a compound against PK3KOL over the IC50 value of the same compound against PK3K8; and Ref. 1 is N—benzyl (2-(difluoromethyl)-1H-benz0[d]imidazol- l -yl)m0rpholino- l ,3 ,5 -triazinamine. -23l- W0 2012/135160 Example 11 ELISA assay for PI3KB Cellular PI3KB activity was determined by measuring the phosphorylation of AKT (Ser473) using an l ELISA assay. PC-3 (prostate carcinoma) cells were obtained from ATCC (ATCC # CRL-1435). Growth medium was DMEM (CellGro # CV013-CV) supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 ug/mL streptomycin, and 1x MEM non-essential amino acids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KCl, 86 mM Na3P04 (dibasic, anhydrous), 28 mM K3P04 (monobasic, ous), pH 7.2. 10x stimulation mixture ned 50 uM LPA (Cayman # 62215) d in serum-free DMEM medium (CellGro # CV013-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted in serum-free DMEM to 2x final assay concentration. 2x fixative solution contained 8% formaldehyde (Amresco # M134) diluted in PBS. Permeabilization solution contained PBS supplemented with 0.1% Triton X-100. Blocking buffer was obtained from LiCor (LiCor # 927-40000). Wash buffer contained PBS supplemented with 0.1% Tween-20. Primary antibody solution was rabbit anti-pAKTS473 monoclonal antibody (Cell Signaling # 4060) and mouse anti-total S6 (Santa Cruz # 74459) diluted 1:500 and 1:2000, respectively, in blocking buffer. Secondary dy solution was IRDye conjugated goat anti-rabbit IgG (LiCor # 926-32211) and IRDye 680LT-conjugated goat anti-mouse IgG (LiCor # 926-68020) diluted 1:2000 and , respectively, in blocking . [005 86] PC-3 cells were subcultured in growth medium and seeded into flat, clear bottom, l plates (Corning # 3904) at 16000 cells/well, then incubated overnight in a 37 °C, 5% C02 incubator. Growth medium in plates was replaced with 100 uL/well serum- free DMEM and incubated overnight in a 37 oC, 5% C02 incubator. 50 uL/well of fresh serum-free DMEM was added to . Compound treatment was med by adding 50 uL/well of 2x compound mixture to plates and incubating for 2 hrs at 37 CC, 5% C02, after which 11 uL/well of 10x stimulation mixture was added and plates were incubated for 10 min at 37 oC, 5% C02. Fixation was performed by adding 110 uL/well of 2x fixative solution to plates and incubating for 20 min at room temperature. Permeabilization was performed by replacing fixation on with 150 uL/well permeabilization on and incubating for 10 min at room temperature. Permeabilization was repeated (for a total of 2 times).

Permeabilization solution was replaced with 100 uL/well blocking buffer and plates were W0 2012/135160 incubated for 1 hr at room temperature, after which 100 uL/well of primary antibody solution was added and plates were incubated ght at 4 oC. Plates were washed with wash buffer, after which 100 uL/well of secondary antibody solution was added to the plates and incubated in the dark for 1 hr at room temperature. Plates were washed with wash , ed by a wash with PBS. After completely removing PBS, plates were scanned on the Licor Odyssey Imager. Images quantified using Licor Odyssey ation software. IC50 values were determined by curve fitting using a Collaborative Drug Discovery database (www.collaborativedrug.com). e III ELISA assay for PI3K5 Cellular PI3K5 activity was determined by measuring the phosphorylation of AKT (Thr308) using a sandwich enzyme-linked immunosorbant assay ). Raj i (Burkitt’s Lymphoma) cells were ed from ATCC (ATCC # CCL-86). Phosphate buffer saline (PBS) contained 2.7 M NaCl, 54 mM KCl, 86 mM Na3P04 (dibasic, anhydrous), and 28 mM K3P04 (monobasic, anhydrous) at pH 7.2. Wash buffer contained PBS supplemented with 0.05% Tween-20. Blocking buffer contained wash buffer supplemented with 1% BSA.

A 10x stimulation mixture contained 5 ug/mL anti-Human IgM antibody (Sigma # I23 86) diluted in serum-free RPMI medium (CellGro # CV040-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), and then diluted in serum-free RPMI to 5 x final assay concentration.

Raj i cells were subcultured in RPMI medium supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 ug/mL streptomycin, and 1x MEM non-essential amino acids. Sandwich ELISA plates were prepared by coating 96-well assay plates (Pierce # 15042) with 100 uL/well e antibody (Cell Signaling Technology # 7142 or 7144) diluted in PBS. Plates were incubated overnight at 4 CC, then washed with wash buffer, after which 200 uL/well blocking buffer was added to the plates and incubated at room temperature for at least 2 hrs. Raj i cells were ended in serum-free RPMI medium and seeded into V-bottom, 2-mL 96-well blocks (Corning # 3961) at 106 cells/well, then incubated for 2 hrs in a 37 °C, 5% C02 tor. Compound treatment was performed by adding the 5 x compound mixture to the cells and incubating for 2 hrs at 37 CC, 5% C02, after which the 10x stimulation e was added to the plates and incubated for 30 min at 37 CC, % C02. Cells were pelleted by centrifuging plates at 1500 RPM for 5 min at room temperature. Media was carefully removed and cells were lysed by adding 100 uL/well cell lysis buffer (Cell Signaling Technology # 9803) supplemented with protease and phosphatase inhibitors (Thermo Fisher # 78443). Plates were incubated on ice for 30 min, then the lysates (80 uL for pAKTTgOS, 10 uL for total AKT) were transferred to prepared assay plates and incubated at 4 CC ght. After washing plates with wash buffer, 100 uL/well detection antibody (Cell Signaling Technology # 7142 or 7144) diluted in blocking buffer was added to the plates and incubated for 1 hr at 37 CC. Plates were washed and 100 uL/well of HRP- conjugated secondary antibody (Cell Signaling Technology # 7142 or 7144) diluted in blocking buffer was added to plates and incubated for 1 hr at room temperature. Plates were washed with wash buffer and 100 uL/well of luminescent substrate was added to plates.

After 1 min on a plate shaker at medium speed, luminescence was read on a Wallac Victor2 plate reader. IC50 values were determined by curve fitting using a orative Drug Discovery se (www.collaborativedrug.com).

Example IV ELISA assay for PI3K0L PI3K alpha (PI3K0L) activity was determined by measuring the phosphorylation ofAKT (Thr308) using an in-cell ELISA assay. MDA-MB-453 (breast carcinoma) cells were obtained from ATCC (ATCC # HTB-l3 1). Growth medium was DMEM ro # 013-CV) supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 ug/mL streptomycin, and 1 x MEM non-essential amino acids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KCl, 86 mM N33PO4 (dibasic, ous), and 28 mM K3PO4 (monobasic, ous) at pH 7.2. Stimulation mixture (10 x) was 1000 ng/mL LONG® R3 human IGF-l (Sigma # 11271) diluted in serum-free DMEM medium ro # CV013-CV). Compounds for testing were ved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted in serum-free DMEM to 2 x final assay concentration. Fixative solution (2 x) was 8% formaldehyde (Amresco # M134) diluted in PBS. Permeabilization solution was PBS supplemented with 0.1% Triton X-100.

Blocking buffer was obtained from LiCor (LiCor # 927-40000). Wash buffer was PBS supplemented with 0.1% Tween-20. Primary antibody on was rabbit AKTT308 monoclonal antibody (Cell Signaling # 2965) and mouse anti-total S6 (Santa Cruz # 74459) diluted 1:500 and 1:2000, respectively, in the blocking buffer. Secondary dy solution —234— was IRDye conjugated goat anti-rabbit IgG (LiCor # 926-32211) and IRDye 680LT- conjugated goat anti-mouse IgG (LiCor # 926-68020) diluted 1:1000 and 12000, respectively, in the blocking buffer.

] MDA-MB-453 cells were subcultured in growth medium and seeded into flat, clear bottom, 96-well plates ng # 3904) at 40000 cells/well, then incubated overnight in a 5% C02 incubator at 37 oC. Growth medium in plates was replaced with 100 uL/well serum-free DMEM and incubated overnight at 37 0C in a 5% C02 incubator. Fresh serum- free DMEM (50 l) was added to plates. Compound treatment was performed by adding 50 uL/well of 2 x compound mixture to plates and incubating for 1 hr at 37 CC and 5% C02, after which 11 uL/well of 10 x stimulation mixture was added and plates were incubated for 10 min at 37 CC and 5% C02. Fixation was performed by adding 110 uL/well of 2 x fixative solution to the plates and ting for 20 min at room temperature.

Permeabilization was performed by replacing fixation solution with 150 uL/well permeabilization solution and incubating for 10 min at room temperature. Permeabilization was repeated (for a total of 2 times). Permeabilization solution was replaced with 100 uL/well ng buffer and plates were ted for 1 hour at room temperature, after which 100 uL/well of primary antibody solution was added and plates were incubated overnight at 4 CC. Plates were washed with wash buffer, after which 100 l of secondary antibody solution was added to the plates and incubated in the dark for 1 hr at room temperature. Plates were washed with wash buffer, followed by a wash with PBS.

After completely removing PBS, plates were scanned on the Licor Odyssey Imager. Images were fied using Licor Odyssey application software. IC50 values were determined by curve fitting using a Collaborative Drug Discovery database (www.collaborativedrug.com).

Example V ELISA assay for PI3Ky PI3K gamma (PI3Ky) activity was ined by measuring the phosphorylation ofAKT (Ser473) using an in-cell ELISA assay. RAW 264.7 (mouse macrophage) cells were ed from ATCC (ATCC # TIB-7l). Growth medium was DMEM (CellGro # CV013-CV) supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, 100 ug/mL streptomycin, and 1 x MEM non-essential amino acids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KCl, 86 mM Na3PO4 (dibasic, W0 2012/135160 ous), and 28 mM K3PO4 asic, anhydrous) at pH 7.2. Stimulation mixture (10 x) was 500 ng/mL recombinant human complement component C5a (R&D systems # 2037- C5-025) diluted in serum-free DMEM medium (CellGro # CV013-CV). Compounds for testing were dissolved and serially diluted in 100% DMSO (total of 10 concentrations), then diluted in serum-free DMEM to 2 x final assay concentration. Fixative solution (2 x) was 8% formaldehyde (Amresco # M134) diluted in PBS. Permeabilization solution was PBS supplemented with 0.1% Triton X-100. Blocking buffer was obtained from LiCor (LiCor # 927-40000). Wash buffer was PBS supplemented with 0.1% Tween-20. Primary antibody solution was rabbit anti-pAKTS473 monoclonal antibody (Cell Signaling # 4060) and mouse anti-total S6 (Santa Cruz # 74459) d 1:500 and 1:2000, respectively, in the blocking buffer. Secondary antibody solution was IRDye 800CW-conjugated goat abbit IgG (LiCor # 926-32211) and IRDye 680LT-conjugated goat ouse IgG (LiCor # 926-68020) diluted 1:1000 and 1:2000, respectively, in the blocking buffer.

RAW 264.7 cells were subcultured in growth medium and seeded into flat, clear bottom, 96-well plates (Corning # 3904) at 70000 cells/well, then incubated overnight in a 37 °C, 5% CO2 incubator. Growth medium in plates was replaced with 100 l serum-free DMEM and incubated ght in a 37 °C, 5% CO2 incubator. Fresh serum-free DMEM (50 uL/well) was added to plates. Compound treatment was performed by adding 50 uL/well of 2 x compound mixture to plates and incubating for 2 hrs at 37 CC, 5% CO2, after which 11 uL/well of 10 x stimulation mixture was added and plates were incubated for 3 min at 37 °C, 5% CO2. Fixation was performed by adding 110 uL/well of 2 x fixative solution to plates and ting for 20 min at room temperature. Permeabilization was performed by replacing fixation solution with 150 l permeabilization solution and ting for 10 min at room temperature. Permeabilization was repeated (for a total of 2 times).

Permeabilization solution was ed with 100 uL/well blocking buffer and plates were ted for 1 hr at room temperature, after which 100 uL/well of primary antibody solution was added and plates were incubated overnight at 4 oC. Plates were washed with wash buffer, after which 100 uL/well of secondary antibody solution was added to the plates and incubated in the dark for 1 hr at room temperature. Plates were washed with wash buffer, followed by a wash with PBS. After completely removing PBS, plates were scanned on the Licor Odyssey Imager. Images were quantified using Licor y application re.

IC50 values were determined by curve fitting using a orative Drug Discovery database (www.collaborativedrug.com).

] The biological results of inhibition of cellular enzymatic activity of PI3Ks are summarized in Table 2, wherein A, B, C, D, A’, B’, C’, and D’ are each as defined in Table l.

TABLE 2 C°mp°und ratio A14 n—--A’ A15 n—--> C’ 3i? Q A III > CO IIII!!! 2D: 2D: Q 3i? 03> u HHI 220 22>, as: Ha: a: m H3i 3i >0 H3i 3i >>D> a: a: >u >D> WOOO> >00 IIllllllllllllllllllllllllH Dikuiuiui? O w iii!!! uuuwuwuwu 22226U> O a 22>»: >u H3i 3i H3i 3i IIIIIIIIHHIIIIHHIIIIIIIIIIIIHIH>> a ratio A66 n—-- B’ A66 nm--D> A’ A68 III >D>O 0U A70 IIIHi! >629: A75 IIIII >>>>> WO>>UU Hill!EH!!! 09060.3:9: A76 I > U IH a: ***** The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein.

Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are orated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims (113)

1. l. A compound ofFormula I: R3 X JL . (\“N DC \z N‘X’MR 0V\J H R58 R5b or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or e thereof; wherein: X, Y, and Z are each ndently N or CRX, with the proviso that at least two of X, Y, and Z are nitrogen atoms; Where Rx is hydrogen or C16 alkyl; R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C16 alkyl, C26 alkenyl, C26 l, Cuo lkyl, C514 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)Rla, —C(O)OR1’, —C(0)NR“’R1°, —C(NR1‘)NR"’R1°,—OR1‘, —OC(O)R1", —OC(O)OR1“, —OC(0)NR“'R‘°, —OC(=NR“')NR"’R1°, R1“, —OS(O)2R1", — OS(O)NR“’R1°,—OS(O)2NR“’R1°,—NR“’R1°, —NR1“C(O)R1“, —NR1“C(O)OR”, —NR1’C(O)NR"’R1°, —NR1’C(=NR“)NR“’R1°, (O)R”, —NR1“S(O)2RI‘1, —NR1‘S(O)NR"’R1°,—NR1’S(O)2NR"’R1°, —SR1=, —S(O)Rl‘, —S(O)2Rl‘, —S(O)NR“’R1°, or —S(O)2NR"’R1°; wherein each R“, R“’, R1“, and R1‘1 is independently (i) hydrogen; (ii) C1-6 alkyl, C26 alkenyl, C26 alkynyl, C3—1o cycloalkyl, C6-14 aryl, C7—15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R“ and Rlc together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently en or C16 alkyl; or R3 and R4 are linked together to form a bond, C16 alkylene, C16 heteroalkylene, C26 lene, or C26 heteroalkenylene; R5a is (a) hydrogen or halo; (b) C16 alkyl, C26 alkenyl, C26 alkynyl, C3-1o cycloalkyl, C6-14 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1“, —C(O)OR1a,—C(O)NR“’R1“, —C(NR“)NR"’R1°, —0R1“, —0C(O)Rl‘, —OC(O)OR1", —OC(O)NR"’R1°,—0C(=NR“)NR“’R1‘, —OS(O)R1“, —OS(O)2R1‘,—OS(O)NR"’R1°, —OS(O)2NRle1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)ORld, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°,—OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)Rld, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R50 is —(CR5fR5g)n—(C6_14 aryl) or —(CR5fR5g)n—heteroaryl; R5d and RS‘3 are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, a)NR1bR1°, —0R1a, R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —OS(O)2NR1bR1°, 1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NRle1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°; R5f and ng are each independently (a) hydrogen or halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, 2R1a, NR1bR1°, —OS(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, (O)2R1d, —NR1aS(O)NRle1°, (O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, R1bR1°; or —S(O)2NR1bR1°; or (d) when one occurrence of R5f and one occurrence of ng are attached to the same carbon atom, the R5f and ng er with the carbon atom to which they are attached form a C340 lkyl or heterocyclyl; R6 is hydrogen, C1_6 alkyl, —S—C1_6 alkyl, —S(O)—C1_6 alkyl, or —SOz—C1_6 alkyl; n1 is 0 or 1; and nis 0, l,2,3,or4; —240— WO 35160 wherein each alkyl, alkylene, alkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, lkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, R4, R6, RX, R”, Rlb, R”, R“, R52 RSb, R5“, RSd, R53, R“, and R5g is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, and heterocyclyl, each of which is filrther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbR°, —C(NRa)NRbR°, —0Ra, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbR°, —OC(=NRa)NRbR°, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbR°, —OS(O)2NRbR°, —NRbR°, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbR°, —NRaC(=NRd)NRbR°, —NRaS(O)Rd, —NRaS(O)2Rd, O)NRbR°, O)2NRbR°, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbR°, and —S(O)2NRbR°, n each Ra, Rb, RC, and Rd is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one ment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is fiarther optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently ed from the group ting of (a) oxo, cyano, halo, and nitro; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRng, )NRng, —0Re, —OC(O)Re, —OC(O)ORe, —OC(O)NRng, —OC(=NRe)NRng, —OS(O)Re, —OS(O)2RB, —OS(O)NRng, —OS(O)2NRng, —NRng, —NReC(O)Rh, —NReC(O)ORh, O)NRng, —NReC(=NRh)NRng, —NReS(O)Rh, —NReS(O)2Rh, O)NRng, —NReS(O)2NRng, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRng, and —S(O)2NRng; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C7_1 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
2. 2. The compound of claim 1, wherein the compoud is not 4-(2-(difluoromethyl)- 1H-benzo[d]imidazol- l -yl)morpholino-N-(2-phenyl(pyrrolidin- l -yl)ethyl)- l ,3 ,5 -triazin- 2-amine or 6-(2-(difluoromethyl)- lH-benzo [d]imidazol- l -yl)-N-( l -(4-((R)-3 - (methoxymethyl)morpholino)phenyl)ethyl)morpholinopyrimidinamine. —241—
3. 3. The nd of claim 1, wherein R5b is (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, or heteroaryl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1°, a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, —S(O)2NR1bR1°, —NR1bR1°, —NR1aC(O)R1d, —NR1aC(O)OR1d, (O)NR1bR1°, —NR1aC(=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2Rld, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°.
4. 4. The compound of claim 1, wherein R5&1 and R5b are each independently (a) halo; (b) C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C340 cycloalkyl, C644 aryl, C745 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, R1a, —C(O)NR1bR1°, —C(NR1a)NR1bR1°, —0R1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1°, —OC(=NR1a)NR1bR1°, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1°, 2NR1bR1°, —NR1bR1°, (O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1°, (=NR1d)NR1bR1°, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1°, —NR1aS(O)2NR1bR1°, —SR1a, —S(O)R1a, R1a, —S(O)NR1bR1°, or —S(O)2NR1bR1°.
5. 5. The compound of claim 4, wherein R5&1 and R5b are each methyl, optionally substituted with one or more halo.
6. 6. The compound of any one of claims 1 to 5, wherein n is l.
7. 7. The compound of any one of claims 1 to 6, wherein R5f and ng are each hydrogen.
8. 8. The compound of any one of claims 1 to 5, wherein n is 0.
9. 9. The compound of any one of claims 1 to 8, wherein m is 0. —242—
10. 10. The compound of any one ofclaims 1 to 9, having the structure ofFormula Ia: R3 X IY RSd R56 F N \Z/LN99wR 0\/\/' H RSa R5b (Ia) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
11. 11. The compound of any one ofclaims 1 to 9, having the ure ula Ib: R3 X r\’\N )KNDQIPXR5C 0 \J H R53 RSb (lb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
12. 12. The compound of any one of claims 1 to 8, having the structure ofFormula II: R2\II \ N / »\ R6 or an isotopic variant thereof; or a pharmaceutically able salt, solvate or hydrate thereof.
13. 13. The compound of claim 12, having the structure ofFormula IIa: R-\// \ N / »\ R6 (Ha) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate f.
14. 14. The compound of claim 12, having the structure ofFormula IIb: R\,’2 \ N / »\R6 - X Y R’ R53 Rab r\’\ N J\\ZANI R50 0V\J H 01b) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof
15. 15. The compound of any one ms 1 to 14, wherein R5c is Can aryl, optionally substituted with one or more substituents Q.
16. 16. The compound of claim 15, wherein R5“ is phenyl, ally substituted with one or more substituents Q.
17. 17. The compound of claim 15, wherein R5c is naphthyl, optionally tuted with one or more substituents Q.
18. 18. The compound of any one ofclaims 1 to 14, wherein R5c is —(CR5f.RSg)u—(C6-l4 aryl), wherein the aryl is optionally substituted with one or more substituents Q.
19. 19. The compound of claim 18, wherein R5c is –phenyl, wherein the phenyl is optionally substituted with one or more substituents Q.
20. 20. The compound of claim 18, wherein R5c is –(CH2)–naphthyl, wherein the naphthyl is ally substituted with one or more tuents Q.
21. 21. The compound of any one of claims 1 to 14, wherein R5c is aryl, optionally substituted with one or more substituents Q.
22. 22. The compound of claim 21, wherein R5c is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
23. 23. The compound of claim 21, wherein R5c is 5- or 6-membered heteroaryl, optionally substituted with one or more substituents Q.
24. 24. The compound of claim 21, wherein R5c is bicyclic aryl, optionally substituted with one or more substituents Q.
25. 25. The compound of any one of claims 1 to 14, wherein R5c is –(CR5fR5g)n–heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents Q.
26. 26. The compound of claim 25, wherein R5c is –(CR5fR5g)n–(monocyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
27. 27. The compound of claim 25, wherein R5c is –(CR5fR5g)n–(5- or 6-membered heteroaryl), wherein the heteroaryl is ally substituted with one or more tuents Q.
28. 28. The compound of claim 25, wherein R5c is –(CR5fR5g)n–(bicyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
29. 29. The compound of any one of claims 1 to 12, having the ure of Formula VII: R'\/ \ N / k J\\ZI va OV\J H R76 R79 R4 R7d (VII) or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate f; wherein: R7“, R7”, R7“, R7“, and K“ are each independently (a) hydrogen, cyano, halo, or nitro; (b) C14; alkyl, C24; alkenyl, C24 alkynyl, C3-1o cycloalkyl, C6-14 aryl, C7.15 aralkyl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q; or (c) —C(0)R‘=, —C(O)OR1", —C(O)NR"’R1°,—C(NR1‘)NR"’R‘°, —0R1a, —0C(0)R1‘, —OC(0)OR1", —0C(0)NR"’R1°,—0C(=NR1‘)NR"’R1°, R1“, —OS(O)2R“, —OS(0)NR"’R‘°, —OS(O)2NR“’R1‘, —NR"’R1°, (O)R1“, (O)OR”, —NR1aC(O)NR"’Rl°, —NR1‘C(=NR“)NR“'R1°, —NRlaS(O)R”, —NR“'S(O)2R”, —NR1"S(O)NR“’R1°,—NR1“S(O)2NR“’R1°, —SR", —S(O)Rla, —S(O)2Rla, —S(O)NR“’R1°, or —S(O)2NR"’R1°; or two of R7“, R7”, R72 R“, and Rh that are adjacent to each other form C3_1o cycloalkenyl, C514 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
30. 30. The compound of claim 29, having the structure ofFormula VIIa: R2 I \ \, N / »\R6 X Y R53 RSb R721 R\/\3 I \ >41, R7b r N Z E O\/ J R76 R76 R4 R7d Wlla) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
31. 31. The compound of claim 29, having the structure ofFormula VIIb: or an isotopic valiant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
32. 32. The compound of any one ofclaims 1 to 12, having the structure of a XI: R\I/2 \ N / NkR6 3 KAY RSaRSIJRh R\/\ \ J\ 7d r N z N R o\,\J H RSf R5g R” (X1) or an enantiomer, a mixture of enantiomers, a e of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or e thereof; R7“, R7”, R7“, R7“, and Rh are each independently (a) hydrogen, cyano, halo, or nitro; (b) C14; alkyl, C245 alkenyl, C24 alkynyl, C3-1o lkyl, C514 aryl, €7.15 aralkyl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q; or (c) “, —C(O)OR1‘, —C(O)NR"’R1°,—C(NR1")NR"’R'°, 4m“, —OC(O)R", —OC(O)OR1", —OC(0)NR“’R1°,—0C(=NR1‘)NR"’R1°, 03mm“, —OS(0)2R", —OS(0)NR"’R'°, —OS(O)2NR"’R1°, —NR“’R1°, —NR“'C(0)R1“, —NR1‘C(O)OR”, —NR1“C(O)NR"’R1°, —NR1‘C(=NR“)NR“’R1°, —NR1"S(O)R”, —NRlaS(O)2RId, (O)NR"’R1°,—NR1‘S(O)2NR“’R1°, —SR1“, —S(O)R1‘,—S(O)2R1‘,—S(O)NR“’R1°, or —S(O)2NR“’R1°; or two of R7”, R7”, R7“, R“, and Rh that are adjacent to each other form €3-10 cycloalkenyl, C6-l4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
33. 33. The compound of claim 32, having the structure ofFormula XIa: or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
34. 34. The nd of claim 32, having the ure ofFormula XIb: or an ic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
35. 35. The compound of any one ofclaims 32 to 34, wherein R7” is hydrogen, halo, C1—6 alkyl optionally substituted with one or more substituents Q, or —0R1".
36. 36. The compound of claim 35, wherein R7a is hydrogen.
37. 37. The compound of claim 35, wherein R7“ is (a) cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or cyclyl, each of which is optionally substituted with one or more substituents Q; or (c) – a, –C(O)OR1a, –C(O)NR1bR1c, –C(NR1a)NR1bR1c, –OR1a, –OC(O)R1a, –OC(O)OR1a, –OC(O)NR1bR1c, R1a)NR1bR1c, R1a, –OS(O)2R1a, –OS(O)NR1bR1c, –OS(O)2NR1bR1c, –NR1bR1c, –NR1aC(O)R1d, –NR1aC(O)OR1d, –NR1aC(O)NR1bR1c, –NR1aC(=NR1d)NR1bR1c, –NR1aS(O)R1d, –NR1aS(O)2R1d, –NR1aS(O)NR1bR1c, –NR1aS(O)2NR1bR1c, –SR1a, –S(O)R1a, R1a, –S(O)NR1bR1c, or –S(O)2NR1bR1c.
38. 38. The compound of claim 35, wherein R7a is (i) halo; (ii) C1-6 alkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) –OR1a or –NR1bR1c.
39. 39. The compound of any one of claims 32 to 38, wherein R7b is en, halo, C1–6 alkyl optionally substituted with one or more substituents Q, or –OR1a.
40. 40. The compound of claim 39, wherein R7b is hydrogen.
41. 41. The compound of any one of claims 32 to 40, wherein R7c is hydrogen, halo, C1–6 alkyl optionally substituted with one or more substituents Q, or –OR1a.
42. 42. The compound of claim 41, wherein R7c is hydrogen, halo, or –OR1a.
43. 43. The compound of claim 41, wherein R7c is chloro.
44. 44. The compound of claim 41, wherein R7c is –O-C1-6 alkyl, optionally substituted with one or more substituents Q.
45. 45. The compound of any one of claims 32 to 44, wherein R7d is hydrogen, halo, C1–6 alkyl optionally tuted with one or more substituents Q, or –OR1a.
46. 46. The compound of claim 45, n R7d is hydrogen.
47. 47. The compound of any one of claims 32 to 46, wherein R7e is hydrogen, halo, C1–6 alkyl optionally substituted with one or more substituents Q, or –OR1a.
48. 48. The compound of claim 47, wherein R7e is hydrogen.
49. 49. The compound of any one of claims 32 to 34, wherein two of R7a, R7b, R7c, R7d, and R7e that are adjacent to each other form C3-10 cycloalkenyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally tuted with one or more substituents Q.
50. 50. The compound of claim 49, n R7a and R7b together with the carbon atoms to which they are attached from C6-14 aryl, optionally tuted with one or more substituents Q.
51. 51. The compound of claim 49, wherein R7b and R7c together with the carbon atoms to which they are attached from C6-14 aryl, optionally substituted with one or more substituents Q.
52. 52. The compound of any one of claims 1 to 3 and 6 to 51, wherein R5a is en.
53. 53. The compound of any one of claims 1 to 51, wherein R5a is C1-6 alkyl, ally substituted with one or more substituents Q.
54. 54. The compound of any one of claims 1 to 51, wherein R5a is hydrogen, methyl, or ethyl.
55. 55. The compound of any one of claims 1 to 4 and 6 to 54, wherein R5b is C1-6 alkyl, optionally substituted with one or more substituents Q.
56. 56. The compound of claim 55, wherein R5b is methyl, ethyl, or propyl.
57. 57. The compound of any one of claims 1 to 4 and 6 to 54, wherein R5b is –C(O)OR1a.
58. 58. The compound of claim 57, wherein R5b is –C(O)O-C1-6 alkyl.
59. 59. The compound of claim 57, wherein R5b is –C(O)OCH3.
60. 60. The compound of claim 32, having the structure of Formula XV: R7a R7c R3 XAIY' R5a R51) \r\’\N \z R“ 0\,\J R7C (XV) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
61. 61. The nd of claim 60, having the structure ofFormula XVa: or an isotopic variant f; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
62. 62. The compound of claim 60, having the ure ofFormula XVb: 0V\J H R7e (XVb) or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
63. 63. The compound of any one of claims 60 to 62, wherein R5a is C1-6 alkyl, optionally substituted with one or more substituents Q.
64. 64. The nd of claim 63, wherein R5a is methyl.
65. 65. The compound of any one of claims 60 to 64, wherein R5b is C1-6 alkyl, optionally substituted with one or more substituents Q.
66. 66. The nd of claim 65, wherein R5b is methyl.
67. 67. The nd of any one of claims 60 to 66, wherein R5a and R5b are methyl.
68. 68. The compound of any one of claims 60 to 67, wherein R7a is hydrogen, halo, C1–6 alkyl, C6–14 aryl, heteroaryl, or heterocyclyl, where the alkyl, aryl, heteroaryl, and heterocyclyl are each optionally tuted with one or more substituents Q.
69. 69. The compound of claim 68, n R7a is C6–14 aryl, optionally substituted with one or more substituents Q.
70. 70. The compound of claim 69, wherein R7a is phenyl, optionally substituted with one or more substituents Q.
71. 71. The compound of claim 69, wherein R7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, fluorophenyl, 4-fluoromethoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, or 3-morpholinylmethylphenyl.
72. 72. The compound of claim 68, wherein R781 is heteroaryl, optionally substituted with one or more tuents Q.
73. 73. The compound of claim 72, wherein R781 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
74. 74. The compound of claim 72 or 73, wherein R7&1 is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
75. 75. The compound of claim 74, wherein R781 is imidazolyl, pyrozolyl, pyridinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q.
76. 76. The nd of claim 74, wherein R781 is imidazol-l-yl, pyrozolyl, l-methyl-pyrozolyl, 2-methylpyrozol-3 -yl, pyridinyl, pyridinyl, pyridinyl, 2-fluoropyridin-3 -yl, 2-methylpyridinyl, 2-(4-methylpiperazin- l -yl)pyridinyl, 2-methoxypyridinyl, pyrimidinyl.
77. 77. The compound of claim 68, wherein R7&1 is heterocyclyl, optionally substituted with one or more substituents Q.
78. 78. The compound of claim 77, wherein R7&1 is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
79. 79. The nd of claim 77 or 78, wherein R7&1 is 5- or 6-membered cyclyl, each optionally substituted with one or more substituents Q.
80. 80. The compound of claim 79, wherein R781 is idinyl, piperidinyl, or zinyl, each optionally substituted with one or more tuents Q.
81. 8 l. The compound of claim 79, wherein R781 is pyrrolidinyl, l-methylpyrrolidinyl, piperidinyl, l-methylpiperidinyl, l-ethylpiperidinyl, l-isopropylpiperidinyl, l-acetylpiperidinyl, l-methylsulfonylpiperidinyl, or 4-methylpiperazin- l -yl.
82. 82. The nd of any one of claims 60 to 81, wherein R7b is hydrogen, halo, or C14 alkyl ally substituted with one or more substituents Q.
83. 83. The compound of claim 82, wherein R7b is hydrogen.
84. 84. The compound of any one of claims 60 to 83, wherein R70 is hydrogen, halo, or C14 alkyl optionally substituted with one or more substituents Q.
85. 85. The compound of claim 84, wherein R70 is hydrogen.
86. 86. The compound of any one of claims 60 to 85, wherein R7d is hydrogen, halo, or C14 alkyl optionally substituted with one or more substituents Q.
87. 87. The compound of claim 86, n R7d is hydrogen.
88. 88. The compound of any one of claims 60 to 87, wherein R7e is hydrogen, halo, or C14 alkyl optionally substituted with one or more substituents Q.
89. 89. The nd of claim 88, wherein R7e is hydrogen.
90. 90. The compound of any one of claims 60 to 62, wherein R781 is C644 aryl, aryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R7b, R7 and R7e are hydrogen. , R“,
91. 91. The compound of any one of claims 1 to 90, wherein R1 is hydrogen.
92. 92. The compound of any one of claims 1 to 90, wherein R1 is —OR1a.
93. 93. The compound of claim 92, wherein R1 is —O-C1_6 alkyl.
94. 94. The compound of claim 92, wherein R1 is methoxy.
95. 95. The compound of any one of claims 1 to 94, wherein R2 is hydrogen.
96. 96. The nd of any one of claims 1 to 94, wherein R2 is —NR1bR1°.
97. 97. The nd of claim 96, wherein R2 is amino.
98. 98. The compound of any one of claims 1 to 97, wherein R3 is hydrogen.
99. 99. The compound of any one of claims 1 to 98, wherein R4 is hydrogen.
100. 100. The compound of any one of claims 1 to 99, wherein R6 is C1_6 alkyl, —254— optionally substituted with one or more substituents Q.
101. 101. The compound of claim 100, wherein R6 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
102. 102. The nd of claim 100, wherein R6 is difluoromethyl.
103. 103. The compound of any one of claims 1 to 102, wherein X is N.
104. 104. The compound of any one of claims 1 to 102, wherein X is CRX.
105. 105. The compound of claim 104, wherein X is CH.
106. 106. The compound of any one of claims 1 to 105, wherein Y is N.
107. 107. The compound of any one of claims 1 to 105, wherein Y is CRX.
108. 108. The compound of claim 107, wherein Y is CH.
109. 109. The compound of any one of claims 1 to 108, wherein Z is N.
110. 110. The nd of any one of claims 1 to 108, wherein Z is CRX.
111. 111. The compound of claim 110, wherein Z is CH.
112. 112. The compound of any one of claims 1 to 102, wherein X, Y, and Z are N.
113. 113. The compound of claim 1 selected from the group consisting of: WO 35160 y H N|A\ NHA N 9 /N NH NIA\ w; 1 N / N N WO 35160 %%NI/A QN“ NH“ mwm% C 9 NH WO 35160 OCH3 2&31 2&32 WO 35160 N N FVHcm CHRu |A\ NIA\ NHA N N /N NHA Nu“ KOJ /N “NH \N N(“NU 2&35 2&36 2&37 CH an C NIA\ Hcm NHA N N NH NH F KONy , \ IN 2&40 WO 35160 1444