ROCK2 inhibitors and uses thereof

Abstract

The present disclosure provides compounds of formula (I) and (II) that can be ROCK2 inhibitors. The present disclosure also provides pharmaceutical compositions and kits that include the compounds, and methods for treating or preventing ROCK2-related diseases and disorders (e.g., fibrotic diseases, autoimmune diseases, inflammatory fibrotic conditions, inflammatory conditions, edema, eye diseases, cardiovascular diseases, central nervous system disorders, cancer) by administering the compounds or pharmaceutical compositions to a subject in need thereof. [Formula 1] TIFF2024529487000747.tif6083

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Nos. 63 / 225,695 (filed July 26, 2021) and 63 / 346,144 (filed May 26, 2022), the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Rho kinase (ROCK) is a family of coiled-coil-forming serine-threonine protein kinases that exists as two isoforms: ROCK1 and ROCK2. ROCK has been identified as an effector molecule of the small GTP-binding protein (G protein), RhoA. Both proteins are ubiquitously expressed in various tissues and play important roles in multiple cell signaling pathways. Upon receptor activation, RhoA activates ROCK, which in turn regulates several cellular functions, including cell migration, cell adhesion, actin reorganization, cytokinesis, and smooth muscle contraction. Therefore, ROCK inhibitors have potential therapeutic applications in a wide variety of pathological conditions. Summary of the Invention

[0003] The present disclosure is based on the recognition that the unique structure and function of ROCK2 provide an opportunity for the design of ROCK2 inhibitors (e.g., selective ROCK2 inhibitors) useful in the treatment of a wide variety of diseases. For example, ROCK2 is a key mediator of both biomechanical (tissue stiffness) and biochemical (TGF-β-mediated) pathways involved in the dysregulation of myofibroblast activation, a cell type believed to underlie the pathogenesis of fibrotic diseases. Abnormal expression and activation of ROCK2 leads to the persistent presence of activated myofibroblasts and the production of excessive extracellular matrix, leading to tissue fibrosis. Recent studies have shown that selective inhibition of ROCK2 inhibits the production of the pathogenic cytokine IL-17 in immune cells. As a result, selective inhibitors of ROCK2 may be effective, particularly in the treatment of fibrotic diseases. Thus, the compounds of the present disclosure provide new compositions and methods for treating ROCK2-associated (e.g., associated with increased ROCK2 activity) diseases and disorders (e.g., fibrotic disorders, autoimmune diseases, inflammatory conditions, edema, eye diseases, cardiovascular diseases, central nervous system disorders, cancer).

[0004] In one embodiment, provided is a compound of formula (I): [ka] and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in formula (I) are as described herein.

[0005] In another embodiment, provided is a compound of formula (II): [ka] and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, and prodrugs thereof, wherein the moieties and variables included in formula (II) are as described herein.

[0006] In another aspect, pharmaceutical compositions are provided that include a provided compound and, optionally, a pharmaceutically acceptable excipient.

[0007] In another aspect, a method of treating a disease or disorder associated with ROCK2 in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0008] In another aspect, a method is provided for preventing a disease or disorder associated with ROCK2 in a subject in need thereof, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0009] In certain embodiments, the ROCK2-associated disease or disorder is edema (eg, lymphedema).

[0010] In another aspect, a method of inhibiting the activity of ROCK2 is provided, the method comprising contacting ROCK2 with an effective amount of a provided compound or pharmaceutical composition.

[0011] In another aspect, the disclosure provides a method of screening a library of compounds, comprising conducting an assay for a provided compound and an additional compound, wherein the additional compound is different from the provided compound.

[0012] In another aspect, kits are provided that include a provided compound or pharmaceutical composition and instructions for using the provided compound or pharmaceutical composition.

[0013] Details of certain embodiments of the invention are set forth in the detailed description set forth below. Other features, objects, and advantages of the invention will become apparent from the definition, examples, and claims.

[0014] definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. (back cover), and specific functional groups are generally defined as described therein. Further information on general principles of organic chemistry and specific functional moieties and reactivities is available in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0015] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0016] In the formula: [ka] is a single bond with no specified stereochemistry at the directly attached moiety, [ka] is absent or a single bond, [ka] is a single or double bond.

[0017] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium. 19 F 18 Substitution with F, or 12 C 13 C or 14 Compounds having the present structures, except for the substitution at C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0018] When a range of values ​​is recited, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0019] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0020] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl (e.g., substituted C 1-6 alkyl, for example, -CF3, Bn).

[0021] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0022] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. In some embodiments, the alkoxy moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkoxy moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkoxy moiety has 1 to 4 carbon atoms ("C1-4 In some embodiments, the alkoxy moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkoxy moiety has 1 to 2 carbon atoms ("C 1-2 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0023] The term "alkoxyalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced by an alkoxy group, as defined herein. In some embodiments, the alkoxyalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkoxyalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkoxyalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkoxyalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms ("C 1-2 alkoxyalkyl").

[0024] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or disposed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 18 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-18In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-16 In some embodiments, heteroalkyl groups are saturated groups having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-14 In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroCi alkyl"). In some embodiments, a heteroalkyl group, as defined herein, is a partially unsaturated group, such as a carbonyl group, having one or more heteroatoms and at least one unsaturated carbon in the parent chain. For example, a heteroalkyl group can include an amide or ester functionality in its parent chain, such that one or more carbon atoms is an unsaturated carbonyl group. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-20 In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 It is alkyl.

[0025] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 In addition to alkenyl groups, examples include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 In alkenyl groups, a C=C double bond with no specified stereochemistry (e.g., -CH=CHCH3 or [ka] may be an (E) double bond or a (Z) double bond.

[0026] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or disposed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroalkenyl"). 2-10In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0027] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 In addition to alkynyl groups, examples include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0028] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or disposed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroalkynyl"). 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2-3In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0029] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms ("C 3-14 "carbocyclyl" refers to a radical that has no heteroatoms in its non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the aforementioned C 3-6 In addition to carbocyclyl groups, examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 The carbocyclyl group includes, but is not limited to, the aforementioned C 3-8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the preceding examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0030] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 In addition to cycloalkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are mentioned. 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 In addition to cycloalkyl groups, cycloheptyl (C7) and cyclooctyl (C8) are included. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0031] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0032] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazomethane, 1H-benzo[e][1,4]dihydropyrrole ... Zepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0034] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, with the radical or point of attachment being on the aryl ring; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0035] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0036] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., a ring system having 6, 10, or 14 π-electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valence allows. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, with the point of attachment being on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on either the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0037] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided by the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0038] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0039] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0040] The term "unsaturated bond" refers to a double or triple bond.

[0041] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0042] The term "saturated" refers to a moiety that contains no double or triple bonds, i.e., only single bonds.

[0043] The addition of the suffix "-ene" to the base indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0044] A group is optionally substituted unless otherwise specified. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group that can be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom present in a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents at each position are the same or different. The term "substituted" includes substitution with any acceptable substituent of an organic compound and is intended to include any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is in no way limited by the exemplary substituents described herein.

[0045] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )3、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa, -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X group; - is a counterion; or two geminal hydrogens on a carbon atom are bonded to groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc Replaced by; R aa Each instance of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa, -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with X group; - is the counterion; R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff)2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may be linked to form =O or =S; X - is the counterion; R ee Each instance of C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff groups linked to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(=NH)NH(C 1-6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2(C 1-6 alkyl), -SO2O(C 1-6 alkyl), -OSO2(C 1-6 alkyl), -SO(C 1-6 alkyl), -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; X - is the counterion.

[0046] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0047] The term "hydroxyl" or "hydroxy" refers to an -OH group. By extension, the term "substituted hydroxyl" or "substituted hydroxyl" refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, including, but not limited to, -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa, -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb )2)2, wherein X - , R aa , R bb , and R cc is as defined herein.

[0048] The term "amino" refers to the group -NH. In turn, the term "substituted amino" refers to a mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0049] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, including -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb )2)2, where R aa , R bb and R cc is as defined herein, and —NH(R bb ) group R bbis not hydrogen.

[0050] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, including -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2)2, where R aa , R bb , and R cc is as defined herein, provided that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0051] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, including -N(R bb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein.

[0052] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein.

[0053] The term "sulfinyl" refers to -S(=O)Raa refers to the group, where R aa is as defined herein.

[0054] The term "acyl" refers to a group having the general formula: -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , or -C(=NR X1 )N(R X1 )2, wherein R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted is unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1 The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc. (each of which may or may not be further substituted)).

[0055] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0056] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2ORcc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined herein.

[0057] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(Rcc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3001, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0058] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0059] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) are methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Troc), Bamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl carbamate, Dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0060] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) are p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- These include, but are not limited to, dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0061] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacyclopentasilane. N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine , quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyl N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorsalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,These include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0062] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). An oxygen protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb)N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including but not limited to, where X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0063] Exemplary oxygen protecting groups are methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-Trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methyl 4-chloroethoxypiperidinyl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxy , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3 -(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DE IPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmeth Oxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p -Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-( Examples of alkyl esters include, but are not limited to, alkyl esters of alkyl esters such as alkyl esters of alkyl esters of alkyl esters of alkyl esters, ... of alkyl esters, alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters, alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters, alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters, alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters, alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters of alkyl esters, alkyl esters of alkyl esters of alkyl esters of alkyl In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0064] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). A sulfur protecting group is a -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including but not limited to, where R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0065] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. Anionic counterions can be monovalent (i.e., containing one formal negative charge). Anionic counterions can also be polyvalent (i.e., containing multiple formal negative charges), e.g., divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 -, Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- 、 B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylate, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

[0066] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present invention is in no way intended to be limited by the above list of exemplary substituents.

[0067] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts.

[0068] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with human and / or animal tissues without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include the following: Adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0069] The term "solvate" refers to a compound or its salt form associated with a solvent, usually through solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, and may also be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, solvates may be isolatable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0070] The term "hydrate" refers to a compound associated with water molecules. Typically, the number of water molecules in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, including monohydrates (x is 1), hypohydrates (x is a number greater than 0 but less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0071] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction resulting in a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0072] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0073] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, if a compound has an asymmetric center and is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0074] The term "polymorph" refers to the crystalline form of a compound (or its salt, hydrate, or solvate). Many compounds can exist in a variety of different crystalline forms (i.e., different polymorphs). Typically, these different crystalline forms have different X-ray diffraction patterns, infrared spectra, and / or may differ in some or all of the following properties: melting point, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate in a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0075] The term "co-crystal" refers to a crystal structure composed of at least two components. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more other component(s), including, but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more acids or bases. In certain embodiments, a co-crystal includes a compound of the present disclosure and one or more components related to said compound, including, but not limited to, isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of said compound.

[0076] The term "prodrug" refers to a compound having a cleavable group that is removed by solvolysis or under physiological conditions to yield a compound described herein that is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both the acid form and the acid derivative, but the acid-sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, aryl, C 7-12 Substituted aryl, and C 7-12 Aryl alkyl esters may be preferred.

[0077] The terms "composition" and "formulation" are used interchangeably.

[0078] A "subject" to which administration is intended refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially important mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially important bird such as a chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease or disorder.

[0079] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, fecal material, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any substance containing biomolecules derived from an initial biological sample.

[0080] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto the body of a subject.

[0081] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting progression of a disease or disorder described herein. In some embodiments, treatment may be performed after one or more signs or symptoms of a disease or disorder have occurred or are observed. In other embodiments, treatment may be performed in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject before symptoms develop (e.g., based on a medical history). Treatment may also be continued after symptoms have resolved to delay or prevent recurrence.

[0082] The terms "prevent," "preventing," or "prevention" refer to the prophylactic treatment of a subject who does not currently or previously have the disease or disorder but is at risk of developing the disease or disorder, or a subject who previously had the disease or disorder and does not currently have the disease or disorder but is at risk of the disease or disorder returning. In certain embodiments, the subject is at higher risk of developing the disease or disorder or at higher risk of the disease or disorder returning than the average healthy member of a population of subjects.

[0083] The terms "condition," "disease," and "disorder" are used interchangeably.

[0084] An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. For example, in the treatment of cancer, an effective amount of the composition of the present invention can prevent tumor regrowth, reduce tumor burden, or stop tumor growth or spread. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple doses.

[0085] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for ROCK2 inhibition (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% inhibition of ROCK2 activity). In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a disease or disorder associated with ROCK2. In certain embodiments, a therapeutically effective amount is an amount sufficient for ROCK2 inhibition and treatment of a disease or disorder associated with ROCK2.

[0086] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition or one or more signs or symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for ROCK2 inhibition. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a disease or disorder associated with ROCK2. In certain embodiments, a prophylactically effective amount is an amount sufficient for ROCK2 inhibition and treatment of a disease or disorder associated with ROCK2.

[0087] As used herein, the term "inhibit" or "inhibition" in the context of an enzyme, e.g., ROCK2, refers to a reduction in the activity of the enzyme. In some embodiments, the term refers to a reduction in the level of enzyme activity, such as ROCK2 activity, to a level that is statistically significantly lower than a starting level, which may be, for example, a baseline level of enzyme activity. In some embodiments, the term refers to a reduction in the level of enzyme activity, such as ROCK2 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the starting level, which may be, for example, a baseline level of enzyme activity. In some embodiments, the term refers to a decrease in the level of enzymatic activity, such as ROCK1 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of a starting level, which may be, for example, a baseline level of enzymatic activity.

[0088] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct adenocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary gland cancer, etc.). cancer), medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue carcinoma; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer (e.g., gallbladder carcinoma); gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); lung cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); blood cancer (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL), as well as non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic leukemia (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom lymphoma), leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-cell lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); Mixed leukemia / lymphoma (one or more); multiple myeloma), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma, hepatocarcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle carcinoma; myelodysplastic syndrome (MDS) mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone carcinoma); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma);papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); peritoneal cancer; pinealoma; pituitary cancer; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer (e.g., salivary gland carcinoma); skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine These include, but are not limited to, intestinal cancer; sweat gland carcinoma; synovial tumor; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0089] The term "immunotherapy" refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to induce or amplify an immune response are classified as activating immunotherapies, whereas immunotherapies that reduce or suppress an immune response are classified as suppressing immunotherapies. Immunotherapies are typically, but not necessarily, biological therapeutic agents. Numerous immunotherapies have been used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.

[0090] The terms "biologic," "biological drug," and "biological product" refer to a wide range of products, including vaccines, blood and blood components, allergens, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologics can contain sugars, proteins, or nucleic acids, or complex combinations of these substances, or can be living organisms such as cells and tissues. Biologics can be isolated from a variety of natural sources (e.g., humans, animals, microorganisms) or can be produced by biotechnological and other techniques.

[0091] The terms "small molecule" or "small molecule therapeutic" refer to molecules having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., by chemical synthesis). Typically, small molecules are organic compounds (i.e., contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocyclic rings, and the like). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges are also possible (e.g., at least about 200 g / mol and up to about 500 g / mol). In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration under the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has already been deemed safe and effective for human or animal use by an appropriate governmental or regulatory agency.For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331-361, and 440-460 (incorporated herein by reference), and veterinary drugs are listed by the FDA under 21 C.F.R. §§ 500-589 (incorporated herein by reference). All listed drugs are considered acceptable for use in accordance with the present invention.

[0092] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, usually beneficial, effect. For example, a therapeutic agent can treat and / or ameliorate a disease or disorder. The therapeutic agents disclosed herein can be biologics or small molecule therapeutics, or a combination thereof.

[0093] The term "chemotherapeutic agent" refers to a therapeutic agent known to be useful in chemotherapy against cancer. DETAILED DESCRIPTION OF THE INVENTION

[0094] Provided herein are compounds that are ROCK inhibitors (e.g., ROCK2 inhibitors). The compounds have advantageous properties, such as selective inhibition of ROCK2, that make them useful as therapeutic agents. In one embodiment, the provided ROCK inhibitors are compounds of formula (I), and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotope-labeled derivatives, prodrugs, and pharmaceutical compositions. In another embodiment, the provided ROCK inhibitors are compounds of formula (II), and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotope-labeled derivatives, prodrugs, and pharmaceutical compositions. Thus, the compounds are useful for treating and / or preventing diseases and disorders associated with ROCK2 in subjects in need thereof.

[0095] The compounds described herein can interact with (e.g., bind to) ROCK2. As described herein, the therapeutic effect can be the result of the inhibition, regulation, binding, and / or modification of ROCK2 by the compounds described herein. The compounds can be provided for use in any of the compositions, kits, or methods described herein as their pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched compounds, or prodrugs.

[0096] compound In one aspect, disclosed is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein: R 1 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 2 is hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl; X is CR 7 or N, Y is CR 8 or N, Z is CR 9 or N, R 3 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; A is, [ka] and R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; B is aryl, heterocyclyl, heteroaryl, or carbocyclyl; Each R 6 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR A , -N3, -N(R A )2, -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )N(R A )2, -C(=O)R A , -C(=O)OR A , -C(=O)N(R A )2, -NO2, -NR A C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)N(R A )2, -NR A C(=NR A )N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)N(R A )2, -NR A S(O)2R A , -OS(O)2R A , or -S(O)R A and n is 1, 2, 3, 4, or 5; Each R 7 , R 8 , and R 9 are independently hydrogen, halogen, —CN, or substituted or unsubstituted alkyl; R 10 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R A each instance of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; or A The groups are linked to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring.

[0097] In certain embodiments, disclosed are compounds of formula (I): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein: R 1 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 2 is hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl; X is CR 7 or N, Y is CR 8 or N, Z is CR 9 or N, R 3 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; A is, [ka] and R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; B is aryl, heterocyclyl, heteroaryl, or carbocyclyl; Each R 6 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR A , -N3, -N(R A )2, -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )N(R A )2, -C(=O)R A , -C(=O)OR A , -C(=O)N(RA )2, -NO2, -NR A C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)N(R A )2, -NR A C(=NR A )N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)N(R A )2, -NR A S(O)2R A , -OS(O)2R A , or -S(O)R A and n is 1, 2, 3, 4, or 5; Each R 7 , R 8 , and R 9 are independently hydrogen, halogen, —CN, or substituted or unsubstituted alkyl; R 10 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R A each instance of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; or A The groups are linked to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring.

[0098] In another aspect, disclosed is a compound of formula (II): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein: R 1 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 2 is hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl; R 2A is hydrogen, halogen, —CN, or substituted or unsubstituted alkyl; Y is CR 8 or N, R 3 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; A is, [ka] and R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; B is aryl, heterocyclyl, heteroaryl, or carbocyclyl; Each R 6are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR A , -N3, -N(R A )2, -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )N(R A )2, -C(=O)R A , -C(=O)OR A , -C(=O)N(R A )2, -NO2, -NR A C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)N(R A )2, -NR A C(=NR A )N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)N(R A )2, -NR A S(O)2R A , -OS(O)2R A , or -S(O)R A and n is 1, 2, 3, 4, or 5; R 8 is hydrogen, halogen, —CN, or substituted or unsubstituted alkyl; R 10 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Aeach instance of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; or A The groups are linked to form a substituted or unsubstituted heterocyclyl ring or a substituted or unsubstituted heteroaryl ring.

[0099] R 1 As described herein, R 1 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, R 1 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 1 is hydrogen or substituted or unsubstituted C 1-4 In certain embodiments, R 1 is hydrogen or unsubstituted C 1-4 In certain embodiments, R 1 is hydrogen or unsubstituted C 1-3 In certain embodiments, R 1 is hydrogen or unsubstituted C 1-2 In certain embodiments, R 1 is hydrogen or methyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0100] R 2 As described herein, R 2 is hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl. 2 is hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. 2 is hydrogen, halogen, —CN, or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen, halogen, or —CN. In certain embodiments, R 2 is hydrogen or halogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is fluoro, chloro, bromo, or iodo. In certain embodiments, R 2 is fluoro, chloro, or bromo. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is chloro. In certain embodiments, R 2 is hydrogen or chloro. In certain embodiments, R 2 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or substituted or unsubstituted C 1-4 In certain embodiments, R 2 is hydrogen or unsubstituted C 1-4 In certain embodiments, R 2 is hydrogen.

[0101] R 2A As described herein, R 2A is hydrogen, halogen, —CN, or substituted or unsubstituted alkyl. In certain embodiments, R 2A is hydrogen, halogen, or —CN. In certain embodiments, R 2A is hydrogen or halogen. In certain embodiments, R 2A is halogen. In certain embodiments, R 2Ais fluoro, chloro, bromo, or iodo. In certain embodiments, R 2A is fluoro, chloro, or bromo. In certain embodiments, R 2A is fluoro or chloro. In certain embodiments, R 2A is chloro. In certain embodiments, R 2A is hydrogen or chloro. In certain embodiments, R 2A is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2A is hydrogen or substituted or unsubstituted C 1-4 In certain embodiments, R 2A is hydrogen or unsubstituted C 1-4 In certain embodiments, R 2A is hydrogen.

[0102] R 3 As described herein, R 3 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, R 3 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 3 is hydrogen or substituted or unsubstituted C 1-4 In certain embodiments, R 3 is hydrogen or unsubstituted C 1-4 In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0103] X, Y, and Z As described herein, X is CR 7 or N, and Y is CR 8 or N, and Z is CR 9 or N, where each R 7 , R 8 , and R 9is independently hydrogen, halogen, —CN, or substituted or unsubstituted alkyl.

[0104] In certain embodiments, X is CR 7 In certain embodiments, X is N. In certain embodiments, X is CR 7 and R 7 is hydrogen, halogen, or -CN. In certain embodiments, X is CR 7 and R 7 is hydrogen or halogen, preferably hydrogen. In certain embodiments, X is CR 7 and R 7 is halogen. In certain embodiments, X is CR 7 and R 7 is fluoro, chloro, bromo, or iodo. In certain embodiments, X is CR 7 and R 7 is fluoro, chloro, or bromo. In certain embodiments, X is CR 7 and R 7 is fluoro or chloro. In certain embodiments, X is CR 7 and R 7 is chloro. In certain embodiments, X is CR 7 and R 7 is hydrogen or chloro. In certain embodiments, X is CR 7 and R 7 is hydrogen. In certain embodiments, X is CR 7 and R 7 is substituted or unsubstituted alkyl. In certain embodiments, X is CR 7 and R 7 is a substituted or unsubstituted C 1-4 In certain embodiments, X is CR 7 and R 7 is the unsubstituted C 1-4 In certain embodiments, X is CR 7 and R 7 is isopropyl.

[0105] In certain embodiments, Y is CR 8 In certain embodiments, Y is N. In certain embodiments, Y is CR 8 and R 8 is hydrogen, halogen, or -CN. In certain embodiments, Y is CR 8 and R 8 is hydrogen or halogen. In certain embodiments, Y is CR 8 and R 8 is hydrogen. In certain embodiments, Z is CR 9 In certain embodiments, Z is N. In certain embodiments, Z is CR 9 and R 9 is hydrogen, halogen, or -CN. In certain embodiments, Z is CR 9 and R 9 is hydrogen or halogen. In certain embodiments, Z is CR 9 and R 9 is hydrogen. In certain embodiments, X is CR 7 (In the formula, R 7 is hydrogen or halogen, preferably hydrogen), and Y is CR 8 (In the formula, R 8 is hydrogen), and Z is CR 9 (In the formula, R 9 is hydrogen).

[0106] B and R 6 As described herein, B is aryl, heterocyclyl, heteroaryl, or carbocyclyl. In certain embodiments, B is aryl, heterocyclyl, or heteroaryl. In certain embodiments, B is aryl or heteroaryl. In certain embodiments, B is a monocyclic aryl or monocyclic heteroaryl. In certain embodiments, B is a 6-membered aryl or a 5- or 6-membered heteroaryl. In certain embodiments, B is phenyl or pyridinyl. In certain embodiments, B is phenyl. In certain embodiments, B is pyridinyl. In certain embodiments, B is 2-pyridinyl. In certain embodiments, B is 3-pyridinyl. In certain embodiments, B is 4-pyridinyl. In certain embodiments, B is carbocyclyl (e.g., monocyclic carbocyclyl). In certain embodiments, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0107] In certain embodiments, n is 1, 2, 3, 4, or 5. In certain embodiments, n is 1, 2, 3, or 4. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, [ka] (-B(R 6 ) n )teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] where R A is a 5- to 6-membered substituted or unsubstituted heteroaryl.

[0108] In certain embodiments, -B(R 6 ) n teeth, [ka] wherein B2 is a 5- to 6-membered monocyclic unsubstituted heteroaryl or a 5- to 6-membered monocyclic unsubstituted heterocyclyl; and R 6 is directly attached to B2. In certain embodiments, -B(R 6 ) n teeth, [ka] wherein B2 is a 5- to 6-membered monocyclic unsubstituted heterocyclyl, and R 6 is directly attached to B2. In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] wherein B2 is a 5-6 membered monocyclic unsubstituted heteroaryl, and R 6 is directly attached to B2. In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0109] As described herein, each R 6 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR A , -N3, -N(R A )2, -SR A , -CN, -SCN, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )N(R A )2, -C(=O)R A , -C(=O)OR A , -C(=O)N(RA )2, -NO2, -NR A C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)N(R A )2, -NR A C(=NR A )N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)N(R A )2, -NR A S(O)2R A , -OS(O)2R A , or -S(O)R A is.

[0110] In certain embodiments, each R 6 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR A , -N(R A )2, -CN, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )N(R A )2, -C(=O)R A , -C(=O)OR A , -C(=O)N(R A )2, -NR A C(=O)R A , -NR A C(=O)OR A , -NR A C(=O)N(R A )2, -NR A C(=NR A )N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)N(R A )2, -NR A S(O)2R A , -OS(O)2R A, or -S(O)R A is.

[0111] In certain embodiments, each R 6 are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, oxo, -C(=O)R A , -C(=O)N(R A )2, -S(O)2R A , -OR A , -N(R A )2, or -NR A C(=O)R A In certain embodiments, each R 6 are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, oxo, -OR A , -N(R A )2, or -NR A C(=O)R A In certain embodiments, each R 6 are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, oxo, -OC 1-4 Alkyl, -OCH2C(=O)N(R A )2, -N(R A )2, or -NR A C(=O)R A In certain embodiments, each R 6 independently, C 1-4 Alkyl, substituted or unsubstituted heteroaryl, oxo, -OC 1-4 Alkyl, -OCH2C(=O)NHC 1-4 alkyl, -NH2, -NHC(=O)aryl, or -NHC(=O)heteroaryl, where each alkyl, aryl, and heteroaryl is substituted or unsubstituted.

[0112] In certain embodiments, each R 6 are independently oxo, -CH3, -OCH3, -F, [ka] [ka] is.

[0113] In certain embodiments, each R 6 are independently oxo, -CH3, -OCH3, -F, [ka] [ka] is.

[0114] In certain embodiments, each R 6 are independently oxo, -CH3, -OCH3, -F, [ka] is.

[0115] In certain embodiments, each R 6 are independently oxo, -CH3, -OCH3, [ka] is.

[0116] In certain embodiments, each R 6 are independently -OCH3, [ka] is.

[0117] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] is.

[0118] In certain embodiments, -B(R6 ) n teeth, [ka] [ka] is.

[0119] In certain embodiments, -B(R 6 ) n teeth, [ka] [ka] is.

[0120] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0121] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0122] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0123] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0124] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0125] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0126] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0127] In certain embodiments, -B(R 6 ) n teeth, [ka] is.

[0128] In certain embodiments, -B(R 6 ) n teeth, [ka] [ka] [ka] [ka] is.

[0129] In certain embodiments, -B(R 6 ) nteeth, [ka] [ka] [ka] [ka] is. Ring A As described herein, A is [ka] where R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 4 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R 10 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0130] In certain embodiments, A is [ka] where R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 4 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R 10 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0131] In certain embodiments, A is [ka] where R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is a substituted or unsubstituted C 1-4 In certain embodiments, R 4 is the unsubstituted C 1-4 Alkyl or C 1-4 In certain embodiments, R 4 is methyl or trifluoromethyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is trifluoromethyl. In certain embodiments, R4 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted monocyclic carbocyclyl). In certain embodiments, R 4 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain embodiments, R 4 is a substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 4 is substituted or unsubstituted aryl. In certain embodiments, R 4 is unsubstituted phenyl. In certain embodiments, R 4 is substituted phenyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 4 is substituted or unsubstituted heteroaryl. In certain embodiments, R 4 is an unsubstituted 5- or 6-membered monocyclic heteroaryl. In certain embodiments, R 4 is a substituted 5- or 6-membered monocyclic heteroaryl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is substituted or unsubstituted alkyl. In certain embodiments, R 5 is a substituted or unsubstituted C 1-4 In certain embodiments, R 5 is the unsubstituted C 1-4 Alkyl or C 1-4 In certain embodiments, R 5 is methyl or trifluoromethyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is trifluoromethyl. In certain embodiments, R5 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted monocyclic carbocyclyl). In certain embodiments, R 5 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain embodiments, R 5 is a substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5 is substituted or unsubstituted aryl. In certain embodiments, R 5 is unsubstituted phenyl. In certain embodiments, R 5 is substituted phenyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5 is substituted or unsubstituted heteroaryl. In certain embodiments, R 5 is an unsubstituted 5- or 6-membered monocyclic heteroaryl. In certain embodiments, R 5 is a substituted 5- or 6-membered monocyclic heteroaryl (eg, substituted with halogen, unsubstituted alkyl, and / or -O-(unsubstituted alkyl)).

[0132] In certain embodiments, A is [ka] where R 4 is hydrogen or substituted or unsubstituted alkyl, and R 5 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 4 is hydrogen or substituted or unsubstituted alkyl, and R 5 is hydrogen. In certain embodiments, R 4 is hydrogen and R 5 is hydrogen. In certain embodiments, R 4 is a substituted or unsubstituted alkyl, and R 5is hydrogen. In certain embodiments, R 4 is a substituted or unsubstituted C 1-4 alkyl, and R 5 is hydrogen. In certain embodiments, R 4 is the unsubstituted C 1-4 Alkyl or C 1-4 haloalkyl, and R 5 is hydrogen. In certain embodiments, R 4 is methyl or trifluoromethyl, and R 5 is hydrogen. In certain embodiments, R 4 is methyl and R 5 is hydrogen. In certain embodiments, R 4 is trifluoromethyl and R 5 is hydrogen. In certain embodiments, R 5 is a substituted or unsubstituted alkyl, and R 4 is hydrogen. In certain embodiments, R 5 is a substituted or unsubstituted C 1-4 alkyl, and R 4 is hydrogen. In certain embodiments, R 5 is the unsubstituted C 1-4 Alkyl or C 1-4 haloalkyl, and R 4 is hydrogen. In certain embodiments, R 5 is methyl or trifluoromethyl, and R 4 is hydrogen. In certain embodiments, R 5 is methyl and R 4 is hydrogen. In certain embodiments, R 5 is trifluoromethyl and R 4 is hydrogen.

[0133] In certain embodiments, A is [ka] where R 4 and R 5taken together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 4 and R 5 taken together with the atoms to which they are attached form a substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl). In certain embodiments, R 4 and R 5 taken together with the atoms to which they are attached form an unsubstituted aryl. In certain embodiments, R 4 and R 5 together with the atom to which they are attached form a substituted or unsubstituted heteroaryl (e.g., a 5-6 membered, monocyclic, substituted or unsubstituted heteroaryl). In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0134] In certain embodiments, R 4 is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is a substituted or unsubstituted alkyl.

[0135] In certain embodiments, R 5 is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is a substituted or unsubstituted alkyl.

[0136] In certain embodiments, A is [ka] where R 4is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is a substituted or unsubstituted C 1-4 In certain embodiments, R 4 is the unsubstituted C 1-4 Alkyl or C 1-4 In certain embodiments, R 4 is methyl or trifluoromethyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 4 is trifluoromethyl. In certain embodiments, R 4 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted monocyclic carbocyclyl). In certain embodiments, R 4 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain embodiments, R 4 is a substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 4 is substituted or unsubstituted aryl. In certain embodiments, R 4 is unsubstituted phenyl. In certain embodiments, R 4 is substituted phenyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 4is substituted or unsubstituted heteroaryl. In certain embodiments, R 4 is an unsubstituted 5- or 6-membered monocyclic heteroaryl. In certain embodiments, R 4 is a substituted 5- or 6-membered monocyclic heteroaryl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is substituted or unsubstituted alkyl. In certain embodiments, R 5 is a substituted or unsubstituted C 1-4 In certain embodiments, R 5 is the unsubstituted C 1-4 Alkyl or C 1-4 In certain embodiments, R 5 is methyl or trifluoromethyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is trifluoromethyl. In certain embodiments, R 5 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted monocyclic carbocyclyl). In certain embodiments, R 5 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain embodiments, R 5 is a substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5 is substituted or unsubstituted aryl. In certain embodiments, R 5 is unsubstituted phenyl. In certain embodiments, R 5 is substituted phenyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5is substituted or unsubstituted heteroaryl. In certain embodiments, R 5 is an unsubstituted 5- or 6-membered monocyclic heteroaryl. In certain embodiments, R 5 is a substituted 5- or 6-membered monocyclic heteroaryl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 5 is trifluoromethyl and R 4 is hydrogen.

[0137] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] In certain embodiments, A is [ka] is.

[0138] In certain embodiments, A is [ka] is.

[0139] In certain embodiments, A is [ka] is.

[0140] In certain embodiments, A is [ka] is.

[0141] In certain embodiments, A is [ka] In certain embodiments, R 10 is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R 10 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 10 is substituted or unsubstituted alkyl. In certain embodiments, R 10 is a substituted or unsubstituted C 1-4 In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted monocyclic carbocyclyl). In certain embodiments, R 10 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In certain embodiments, R 10is a substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 10 is substituted or unsubstituted aryl. In certain embodiments, R 10 is unsubstituted phenyl. In certain embodiments, R 10 is substituted phenyl (e.g., substituted with halogen, unsubstituted alkyl, and / or —O-(unsubstituted alkyl)). In certain embodiments, R 10 is substituted or unsubstituted heteroaryl. In certain embodiments, R 10 is an unsubstituted 5- or 6-membered monocyclic heteroaryl. In certain embodiments, R 10 is a substituted 5- or 6-membered monocyclic heteroaryl (eg, substituted with halogen, unsubstituted alkyl, and / or -O-(unsubstituted alkyl)).

[0142] Specific Embodiments In certain embodiments, the compound of formula (I) has formula (Ia): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, Z, B, and n are as defined herein.

[0143] In certain embodiments, the compound of formula (I) has the formula (Ia-1): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 3 , R 4 , R 5 , R 6 , X, Y, Z, B, and n are as defined herein.

[0144] In certain embodiments, the compound of formula (I) has the formula (Ia-2): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , X, Y, Z, B, and n are as defined herein.

[0145] In certain embodiments, the compound of formula (I) has formula (Ia-3): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , R 7 , B, and n are as defined herein.

[0146] In certain embodiments, the compound of formula (I) has formula (Ia-4): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6, R 7 , and n is as defined herein.

[0147] In certain embodiments, the compound of formula (I) has the formula (Ia-4a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , R 7 , and n is as defined herein.

[0148] In certain embodiments, the compound of formula (I) has formula (Ia-5): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 6 , R 7 , and n is as defined herein.

[0149] In certain embodiments, the compound of formula (I) has the formula (Ia-5a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 6 , R 7 , and n is as defined herein.

[0150] In certain embodiments, the compound of Formula (I) has the formula (Ia-6): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 7 , and n is as defined herein.

[0151] In certain embodiments, the compound of formula (I) has the formula (Ia-6a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 7 , and n is as defined herein.

[0152] In certain embodiments, the compound of Formula (I) has the formula (Ia-7): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , and R 7 is as defined herein.

[0153] In certain embodiments, the compound of formula (I) has the formula (Ia-7a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , and R7 is as defined herein.

[0154] In certain embodiments, the compound of Formula (I) has the formula (Ia-8): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , and R 7 is as defined herein.

[0155] In certain embodiments, the compound of formula (I) has the formula (Ia-8a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , and R 7 is as defined herein.

[0156] In certain embodiments, the compound of Formula (I) has the formula (Ia-9): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , and R 7 is as defined herein.

[0157] In certain embodiments, the compound of formula (I) has the formula (Ia-9a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 6 , and R 7 is as defined herein.

[0158] In certain embodiments, the compound of formula (I) has formula (Ia-10): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 7 , and R A is as defined herein.

[0159] In certain embodiments, the compound of formula (I) has the formula (Ia-10a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 4 , R 5 , R 7 , and R A is as defined herein.

[0160] In certain embodiments, the compound of formula (I) has formula (Ib): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 1, R 2 , R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0161] In certain embodiments, the compound of formula (I) has the formula (Ib-1): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0162] In certain embodiments, the compound of formula (I) has the formula (Ib-2): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 , X, Y, Z, B, and n are as defined herein.

[0163] In certain embodiments, the compound of formula (I) has the formula (Ib-3): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , B, and n are as defined herein.

[0164] In certain embodiments, the compound of formula (I) has formula (Ib-4): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0165] In certain embodiments, the compound of formula (I) has the formula (Ib-4a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0166] In certain embodiments, the compound of formula (I) has the formula (Ib-5): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0167] In certain embodiments, the compound of formula (I) has the formula (Ib-5a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0168] In certain embodiments, the compound of formula (I) has formula (Ib-6): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0169] In certain embodiments, the compound of formula (I) has the formula (Ib-6a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0170] In certain embodiments, the compound of formula (I) has formula (Ib-7): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0171] In certain embodiments, the compound of formula (I) has formula (Ib-7a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0172] In certain embodiments, the compound of formula (I) has formula (Ib-8): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0173] In certain embodiments, the compound of formula (I) has the formula (Ib-8a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0174] In certain embodiments, the compound of formula (I) has formula (Ic): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0175] In certain embodiments, the compound of formula (I) has the formula (Ic-1): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0176] In certain embodiments, the compound of formula (I) has the formula (Ic-2): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 , X, Y, Z, B, and n are as defined herein.

[0177] In certain embodiments, the compound of formula (I) has the formula (Ic-3): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , B, and n are as defined herein.

[0178] In certain embodiments, the compound of formula (I) has formula (Ic-4): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0179] In certain embodiments, the compound of formula (I) has the formula (Ic-4a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0180] In certain embodiments, the compound of formula (I) has the formula (Ic-5): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0181] In certain embodiments, the compound of formula (I) has the formula (Ic-5a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0182] In certain embodiments, the compound of formula (I) has the formula (Ic-6): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0183] In certain embodiments, the compound of formula (I) has the formula (Ic-6a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0184] In certain embodiments, the compound of formula (I) has the formula (Ic-7): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0185] In certain embodiments, the compound of formula (I) has the formula (Ic-7a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0186] In certain embodiments, the compound of formula (I) has the formula (Ic-8): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0187] In certain embodiments, the compound of formula (I) has the formula (Ic-8a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0188] In certain embodiments, the compound of formula (I) has the formula (Id): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0189] In certain embodiments, the compound of formula (I) has the formula (Id-1): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0190] In certain embodiments, the compound of formula (I) has the formula (Id-2): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 , X, Y, Z, B, and n are as defined herein.

[0191] In certain embodiments, the compound of formula (I) has the formula (Id-3): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , B, and n are as defined herein.

[0192] In certain embodiments, the compound of formula (I) has the formula (Id-4): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0193] In certain embodiments, the compound of formula (I) has the formula (Id-4a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0194] In certain embodiments, the compound of formula (I) has the formula (Id-5): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0195] In certain embodiments, the compound of formula (I) has the formula (Id-5a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0196] In certain embodiments, the compound of formula (I) has the formula (Id-6): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0197] In certain embodiments, the compound of formula (I) has the formula (Id-6a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0198] In certain embodiments, the compound of formula (I) has the formula (Id-7): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0199] In certain embodiments, the compound of formula (I) has the formula (Id-7a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0200] In certain embodiments, the compound of formula (I) has the formula (Id-8): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0201] In certain embodiments, the compound of formula (I) has the formula (Id-8a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7is as defined herein.

[0202] In certain embodiments, the compound of formula (I) has formula (Ie): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0203] In certain embodiments, the compound of formula (I) has the formula (Ie-1): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0204] In certain embodiments, the compound of formula (I) has the formula (Ie-2): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 , X, Y, Z, B, and n are as defined herein.

[0205] In certain embodiments, the compound of formula (I) has the formula (Ie-3): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , B, and n are as defined herein.

[0206] In certain embodiments, the compound of formula (I) has formula (Ie-4): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0207] In certain embodiments, the compound of formula (I) has the formula (Ie-4a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0208] In certain embodiments, the compound of formula (I) has the formula (Ie-5): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0209] In certain embodiments, the compound of formula (I) has the formula (Ie-5a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0210] In certain embodiments, the compound of formula (I) has the formula (Ie-6): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0211] In certain embodiments, the compound of formula (I) has the formula (Ie-6a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0212] In certain embodiments, the compound of formula (I) has the formula (Ie-7): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0213] In certain embodiments, the compound of formula (I) has the formula (Ie-7a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0214] In certain embodiments, the compound of formula (I) has the formula (Ie-8): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0215] In certain embodiments, the compound of formula (I) has the formula (Ie-8a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0216] In certain embodiments, the compound of formula (I) has the formula (If): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 1 , R 2 , R 3 , R6 , R 10 , X, Y, Z, B, and n are as defined herein.

[0217] In certain embodiments, the compound of formula (I) has the formula (If-1): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 3 , R 6 , X, Y, Z, B, and n are as defined herein.

[0218] In certain embodiments, the compound of formula (I) has the formula (If-2): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 , X, Y, Z, B, and n are as defined herein.

[0219] In certain embodiments, the compound of formula (I) has the formula (If-3): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , B, and n are as defined herein.

[0220] In certain embodiments, the compound of formula (I) has the formula (If-4): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0221] In certain embodiments, the compound of formula (I) has the formula (If-4a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 7 , R 6 , and n is as defined herein.

[0222] In certain embodiments, the compound of formula (I) has the formula (If-5): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0223] In certain embodiments, the compound of formula (I) has the formula (If-5a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0224] In certain embodiments, the compound of formula (I) has the formula (If-6): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0225] In certain embodiments, the compound of formula (I) has the formula (If-6a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0226] In certain embodiments, the compound of formula (I) has the formula (If-7): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0227] In certain embodiments, the compound of formula (I) has the formula (If-7a): [ka]

[0228] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R 6 and R 7 is as defined herein.

[0229] In certain embodiments, the compound of formula (I) has the formula (If-8): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0230] In certain embodiments, the compound of formula (I) has the formula (If-8a): [ka] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein R A and R 7 is as defined herein.

[0231] In certain embodiments, the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0232] In certain embodiments, the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof: [ka] [ka] [ka] [ka] [ka]

[0233] In certain embodiments, the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0234] In certain embodiments, the provided compound (compound described herein, compound of the present disclosure) is a compound of formula (I), or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof. In certain embodiments, the provided compound is a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or isotopically enriched compound thereof. In certain embodiments, the provided compound is a compound of formula (I), or a pharmaceutically acceptable salt or tautomer thereof. In certain embodiments, the provided compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0235] In certain embodiments, the compound of Formula (II) is one of the following compounds, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof: [ka] [ka]

[0236] In certain embodiments, the provided compound (compound described herein, compound of the present disclosure) is a compound of formula (II), or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof. In certain embodiments, the provided compound is a compound of formula (II), or a pharmaceutically acceptable salt, tautomer, or isotopically enriched compound thereof. In certain embodiments, the provided compound is a compound of formula (II), or a pharmaceutically acceptable salt or tautomer thereof. In certain embodiments, the provided compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0237] In certain embodiments, provided compounds (e.g., compounds of Formula (I) and (II)) have an IC of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. 50 inhibits ROCK1.

[0238] In certain embodiments, provided compounds (e.g., compounds of Formula (I) and (II)) have an IC of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. 50 inhibits ROCK2.

[0239] In certain embodiments, provided compounds (e.g., compounds of Formulas (I) and (II)) selectively inhibit ROCK2 over ROCK1. In certain embodiments, the compounds are 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1,000-fold, or 10,000-fold more selective inhibitors of ROCK2 than ROCK1.

[0240] Pharmaceutical Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising a provided compound, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a provided compound and a pharmaceutically acceptable excipient.

[0241] In certain embodiments, the pharmaceutical composition comprises an effective amount of a provided compound. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to treat a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a ROCK2-associated disease or disorder. In certain embodiments, the effective amount is an amount effective to reduce the risk of developing a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to inhibit ROCK2. In certain embodiments, inhibiting ROCK2 refers to inhibiting ROCK2 activity (e.g., abnormal activity, such as increased activity) (e.g., in a subject, tissue, biological sample, or cell).

[0242] In certain embodiments, the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12 to 18 years (excluding the end values). In certain embodiments, the subject is a human aged 2 to 12 years (inclusive). In certain embodiments, the subject is a human under the age of 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal.

[0243] In certain embodiments, an effective amount is an amount effective to inhibit the activity of ROCK2 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of ROCK2 by a range between a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0244] In certain embodiments, the pharmaceutical composition is for use in treating a disease or disorder associated with ROCK2. In certain embodiments, the pharmaceutical composition is for use in preventing a disease or disorder associated with ROCK2. In certain embodiments, the pharmaceutical composition is for use in inhibiting ROCK2.

[0245] The compounds or compositions described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., efficacy and / or effectiveness)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell, for example, in treating a ROCK2-related disease or disorder in a subject in need thereof, preventing a ROCK2-related disease or disorder in a subject in need thereof, and / or reducing the risk of developing a ROCK2-related disease or disorder in a subject in need thereof. It will also be understood that the additional pharmaceutical agents used can achieve the desired effect on the same disorder and / or can achieve different effects. In certain embodiments, the pharmaceutical compositions described herein, comprising a compound described herein and an additional pharmaceutical agent, exhibit a synergistic effect that is not present in pharmaceutical compositions comprising one of the compound and the additional pharmaceutical agent, but not both.

[0246] The compound or composition may be administered simultaneously with, before, or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration under the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides, synthetic proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease or disorder associated with ROCK2. Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may be administered together with each other and / or with the compounds or compositions described herein in a single dose, or may be administered separately in different doses. The specific combination used in the regimen will take into account the compatibility of the compounds described herein with the additional pharmaceutical agent(s), and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that the combined additional pharmaceutical agent(s) will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

[0247] Additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, anti-inflammatory agents, and immunosuppressants. In certain embodiments, the additional pharmaceutical agent is an anti-inflammatory agent. In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the additional pharmaceutical agent is an antiproliferative agent. In certain embodiments, the additional pharmaceutical agent is an anticancer agent. In certain embodiments, the anti-cancer agent is an epigenetic or transcriptional modulator (e.g., DNA methyltransferase inhibitors, HDAC inhibitors, lysine methyltransferase inhibitors), antimitotic agents (e.g., taxanes and vinca alkaloids), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporphine (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypocrelin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide ... famide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vin blastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents such as nanoparticle albumin-bound paclitaxel (ABRAXANE)), docosahexaenoic acid-conjugated paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamic acid-conjugated paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrugs (TAPs),ANG1005 (Angiopep-2 conjugated to three paclitaxel molecules), paclitaxel-EC-1 (paclitaxel conjugated to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors ( methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca, 2+ATPase inhibitors (e.g., thapsigargin), thalidomide, lenalidomide, pomalidomide, tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cediranib (RECENTIN™), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®), lapatinib (TYKERB®, TYVERB®), lestaurtinib, neratinib, nilotinib (TASIGNA®), semaxanib, sunidomide, tinib (SUTENT®), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK (trademark)), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosin, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine. In certain embodiments, the additional pharmaceutical agent is cisplatin. In certain embodiments, the additional pharmaceutical agent is paclitaxel. In certain embodiments, the additional pharmaceutical agent is vincristine.

[0248] In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the immunotherapy is useful in the treatment of cancer. Exemplary immunotherapies include, but are not limited to, T cell therapy, interferons, cytokines (e.g., tumor necrosis factor, interferon alpha, interferon gamma), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulatory and / or immunomodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF), and antibodies. In certain embodiments, the immunotherapy is a T cell therapy. In certain embodiments, the T cell therapy is a chimeric antigen receptor T cell (CAR-T). In certain embodiments, the immunotherapy is an antibody. In certain embodiments, the antibodies are anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-TIM3 antibodies, anti-OX40 antibodies, anti-GITR antibodies, anti-LAG-3 antibodies, anti-CD137 antibodies, anti-CD27 antibodies, anti-CD28 antibodies, anti-CD28H antibodies, anti-CD30 antibodies, anti-CD39 antibodies, anti-CD40 antibodies, anti-CD47 antibodies, anti-CD48 antibodies, Anti-CD70 antibody, anti-CD73 antibody, anti-CD96 antibody, anti-CD160 antibody, anti-CD200 antibody, anti-CD244 antibody, anti-ICOS antibody, anti-TNFRSF25 antibody, anti-TMIGD2 antibody, anti-DNAM1 antibody, anti-BTLA antibody, anti-LIGHT antibody, anti-TIGIT antibody, anti-VISTA antibody, anti-HVEM antibody, anti-Siglec antibody, anti-GAL1 Antibodies, anti-GAL3 antibody, anti-GAL9 antibody, anti-BTNL2 (butrophylins) antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H5 antibody, anti-B7-H6 antibody, anti-KIR antibody, anti-LIR antibody, anti-ILT antibody, anti-MICA antibody, anti-MICB antibody, anti-NKG2D antibody, anti-NKG2A antibody, anti-TGFβ antibody anti-TGFβR antibody, anti-CXCR4 antibody, anti-CXCL12 antibody, anti-CCL2 antibody, anti-IL-10 antibody, anti-IL-13 antibody, anti-IL-23 antibody, anti-phosphatidylserine antibody, anti-neuropilin antibody, anti-GalCer antibody, anti-HER2 antibody, anti-VEGFA antibody, anti-VEGFR antibody, anti-EGFR antibody, or anti-Tie2 antibody.In certain embodiments, the antibody is selected from the group consisting of pembrolizumab, rivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lurizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS-986016 , BMS-986178, IMP321, IPH2101, IPH2201, valilumab, urocupulumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002, CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092, CX-072, CX-2009, CP-870893, lucatumumab, dacetuzumab, Chi Lob 7 / 4, RG6058, RG7686, RG7876, RG7888, TRX518, MK-4166, MGA271, IMC-CS4, emactuzumab, pertuzumab, obinutuzumab, cabilalizumab, margetuximab, enoblitzumab, mogamulizumab, carlumab, bevacizumab, trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), alemtuzumab (CAMPATH®), or ranibizumab (Lucentis®).

[0249] In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with anti-cancer therapies, including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation).

[0250] In certain embodiments, the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to form a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to form an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parenteral injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for subcutaneous injection.

[0251] After being formulated with appropriate pharmaceutically acceptable excipients at a desired dosage, the pharmaceutical compositions of the present disclosure can be administered orally, parenterally, intracisternally, intraperitoneally, topically, bucally, etc. to humans and other animals depending on the disease or disorder.

[0252] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (I) or (II) are administered orally or parenterally at a dosage level of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg of the subject's body weight per day, in one or more doses (depending on the mode of administration), over one or more days. In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 10 mg / kg of the subject's body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. In certain embodiments, the compounds described herein may be administered at a dosage level sufficient to deliver about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and more preferably about 1 mg / kg to about 25 mg / kg of body weight per day, one or more times daily, to achieve the desired therapeutic and / or prophylactic effect. The desired dosage may be delivered three times daily, twice daily, once daily, every other day, every third day, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations). In certain embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes nonspecific effects.

[0253] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0254] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology.In general, such preparation methods include the steps of bringing into association a composition comprising a compound of formula (I) or (II) with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0255] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses.As used herein, " unit dose " is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is approximately equal to the dosage of active ingredient that will be administered to a subject and / or a convenient fraction of such dosage, such as half or one-third of such dosage.

[0256] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0257] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and perfuming agents may also be present in the compositions.

[0258] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0259] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0260] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij30), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0261] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Chorizoides extract, Panwah gum, Gahatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0262] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0263] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0264] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0265] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0266] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0267] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0268] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0269] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0270] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0271] Exemplary natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea Cubeba oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0272] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. In certain embodiments for parenteral administration, the agents of the invention are mixed with solubilizing agents, such as CREMOPHOR EL® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0273] Injectable preparations, for example, sterile aqueous or oily injection suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions.Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution.In addition, sterile fixed oils are commonly used as solvents or suspending media.For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides.In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0274] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0275] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0276] Solid compositions of a similar type may be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. These may optionally contain opacifying agents and may be composed so that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0277] The active agent may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active agent may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. According to common practice, such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0278] Formulations suitable for topical administration include liquid or semi-liquid preparations, such as solutions or suspensions, including liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes, or drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier, such as a lotion, cream, ointment, or soap. Useful carriers can form a film or layer on the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the drug can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to tissue surfaces. For example, hydroxypropyl cellulose or fibrinogen / thrombin solutions can be advantageously used. Alternatively, tissue coating solutions, such as pectin-containing formulations, may be used. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of drugs to the body. Such dosage forms can be made by dissolving or dispensing the drug in a suitable vehicle. Absorption enhancers can also be used to increase the flux of the drug across the skin. The rate can be controlled by using rate-controlling membranes or by dispersing the drug in a polymer matrix or gel.

[0279] Furthermore, carriers for topical formulations can be in the form of hydroalcoholic systems (e.g., liquids and gels), anhydrous oil or silicone-based systems, or emulsion systems (including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions). Emulsions can cover a wide range of viscosities, including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, etc. Emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semi-solids (such as gels and sticks), and aqueous-based mousse systems.

[0280] The present disclosure also encompasses kits (e.g., pharmaceutical packs). The provided kits may include the pharmaceutical compositions or compounds described herein. In certain embodiments, the kits further include a first container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein provided in the first container and the second container are combined to form a single unit dosage form.

[0281] In certain embodiments, the kit is useful for treating a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the kit is useful for preventing a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the kit is useful for reducing the risk of developing a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the kit is useful for inhibiting ROCK2 activity (e.g., abnormal activity, such as increased activity) in a subject or cell.

[0282] In certain embodiments, the kits described herein further include instructions for using the pharmaceutical composition or compound. The kits described herein may also include information required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions are for treating a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the kit and instructions are for preventing a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the kit and instructions are for reducing the risk of developing a ROCK2-associated disease or disorder in a subject in need thereof. In certain embodiments, the kit and instructions are for inhibiting ROCK2 activity (e.g., aberrant activity, such as increased activity) in a subject or cell. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

[0283] How to use The present disclosure also provides a method of treating a ROCK2-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0284] The present disclosure also provides a method for preventing a ROCK2-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.

[0285] In certain embodiments, the ROCK2-associated disease or disorder is a fibrotic disorder, an autoimmune disease, an inflammatory condition, edema, an eye disease, a cardiovascular disease, a central nervous system disorder, or cancer.

[0286] In certain embodiments, the disease or disorder associated with ROCK2 is a fibrotic disorder. In certain embodiments, the disease or disorder associated with ROCK2 is pulmonary fibrosis, cystic pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, previous myocardial infarction, arterial stiffness, atherosclerosis, restenosis, arthrofibrosis, Crohn's disease, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloid and hypertrophic scars, glial scars, or renal fibrosis.

[0287] In certain embodiments, the disease or disorder associated with ROCK2 is a central nervous system disorder. In certain embodiments, the disease or disorder associated with ROCK2 is Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Batten disease, dementia, spinal muscular atrophy, motor neuron disease, spinocerebellar ataxia, acute or chronic pain, dementia, neurodegeneration, spinal cord injury, or cerebral vasospasm.

[0288] In certain embodiments, the ROCK2-associated disease or disorder is an ocular disease. In certain embodiments, the ROCK2-associated disease or disorder is glaucoma.

[0289] In certain embodiments, the ROCK2-associated disease or disorder is an autoimmune disease. In certain embodiments, the ROCK2-associated disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD).

[0290] In certain embodiments, the ROCK2-associated disease or disorder is an inflammatory condition. In certain embodiments, the ROCK2-associated disease or disorder is asthma, cardiovascular inflammation, renal inflammation, or arteriosclerosis.

[0291] In certain embodiments, the disease or disorder associated with ROCK2 is cardiovascular disease.In certain embodiments, the disease or disorder associated with ROCK2 is hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral arterial disease, peripheral circulatory disorder, cerebral cavernous malformation, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, acute respiratory distress syndrome (ARDS) or erectile dysfunction.

[0292] In certain embodiments, the ROCK2-associated disease or disorder is edema. In certain embodiments, the ROCK2-associated disease or disorder is lymphedema. In certain embodiments, the lymphedema is caused by at least a parasitic disease. In certain embodiments, the lymphedema is caused by at least filariasis. In certain embodiments, the lymphedema is caused by at least elephantiasis. In certain embodiments, the ROCK2-associated disease or disorder is angioedema, cerebral edema, CHAPLE syndrome, cardiac edema, hydrops fetalis, inflammatory edema, macular edema, myxedema, pulmonary edema, peripheral edema, periorbital edema, or skin edema. In certain embodiments, the ROCK2-associated disease or disorder is hereditary angioedema, cystoid macular edema, Irvine-Gass syndrome, diabetic macular edema, or foot edema. In certain embodiments, edema is at least caused by sitting or standing still in one position for a long time, excessive sodium intake, menstruation, or pregnancy, or a combination thereof.In certain embodiments, edema is a side effect of high blood pressure medication, nonsteroidal anti-inflammatory drugs, steroids, estrogen, or thiazolidinedione.In certain embodiments, edema is at least caused by congestive heart failure, cirrhosis, kidney disease, kidney damage, weakened or damaged leg veins, insufficient lymphatic system, or severe and / or prolonged protein binding, or a combination thereof.In certain embodiments, the method is a method for reducing the symptoms of edema (for example, swelling of tissues under (e.g., directly under) the skin, stretched skin, shiny skin, skin that remains depressed after being pressed for several seconds, or increased abdominal size).In certain embodiments, the skin is the skin of the leg or arm.

[0293] In certain embodiments, the ROCK2-associated disease or disorder is cancer. In certain embodiments, the ROCK2-associated disease or disorder is a solid tumor. In certain embodiments, the ROCK2-associated disease or disorder is a hematological malignancy.

[0294] The present disclosure also provides a method for inhibiting the activity of ROCK2, comprising contacting ROCK2 with an effective amount of a provided compound or pharmaceutical composition. In certain embodiments, ROCK2 is in vitro. In certain embodiments, ROCK2 is in vivo. In certain embodiments, ROCK2 is in a cell (e.g., a human cell). In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in vivo.

[0295] In another aspect, the disclosure provides a method of screening a library of compounds, comprising conducting an assay for a provided compound and an additional compound, wherein the additional compound is different from the provided compound. In certain embodiments, the assay is an in vitro assay. In certain embodiments, the assay is a biochemical assay. In certain embodiments, the assay is an enzyme assay. In certain embodiments, the assay is a cell-based assay. In certain embodiments, the assay is an assay described herein. In certain embodiments, the method of screening a library of compounds further comprises identifying an additional compound that is useful in the methods described herein.

[0296] The present disclosure also provides for the use of provided compounds in the methods described herein.The present disclosure also provides for the use of provided pharmaceutical compositions in the methods described herein.The present disclosure also provides provided compounds for use in the methods described herein.The present disclosure also provides for the use of provided pharmaceutical compositions in the methods described herein.The present disclosure also provides provided pharmaceutical compositions for use in the methods described herein.

[0297] example In order that the invention described herein may be more fully understood, the following examples are set forth: The examples described in this application are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as in any way limiting the scope thereof.

[0298] Synthesis method General Details

[0299] As used herein, the following terms have the meanings given: "DMF" refers to N,N-dimethylformamide; "EtOAc" refers to ethyl acetate; "DCM" refers to dichloromethane; "DMSO" refers to dimethylsulfoxide; "THF" refers to tetrahydrofuran; "2-MeTHF" refers to 2-methyltetrahydrofuran; "MeOH" refers to methanol; "EtOH" refers to ethanol; "MeCN" refers to acetonitrile; "DIPEA" or "DIEA" refers to N,N-dimethylformamide; "TEA" refers to isopropylethylamine; "TEA" refers to trimethylamine; "Py" refers to pyridine; "t-BuOK" refers to potassium tert-butoxide; "KOAc" refers to potassium acetate; "n-BuLi" refers to n-butyllithium; "TFA" refers to trifluoroacetic acid, "FA" refers to formic acid; "Ac2O" refers to acetic anhydride; "DHP" refers to 3,4-dihydro-2H-pyran; "NCS" refers to 1-chloropyrrolidine-2,5-dione; "MeI" refers to methyl iodide; "Fe " refers to iron powder; "TosCl" refers to paratoluenesulfonyl chloride; "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; "EDCI" refers to 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride; "PyBOP" refers to benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; "Xantphos" refers to 4,5-bis(diphenyl "Pd2dba3" refers to tris(dibenzylideneacetone)dipalladium; "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium; "Pd(dppf)Cl2" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); "HPLC" refers to high-performance liquid chromatography; "LCMS" or "LC-MS" refers to liquid chromatography / mass spectrometry; "min" refers to minute; "Pet."Ether" refers to petroleum ether; "TLC" refers to thin layer chromatography; "Rf" refers to retention factor; "RT" refers to retention time; "rt" refers to room temperature.

[0300] Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were conducted at room temperature (rt) unless otherwise noted.

[0301] Compound identity and purity were confirmed by LCMS UV using a SHIMADZU LCMS-2020. The PDA wavelengths were 220 nM and 254 nM, and MS was in positive electrospray mode (m / z: 100-1000). Aliquots were injected onto a series of HPLC columns (Kinetex® EVO C18 2.1*30 mm, 2.6 μm) maintained at 50 °C. Samples were eluted at a flow rate of 1.5 mL / min using a mobile phase system consisting of A (0.0375% (v / v) TFA in water) and B (0.01875% (v / v) TFA in acetonitrile) according to the gradient outlined in Table 1 below. Retention times (RT) are reported in minutes.

[0302] [Table 1]

[0303] Compound identity and purity were confirmed by LCMS UV using a SHIMADZU LCMS-2020. The PDA wavelengths were 220 nM and 254 nM, and MS was in positive electrospray mode (m / z: 100-1000). Aliquots were injected onto a series of HPLC columns (XBridge C18 2.1*50 mm, 5 μm) maintained at 40 °C. Samples were eluted at a flow rate of 1.5–2.0 mL / min using a mobile phase system consisting of A (water containing 0.025% (v / v) NH₃·H₂O) and B (acetonitrile) according to the gradient outlined in Table 2 below. Retention times (RT) are reported in minutes.

[0304] [Table 2]

[0305] Compound identity and purity were confirmed by LCMS UV using an Agilent 1260 G6125B column. The DAD wavelengths were 220 nM and 254 nM, and MS was in positive electrospray mode (m / z: 100-1000). Aliquots were injected onto a series of HPLC columns (XBridge C18 2.1*50 mm, 5 μm) maintained at 40 °C. Samples were eluted at a flow rate of 1.5–2.0 mL / min using a mobile phase system consisting of A (water containing 0.025% (v / v) NH₃·H₂O) and B (acetonitrile) according to the gradient outlined in Table 3 below. Retention times (RT) are reported in minutes.

[0306] [Table 3]

[0307] NMR was also used to characterize the final compounds. 1 H NMR spectra were acquired at room temperature on a Bruker AVANCE III 400 equipped with a 5mm BBO probe with a Z-gradient, a Bruker AVANCE III HD 400 equipped with a 5mm BBO probe with a Z-gradient, a Bruker AVANCE NEO 400 equipped with either a 5mm BBO probe with a Z-gradient or a 5mm BBO prodigy cryoprobe, and a Bruker NEO NANOBAY 400 equipped with either a 5mm BBO probe with a Z-gradient or a 5mm BBO iProbe, unless otherwise noted. Chemical shifts are reported in ppm and referenced to either DMSO-d6 (2.50 ppm), CDCl3 (7.26 ppm), or MeOD-d4 (3.31 ppm). NH or OH signals that exchange with deuterated solvents are not reported.

[0308] In some cases, compound Rf values ​​were measured on silica thin-layer chromatography (TLC) plates. Compound purification was performed by flash column chromatography on silica or preparative HPLC. HPLC purification was performed using either a Gilson-281 or a Shimadzu LC-20AP in positive electrospray mode (m / z: 100-1000) equipped with a Shimadzu SPD-20A. The samples were eluted on a Phenomenex Luna C18 150*25mm*10um column at a flow rate of 25mL / min using a mobile phase system consisting of: 1. Basic condition: A (0.05% ammonia (v / v) in H2O) and B (acetonitrile), 2. TFA condition: A (0.075% TFA (v / v) in H2O and B (acetonitrile), 3. A (0.225% FA (v / v) in H2O and B (acetonitrile), 4. HCl condition: A (0.05% HCl (v / v) in H2O and B (acetonitrile), 5. Neutral condition: A (H2O) and B (acetonitrile) or A (10mmol NH4·HCO3) in H2O and B (acetonitrile), following different linear gradients for the sample.

[0309] Schematic route for the synthesis of intermediates 1-4: [ka]

[0310] Step 1: 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0311] [ka] To a suspension of 5-nitro-1H-indazole (35 g, 215 mmol) in DCM (450 mL) was added DHP (54 g, 644 mmol) at room temperature, followed by the addition of p-TsOH (3.69 g, 21.5 mmol) in one portion. The reaction was stirred at 30 °C for 16 h. The reaction was poured into brine (300 mL). The organic layer was washed with brine (2 × 300 mL), dried over Na SO , filtered, and concentrated. The residue was triturated with pet ether (500 mL) and stirred for 0.5 h. The mixture was filtered, and the solid was collected and dried under reduced pressure to give 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (42.2 g, 171 mmol, 80% yield) as a brown solid.

[0312] Intermediate 1: 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

[0313] [ka] To a solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5 g, 20.22 mmol) in MeOH (100 mL) was added 10 wt% palladium on carbon powder (0.5 g) under N2. The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred at room temperature under H2 (30 psi) for 16 h. The reaction mixture was filtered through a Celite pad, and the mother liquor was concentrated to give a residue, which was triturated with pet. ether / EtOAc / MeOH (50 mL / 10 mL / 5 mL) for 1 h. The mixture was filtered to give 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (4 g, 17.49 mmol, 87% yield) as a brown solid. LC-MS (ES) + , Method A), 0.27min, m / z 218.3[M+H] + .

[0314] Intermediate 2: Phenyl(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate

[0315] [ka] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (2 g, 9.21 mmol), NaHCO (1.55 g, 18.41 mmol) in THF (10 mL) and HO (10 mL) was added phenyl carbonochloridate (1.59 g, 10.13 mmol) at 0 °C, and the reaction was stirred at 0 °C for 0.5 h. The reaction mixture was filtered, and the filter cake was dried to give phenyl (1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate (2.50 g, 7.41 mmol, 80% yield) as a pink solid. LC-MS (ES+, Method D), 0.88 min, m / z 338.0 [M+H] + .

[0316] Intermediate 3: 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

[0317] [ka] NCS (6.15 g, 46.03 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (5 g, 23.01 mmol) in MeCN (80 mL) at 0 °C, and the reaction solution was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of aqueous sodium sulfite (10 wt%, 80 mL) and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by preparative HPLC (30–80% MeCN / HO) to give 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1.7 g, 6.75 mmol, 29.4% yield). LC-MS (ES) analysis revealed that the 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1.7 g, 6.75 mmol, 29.4% yield) was obtained. + , Method A), 0.51min, m / z 252.1[M+H] + .

[0318] Intermediate 4: Phenyl (4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate

[0319] [ka] To a solution of 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1 g, 3.97 mmol) and NaHCO (667 mg, 7.95 mmol) in THF (10 mL) and HO (10 mL) was added phenyl carbonochloridate (684 mg, 4.37 mmol) at 0° C. The reaction solution was stirred at 0° C. for 0.5 h. The reaction solution was filtered, and the filter cake was washed with EtOAc (20×3 mL) to give phenyl (4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate (1 g, 2.69 mmol, 67.7% yield) as a brown solid.

[0320] Intermediate 5: 1H-imidazole-4-carbonyl chloride

[0321] [ka] To a mixture of 1H-imidazole-4-carboxylic acid (100 mg, 892 μmol) in DCM (10 mL) was added (COCl) (1.45 g, 11.4 mmol) and DMF (97.82 mg, 1.34 mmol) at room temperature under N. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give 1H-imidazole-4-carbonyl chloride (115 mg, 881 μmol) as a yellow solid.

[0322] Schematic route for the synthesis of intermediate 6: [ka]

[0323] Step 1: Methyl 2-methoxypyrimidine-5-carboxylate

[0324] [ka] To a solution of methyl 2-chloropyrimidine-5-carboxylate (1 g, 5.79 mmol) in MeOH (10 mL) was added sodium methoxide in CHOH (5.4 M, 1.07 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction solvent was removed under reduced pressure, and the residue was washed with HO (20 mL). The mixture was filtered, and methyl 2-methoxypyrimidine-5-carboxylate (950 mg, 5.65 mmol, 98% yield) was obtained from the filter cake as a pale yellow solid. LC-MS (ES) + , Method A), 0.31min, m / z 169.1[M+H] + .

[0325] Intermediate 6: 2-Methoxypyrimidine-5-carboxylic acid

[0326] [ka] To a solution of methyl 2-methoxypyrimidine-5-carboxylate (500 mg, 2.97 mmol) in MeOH (6 mL), dioxane (4 mL), and HO (2 mL) was added NaOH (238 mg, 5.95 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction mixture was acidified to pH = 2 with aqueous HCl (1 M), and the solvent was removed under reduced pressure to give 2-methoxypyrimidine-5-carboxylic acid (500 mg, crude) as a yellow solid. LC-MS (ES) + , Method A), 0.14min, m / z 155.1[M+H] + .

[0327] Schematic Route for the Synthesis of Examples 1-9: [ka]

[0328] Step 1: 3-Iodo-1-(3-nitrophenyl)-1H-pyrazole

[0329] [ka] To a mixture of (3-nitrophenyl)boronic acid (5.16 g, 30.93 mmol) and 3-iodo-1H-pyrazole (3 g, 15.47 mmol) in DCM (10 mL) was added 4 Å molecular sieves (10 g, 1.55 mmol), Py (2.45 g, 30.93 mmol), and Cu(OAc) (4.21 g, 23.20 mmol) at room temperature. The mixture was stirred at room temperature under O (15 psi) for 16 h. The reaction mixture was poured into EtOAc (500 mL) and filtered to remove 4 Å MS and copper salts, and the mother liquor was concentrated to give a residue. The residue was purified by flash silica gel chromatography eluting with 0–10% EtOAc / pet. ether to give 3-iodo-1-(3-nitrophenyl)-1H-pyrazole (6.3 g, crude). The crude material was repurified by reverse-phase MPLC (FA conditions) to give 3-iodo-1-(3-nitrophenyl)-1H-pyrazole (4.6 g, 14.60 mmol, 94% yield) as a yellow solid. LC-MS (ES + , Method A), 0.96min, m / z 316.0[M+H] + .

[0330] Step 2: N-(1-(3-nitrophenyl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

[0331] [ka] To a mixture of 3-iodo-1-(3-nitrophenyl)pyrazole (2.5 g, 7.93 mmol) and 1-tetrahydropyran-2-ylindazol-5-amine (1.74 g, 7.93 mmol) in dioxane (50 mL) was added Xantphos (459 mg, 793.48 μmol), CsCO (5.17 g, 15.87 mmol), and Pd(dba) (727 mg, 793.48 μmol) at room temperature under N. The suspension was degassed under reduced pressure and purged with N for 5 minutes. The mixture was heated to 110 °C and stirred for 16 hours. The mixture was poured into EtOAc (150 mL) and water (300 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0-30% EtOAc / pet. ether to afford N-(1-(3-nitrophenyl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1.9 g, 4.28 mmol, 54% yield) as a yellow solid. LC-MS (ES) analysis revealed that the 4-hydroxybenzoic acid moiety was soluble in 1% CO₂O, 2% ethanol, and 1% ethanol. + , Method A), 1.0min, m / z 405.2[M+H] + .

[0332] Step 3: N-(1-(3-aminophenyl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

[0333] [ka] To a mixture of N-[1-(3-nitrophenyl)pyrazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine (1.3 g, 3.09 mmol) in EtOH (80 mL) and HO (16 mL) was added NH4Cl (990 mg, 18.52 mmol) at room temperature under N2. The mixture was heated to 50 °C, and Fe (948 mg, 16.97 mmol) was added. The mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, and EtOAc (100 mL) was added to the mixture, which was then filtered through a Celite pad. The filter cake was washed with EtOAc (100 mL). The mother liquor was concentrated to give a residue. The residue was poured into water (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-(1-(3-aminophenyl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1.25 g, 2.87 mmol, 93% yield) as a red oil. LC-MS (ES) + , Method A), 0.86min, m / z 375.2[M+H] + .

[0334] Step 4: N-(1-(3-aminophenyl)-1H-pyrazol-3-yl)-1H-indazol-5-amine

[0335] [ka] To a mixture of N-[1-(3-aminophenyl)pyrazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine (1.25 g, 2.87 mmol) in DCM (25 mL) and MeOH (25 mL) was added HCl / dioxane (4 M, 25 mL) at 25 °C under N2. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a residue. EtOAc (50 mL) was added to the residue and stirred at room temperature for 1 hour. The mixture was filtered and the solid was collected to give N-(1-(3-aminophenyl)-1H-pyrazol-3-yl)-1H-indazol-5-amine (510 mg, 1.49 mmol, 52% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.70min, m / z 291.2[M+H] + .

[0336] Schematic method A: [ka]

[0337] Example 1: N-(3-(3-((1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0338] [ka] To a mixture of N-(1-(3-aminophenyl)-1H-pyrazol-3-yl)-1H-indazol-5-amine (100 mg, 293 μmol) and 1-methylpyrazole-4-carboxylic acid (36.9 mg, 293 μmol) in DMF (3 mL) was added DIPEA (114 mg, 878 μmol) and HATU (167 mg, 439 μmol) at room temperature under N. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and HO (0.5 mL), KCO (100 mg) was added, and the mixture was stirred at room temperature for 0.5 hours and then concentrated to give a residue. The residue was purified by preparative HPLC (25-55% MeCN / HO) to give N-(3-(3-((1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide (32.6 mg, 78.6 μmol, 27% yield) as a gray solid. LC-MS (ES) + , Method A), 0.87min, m / z 399.4[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 9.98 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.22 (t, J = 2.0 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.58-7.61 (m, 1H), 7.50-7.46 (m, 1H), 7.45-7.38 (m, 2H), 7.31 (dd, J = 2.0, 8.8 Hz, 1H), 6.11 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H).

[0339] Schematic method B: [ka]

[0340] Example 2: N-(3-(3-((1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1H-imidazole-4-carboxamide

[0341] [ka] To a mixture of N-(1-(3-aminophenyl)-1H-pyrazol-3-yl)-1H-indazol-5-amine (100 mg, 293 μmol) in Py (5 mL) was added 1H-imidazole-4-carbonyl chloride (174 mg, 1.33 mmol) in Py (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and poured into ice water (50 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (20-40% MeCN / HO) to give N-(3-(3-((1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1H-imidazole-4-carboxamide (63.6 mg, 162.15 μmol, 55% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.79min, m / z 385.4[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.83-12.75 (m, 1H), 12.75-12.59 (m, 1H), 9.93 (s, 1H), 8.72 (s, 1H), 8.34 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H), 7.85 (s, 2H), 7.67-7.71 (m, 1H), 7.52-7.47 (m, 1H), 7.45-7.37 (m, 2H), 7.32 (dd, J = 2.0, 9.2 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H).

[0342] Schematic method C: [ka]

[0343] Step 1: 1-methyl-N-(3-(4-methyl-3-((1-(1-methyl-1H-pyrazole-4-carbonyl)-1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1H-pyrazole-4-carboxamide

[0344] [ka] To a solution of N-(1-(3-aminophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-indazol-5-amine (150 mg, 492.86 μmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (93.23 mg, 739.28 μmol) in Py (9 mL) was added EDCI (236.20 mg, 1.23 mmol). The mixture was stirred at room temperature for 16 hours. The residue was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (60 mL), dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 1-methyl-N-(3-(4-methyl-3-((1-(1-methyl-1H-pyrazole-4-carbonyl)-1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1H-pyrazole-4-carboxamide (256 mg, crude) as a yellow solid.

[0345] Example 3: N-(3-(3-((1H-indazol-5-yl)amino)-4-methyl-1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0346] [ka] To a solution of 1-methyl-N-(3-(4-methyl-3-((1-(1-methyl-1H-pyrazole-4-carbonyl)-1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenyl)-1H-pyrazole-4-carboxamide (256 mg, 492 μmol) in EtOH (5 mL) was added KCO (256 mg, 1.85 mmol) and HO (2 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give N-(3-(3-((1H-indazol-5-yl)amino)-4-methyl-1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide (26.6 mg, 61.27 μmol, 12.5% ​​yield) as a yellow solid. LC-MS (ES) + , Method A), 0.55min, m / z 413.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.96 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 10.4 Hz, 2H), 7.99-7.95 (m, 2H), 7.55-7.48 (m, 1H), 7.47-7.43 (m, 1H), 7.40-7.37 (m, 3H), 3.92, (s, 3H), 2.08 (d, J = 7.6 Hz, 6H).

[0347] Schematic method D: [ka]

[0348] Example 4: N-(3-(3-((1H-indazol-5-yl)amino)-4-methyl-1H-pyrazol-1-yl)phenyl)nicotinamide

[0349] [ka] To a solution of N-(1-(3-aminophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-indazol-5-amine (150 mg, 492.86 μmol) and nicotinic acid (91.0 mg, 739.28 μmol) in Py (10 mL) was added EDCI (236.2 mg, 1.23 mmol). The mixture was stirred at room temperature for 16 hours. The residue was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (60 mL), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give a residue that was purified by preparative HPLC (30-80% MeCN / HO) to give N-(3-(3-((1H-indazol-5-yl)amino)-4-methyl-1H-pyrazol-1-yl)phenyl)nicotinamide (34.8 mg, 82.4 μmol, 16.7% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.53min, m / z 410.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H) 10.59 (s, 1H) 9.16 (d, J = 1.6 Hz, 1H), 8.79-8.78 (m, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.60-7.59 (m, 2H), 7.48-7.47 (m, 2H), 7.42-7.41 (m, 2H), 2.10 (s, 3H).

[0350] General method E: [ka]

[0351] Example 5: N-(3-(3-((1H-indazol-5-yl)amino)-5-methyl-1H-pyrazol-1-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0352] [ka] To a DMF solution (1 mL) of 1H-imidazole-4-carboxylic acid (40.5 mg, 361 μmol) and N-[1-(3-aminophenyl)-5-methyl-pyrazol-3-yl]-1H-indazol-5-amine (110 mg, 361 μmol), DIEA (12.74 mg, 98.6 μmol) and PyBOP (34.2 mg, 65.7 μmol) were added at room temperature, and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was poured into water (20 mL) and filtered through filter paper. The filter cake was washed with MeOH (10 mL), and the filter layer was concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (35–65% MeCN / HO) to give N-(3-(3-((1H-indazol-5-yl)amino)-5-methyl-1H-pyrazol-1-yl)phenyl)-1H-imidazole-4-carboxamide (50 mg, 109 μmol, 30% yield) as a yellow solid. LC-MS (ES+, Method A), 0.35 min, m / z 399.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.19 (s, 1H), 8.67 (s, 1H), 8.13 (t, J = 2.0 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.93 (s, 1H), 7.78 (dd, J = 1.2, 8.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.28 (dd, J = 2.0, 8.8 Hz, 1H), 5.92 (s, 1H), 2.40 (s, 3H).

[0353] Compounds prepared in a similar manner to those described above are shown in Table 4 below: [Table 4]

[0354] Schematic Route for the Synthesis of Examples 10-15: [ka]

[0355] Step 1: tert-Butyl 2-(4-(3-iodo-1H-pyrazol-1-yl)phenoxy)acetate

[0356] [ka] To a mixture of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (1 g, 2.99 mmol), 3-iodo-1H-pyrazole (638.42 mg, 3.29 mmol) in MeCN (20 mL) was added boronic acid (370 mg, 5.98 mmol), Py (473.4 mg, 5.98 mmol), 4Å MS (1 g, 2.99 mmol), and Cu(OAc) (815.2 mg, 4.49 mmol) at room temperature. The reaction was purged with O and stirred at 60 °C under O (15 Psi) for 16 h. The reaction mixture was cooled to room temperature, and EtOAc (100 mL) was added. The mixture was filtered through a Celite pad, and the mother liquor was concentrated to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-30% EtOAc / Pet. ether to give tert-butyl 2-(4-(3-iodo-1H-pyrazol-1-yl)phenoxy)acetate (750 mg, 1.82 mmol) as a colorless oil. LC-MS (ES) + , Method A), 1.07min, m / z 401.0[M+H] + .

[0357] Step 2: tert-butyl 2-(4-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenoxy)acetate

[0358] [ka] To a mixture of tert-butyl 2-(4-(3-iodo-1H-pyrazol-1-yl)phenoxy)acetate (280 mg, 678.64 μmol) and 1-tetrahydropyran-2-ylindazol-5-amine (162.2 mg, 746.51 μmol) in dioxane (5 mL), XPhos (64.7 mg, 135.73 μmol), CsCO (442.2 mg, 1.36 mmol), and Pd(dba) (62.1 mg, 67.86 μmol) were added at room temperature under N. The suspension was degassed under reduced pressure and purged with N for 5 minutes. The mixture was heated to 100° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, and EtOAc (100 mL) and water (100 mL) were added. The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 15-40% EtOAc / Pet. ether to afford tert-butyl 2-(4-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenoxy)acetate (150 mg, 300.27 μmol, 44% yield) as a colorless oil. LC-MS (ES) + , Method A), 1.00min, m / z 490.3[M+H] + .

[0359] Step 3: 2-(4-(3-((1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenoxy)acetic acid

[0360] [ka] To a mixture of tert-butyl 2-(4-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenoxy)acetate (230 mg, 469.80 μmol) in DCM (5 mL) was added TFA (3 mL) in one portion at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated to give 2-(4-(3-((1H-indazol-5-yl)amino)-1H-pyrazol-1-yl)phenoxy)acetic acid (230 mg, 658.38 μmol) as a yellow oil. LC-MS (ES) + , Method A), 0.83min, m / z 350.1[M+H] + .

[0361] Compounds prepared in a similar manner as described above are shown in Table 5 below: [Table 5-1] [Table 5-2]

[0362] Schematic Route for the Synthesis of Examples 16-20: [ka]

[0363] Step 1: tert-Butyl 2-(4-bromophenoxy)acetate

[0364] [ka] To a solution of 4-bromophenol (30 g, 173.40 mmol) and tert-butyl 2-bromoacetate (43.97 g, 225.42 mmol) in MeCN (350 mL) was added K2CO3 (47.93 g, 346.80 mmol). The mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature and filtered. The solid was washed with EtOAc (200 mL). The filtrate was concentrated. The residue was purified by reverse-phase column chromatography (basic conditions) to give tert-butyl 2-(4-bromophenoxy)acetate (41 g, 142.78 mmol, 82% yield) as a brown oil.

[0365] Step 2: tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

[0366] [ka] A mixture of tert-butyl 2-(4-bromophenoxy)acetate (41 g, 142.78 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (43.5 g, 171.34 mmol), and KOAc (28 g, 285.57 mmol) in dioxane (500 mL) was degassed with N for 5 minutes. Pd(dppf)Cl (5.22 g, 7.14 mmol) was then added, and the reaction mixture was degassed with N for an additional 5 minutes. The reaction was stirred at 90 °C for 16 hours. The reaction was cooled to room temperature and concentrated to remove the solvent to give a residue. The residue was purified by column chromatography eluting with 0–10% EtOAc / Pet. ether to give the crude product. The crude product was repurified by reverse phase column (basic condition) to give tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (30.3 g, 90.66 mmol, 64% yield) as a white solid.

[0367] Step 3: tert-Butyl 2-(4-(3-iodo-1H-indazol-1-yl)phenoxy)acetate

[0368] [ka] To a mixture of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (1 g, 2.99 mmol), 3-iodo-1H-indazole (803 mg, 3.29 mmol) in MeCN (20 mL) was added boronic acid (370 mg, 5.98 mmol), Py (473 mg, 5.98 mmol), 4Å MS (1 g, 2.99 mmol), and Cu(OAc) (815 mg, 4.49 mmol) at room temperature. The reaction was purged with O and stirred at 60 °C under O (15 Psi) for 16 h. The reaction mixture was cooled to room temperature, and EtOAc (100 mL) was added. The mixture was filtered through a Celite pad, and the mother liquor was concentrated to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-30% EtOAc / Pet. ether to give tert-butyl 2-(4-(3-iodo-1H-indazol-1-yl)phenoxy)acetate (930 mg, 2.00 mmol) as a colorless oil. LC-MS (ES) + , Method A), 1.13min, m / z 451.2[M+H] + .

[0369] Step 4: tert-butyl 2-(4-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenoxy)acetate

[0370] [ka] To a mixture of tert-butyl 2-(4-(3-iodo-1H-indazol-1-yl)phenoxy)acetate (930 mg, 2.00 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (440 mg, 2.00 mmol) in dioxane (12 mL), Xantphos (116 mg, 200.35 μmol), CsCO (1.31 g, 4.01 mmol), and Pd(dba) (183 mg, 200.35 μmol) were added at room temperature under N. The suspension was degassed under reduced pressure and purged with N for 5 minutes. The mixture was heated to 105° C. and stirred for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0-16% EtOAc / pet. ether to afford tert-butyl 2-(4-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenoxy)acetate (560 mg, 985.87 μmol, 49% yield) as a colorless oil. LC-MS (ES) + , Method A), 1.16min, m / z 540.3[M+H] + .

[0371] Step 5: 2-(4-(3-((1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenoxy)acetic acid

[0372] [ka] To a solution of tert-butyl 2-(4-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenoxy)acetate (200 mg, 352.10 μmol) in DCM (8 mL) was added TFA (6.16 g, 54.02 mmol) at 0° C. under N2. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 2-(4-(3-((1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenoxy)acetic acid (140 mg, 350.52 μmol, 99% yield) as a yellow oil. LC-MS (ES) + , Method A), 0.92min, m / z 400.1[M+H] + .

[0373] Compounds prepared in a similar manner as described above are shown in Table 6 below: [Table 6-1] [Table 6-2]

[0374] Schematic Route for the Synthesis of Examples 21-32: [ka]

[0375] Step 1: 3-Iodo-1-(3-nitrophenyl)-1H-indazole

[0376] [ka] To a mixture of (3-nitrophenyl)boronic acid (4.10 g, 24.6 mmol) and 3-iodo-1H-indazole (3 g, 12.3 mmol) in DCM (8 mL) was added 4Å MS (0.8 g, 1.23 mmol), Py (1.94 g, 24.6 mmol), and Cu(OAc)2 (3.35 g, 18.4 mmol) at room temperature. The mixture was stirred at room temperature under O2 (15 psi) for 16 h. The reaction mixture was poured into EtOAc (500 mL) and filtered to remove 4Å MS and copper salts. The mother liquor was concentrated to give a residue, which was purified by flash silica gel chromatography eluting with 0–10% EtOAc / pet. ether to give 3-iodo-1-(3-nitrophenyl)-1H-indazole (3.95 g, 10.3 mmol, 84% yield) as a yellow solid. LC-MS(ES + , Method A), 1.07min, m / z 366.2[M+H] + .

[0377] Step 2: 1-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine

[0378] [ka] To a mixture of 3-iodo-1-(3-nitrophenyl)-1H-indazole (650 mg, 1.76 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (423 mg, 1.85 mmol) in dioxane (12 mL), Xantphos (102 mg, 176 μmol), CsCO (1.15 g, 3.52 mmol), and Pd(dba) (161 mg, 176 μmol) were added at room temperature under N. The suspension was degassed under reduced pressure and purged with N for 5 minutes. The mixture was heated to 105 °C and stirred for 16 hours. The reaction mixture was cooled to 20 °C and poured into water (50 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0-30% EtOAc / pet. ether to afford 1-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (720 mg, 1.58 mmol, 90% yield) as a red oil. LC-MS (ES) analysis revealed the following: + , Method A), 1.07min, m / z 455.2[M+H] + .

[0379] Step 3: 1-(3-aminophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine

[0380] [ka] To a mixture of 1-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (670 mg, 1.47 mmol) in EtOH (40 mL) and HO (8 mL) was added NHCl (473 mg, 8.85 mmol) at room temperature under N. The mixture was heated to 50 °C, and Fe (453 mg, 8.11 mmol) was added. The mixture was stirred at 80 °C for 1 h. EtOAc (100 mL) was added, and the mixture was filtered through a Celite pad. The mother liquor was concentrated to a residue. EtOAc (100 mL) and water (100 mL) were added, and the organic layer was separated. The aqueous phase was then extracted with EtOAc (50 mL x 2), and the combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(3-aminophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (625 mg, 1.38 mmol, 94% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.89min, m / z 425.2[M+H] + .

[0381] Step 4: 1-(3-aminophenyl)-N-(1H-indazol-5-yl)-1H-indazol-3-amine

[0382] [ka] To a solution of 1-(3-aminophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (575 mg, 1.27 mmol) in DCM (10 mL) and MeOH (10 mL) was added HCl / dioxane (4 M, 11.5 mL) at room temperature under N2. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a residue. EtOAc (50 mL) was added to the residue and stirred at room temperature for 1 hour. The mixture was filtered to give 1-(3-aminophenyl)-N-(1H-indazol-5-yl)-1H-indazol-3-amine (470 mg, 1.21 mmol, 95% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.84min, m / z 341.2[M+H] + .

[0383] General procedure for the synthesis of Example 24: [ka]

[0384] Step 1: N-(3-(3-((1-acetyl-1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenyl)acetamide

[0385] [ka] To a solution of 1-(3-aminophenyl)-N-(1H-indazol-5-yl)-1H-indazol-3-amine (70 mg, 205.65 μmol) in THF (2 mL) was added AcO (1.14 g, 11.21 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was partitioned between HO (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give N-(3-(3-((1-acetyl-1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenyl)acetamide (70 mg, crude) as a brown solid. LC-MS (ES) + , Method A), 0.64min, m / z 425.3[M+H] + .

[0386] Example 24: N-(3-(3-((1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenyl)acetamide

[0387] [ka] To a solution of N-(3-(3-((1-acetyl-1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenyl)acetamide (70 mg, 164.92 μmol) in EtOH (2 mL) and HO (1 mL) was added KCO (70 mg, 506.49 μmol) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (30-60% MeCN / HO) to give N-(3-(3-((1H-indazol-5-yl)amino)-1H-indazol-1-yl)phenyl)acetamide (23.38 mg, 60.28 μmol, 37% yield) as a white solid. LC-MS (ES) + , Method A), 0.57min, m / z 383.3[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 10.17 (s, 1H), 9.15 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.22-8.14 (m, 2H), 8.01 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.53-7.48 (m, 5H), 7.25 (t, J = 7.6 Hz, 1H), 2.12 (s, 3H).

[0388] Compounds prepared in a similar manner to those described above are shown in Table 7 below: [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0389] Schematic Route for the Synthesis of Examples 33-35: [ka]

[0390] Step 1: 3,3-bis(methylthio)-1-(3-nitrophenyl)prop-2-en-1-one

[0391] [ka] To a solution of 1-(3-nitrophenyl)ethanone (2 g, 12.11 mmol) and CS2 (2.03 g, 26.64 mmol) in THF (20 mL) was added t-BuOK (1 M, 26.64 mL) at 0 °C under N2. The mixture was stirred at room temperature for 0.5 h. CHCl (8.59 g, 60.55 mmol) was added to the mixture, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3,3-bis(methylthio)-1-(3-nitrophenyl)prop-2-en-1-one (3.0 g, 11.14 mmol, 92% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.64min, m / z 270.0[M+H] + .

[0392] Step 2: (Z)-3-(methylthio)-1-(3-nitrophenyl)-3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)prop-2-en-1-one

[0393] [ka] To a solution of 3,3-bis(methylthio)-1-(3-nitrophenyl)prop-2-en-1-one (2.40 g, 8.91 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (2.90 g, 13.37 mmol) in toluene (72 mL) was added BF3.Et2O (126 mg, 891 μmol). The mixture was stirred at 110 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was poured into water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase MPLC (FA conditions) to give (Z)-3-(methylthio)-1-(3-nitrophenyl)-3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)prop-2-en-1-one (1.9 g, 3.86 mmol, 43% yield) as a yellow oil. LC-MS (ES) + , Method A), 0.74min, m / z 439.2[M+H] + .

[0394] Step 3: (Z)-N'-Hydroxy-3-(3-nitrophenyl)-3-oxo-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanimidamide

[0395] [ka] To a solution of NH2OH.HCl (950 mg, 13.68 mmol) and (Z)-3-(methylthio)-1-(3-nitrophenyl)-3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)prop-2-en-1-one (1.5 g, 3.42 mmol) in EtOH (200 mL) was added KOH (768 mg, 13.68 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give (Z)-N'-hydroxy-3-(3-nitrophenyl)-3-oxo-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanimidamide (2 g, crude) as a yellow solid. LC-MS (ES) + , Method B), 0.74min, m / z 424.4[M+H] + .

[0396] Step 4: 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)isoxazol-3-amine

[0397] [ka] A solution of (Z)-N'-hydroxy-3-(3-nitrophenyl)-3-oxo-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanimidamide (2 g, 4.72 mmol) in toluene (200 mL) was stirred at 110 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (55-85% MeCN / HO) to give 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)isoxazol-3-amine (280 mg, 690.67 μmol, 56% yield) as a yellow solid. LC-MS (ES) analysis revealed that the 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)isoxazol-3-amine yield was 56%. + , Method A), 0.70min, m / z 406.1[M+H] + .

[0398] Step 5: 5-(3-aminophenyl)-N-(1H-indazol-5-yl)isoxazol-3-amine

[0399] [ka] To a solution of 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)isoxazol-3-amine (250 mg, 616.67 μmol) in EtOH (10 mL) and HO (0.5 mL), SnCl.2HO (695.7 mg, 3.08 mmol) was added in one portion at room temperature, and the reaction solution was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (12-42% MeCN / HO) to give 5-(3-aminophenyl)-N-(1H-indazol-5-yl)isoxazol-3-amine (70.1 mg, 226.33 μmol, 37% yield) as a yellow solid. LC-MS (ES) analysis revealed that the 5-(3-aminophenyl)-N-(1H-indazol-5-yl)isoxazol-3-amine was eluted. + , Method A), 0.45min, m / z 292.1[M+H] + .

[0400] General Method G for the Synthesis of Example 34: [ka]

[0401] Example 34: N-(3-(3-((1H-indazol-5-yl)amino)isoxazol-5-yl)phenyl)-1H-imidazole-4-carboxamide

[0402] [ka] To a DMF solution (1 mL) of 5-(3-aminophenyl)-N-(1H-indazol-5-yl)isoxazol-3-amine (51 mg, 175.07 μmol) and 1H-imidazole-4-carboxylic acid (39 mg, 350.15 μmol) was added DIPEA (68 mg, 525.22 μmol) and PyBOP (182 mg, 350.15 μmol) at room temperature. The mixture was then stirred at 50° C. for 48 hours. The reaction mixture was poured into water (20 mL) and filtered. The filter cake was washed with EtOAc (30 mL). To a mixture of the filter cake in MeOH (2 mL) was then added KCO (60 mg), and the mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water (20 mL) and filtered. The filter cake was washed with EtOAc (30 mL). The crude product was purified by preparative HPLC (12-42% MeCN / HO) to give N-(3-(3-((1H-indazol-5-yl)amino)isoxazol-5-yl)phenyl)-1H-imidazole-4-carboxamide (20.90 mg, 53.69 μmol, 31% yield) as an off-white solid. LC-MS (ES) + , Method A), 0.37min, m / z 386.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 12.68 (s, 1H), 10.04 (s, 1H), 9.19 (s, 1H), 8.36 (s, 1H), 7.99-7.97 (m, 3H), 7.90-7.80 (m, 2H), 7.55-7.53 (m, 1H), 7.50-7.45 (m, 2H), 7.32 (d, J = 9.2 Hz, 1H), 6.52 (s, 1H).

[0403] Compounds prepared in a similar manner to those described above are shown in Table 8 below: [Table 8]

[0404] Schematic Route for the Synthesis of Examples 36-38: [ka]

[0405] Step 1: tert-Butyl 2-(3-nitrobenzoyl)hydrazinecarboxylate

[0406] [ka] To a solution of 3-nitrobenzoic acid (5 g, 29.92 mmol) and tert-butyl hydrazine carboxylate (3.95 g, 29.92 mmol) in DMF (250 mL) was added HATU (11.38 g, 29.92 mmol) and DIEA (5.80 g, 44.88 mmol) at room temperature. The reaction was stirred at room temperature for 12 hours. The reaction was partitioned between HO (1000 mL) and EtOAc (150 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 150 mL). The combined organics were washed with brine (2 × 100 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-75% EtOAc / Pet. ether to give tert-butyl 2-(3-nitrobenzoyl)hydrazinecarboxylate (8.20 g, 29.15 mmol, 97% yield) as a white solid. LC-MS (ES) + , Method A), 0.47min, m / z 225.9[M-56+H] + .

[0407] Step 2: 3-Nitrobenzohydrazide

[0408] [ka] To a solution of tert-butyl 2-(3-nitrobenzoyl)hydrazinecarboxylate (7 g, 24.89 mmol) in dioxane (50 mL) was added HCl / dioxane (4 M, 50 mL) at room temperature, and the solution was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was added to aqueous NaHCO3 (1 M), and the solution was stirred at room temperature for 2 hours. The reaction was partitioned between HO (50 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (2 × 20 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 3-nitrobenzohydrazide (3.50 g, 19.32 mmol, 78% yield) as a white solid. LC-MS (ES) + , Method A), 0.18min, m / z 182.2[M+H] + .

[0409] Step 3: 2-(3-nitrobenzoyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)hydrazinecarboxamide

[0410] [ka] To a solution of phenyl (1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate (1.25 g, 3.71 mmol) and 3-nitrobenzohydrazide (671 mg, 3.71 mmol) in dioxane (30 mL) was added DIEA (958 mg, 7.41 mmol) at room temperature, and the reaction was stirred at 80 °C for 12 h. The reaction mixture was diluted with HO (50 mL) and acidified to pH = 7 with 1 M aqueous HCl. The mixture was filtered, and the filter cake was dried to give 2-(3-nitrobenzoyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)hydrazinecarboxamide (1.37 g, 3.23 mmol, 87% yield) as a pale yellow solid. LC-MS (ES) + , Method A), 0.50min, m / z 425.3[M+H] + .

[0411] Step 4: 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine

[0412] [ka] To a solution of 2-(3-nitrobenzoyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)hydrazinecarboxamide (1.36 g, 3.20 mmol) in DCM (50 mL) was added 4-methylbenzenesulfonyl chloride (855 mg, 4.49 mmol) and TEA (973 mg, 9.61 mmol) at 0° C., and the reaction was stirred at 0° C. for 1.5 hours. The reaction mixture was filtered, and the filter cake was dried to give 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine (660 mg, 1.62 mmol, 51% yield) as a pale yellow solid. LC-MS (ES) + , Method A), 0.60min, m / z 407.2[M+H] + .

[0413] Step 5: 5-(3-aminophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine

[0414] [ka] To a solution of 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine (650 mg, 1.60 mmol) in EtOH (12 mL) and HO (6 mL) was added Fe (447 mg, 8.00 mmol) and NHCl (856 mg, 15.99 mmol) at room temperature. The reaction was stirred at 80 °C for 1 h. It was then cooled to room temperature. The reaction mixture was then diluted with EtOAc (50 mL). The solution was filtered and the filter cake was triturated with EtOAc (10 mL) to give 5-(3-aminophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine (490 mg, 1.30 mmol, 81% yield) as a pale yellow solid. LC-MS (ES) + , Method A), 0.44min, m / z 377.3[M+H] + .

[0415] Step 6: 5-(3-aminophenyl)-N-(1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine

[0416] [ka] To a solution of 5-(3-aminophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine (430 mg, 1.14 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 10 mL) at room temperature. The reaction was stirred at room temperature for 2.5 hours. The reaction mixture was filtered and the filter cake was dried to give 5-(3-aminophenyl)-N-(1H-indazol-5-yl)-1,3,4-oxadiazol-2-amine (270 mg, 821.28 μmol, 72% yield) as a pale yellow solid. LC-MS (ES) + , Method A), 0.35min, m / z 393.3[M+H] + .

[0417] Compounds prepared in a similar manner to those described above (methods of Examples 1-5) are shown in Table 9 below: [Table 9]

[0418] Schematic Route for the Synthesis of Examples 39-41: [ka]

[0419] Step 1: 3-Nitrobenzoyl Isothiocyanate [ka]

[0420] A solution of 3-nitrobenzoyl chloride (3.5 g, 18.86 mmol) and KSCN (1.83 g, 18.86 mmol) in MeCN (40 mL) was stirred for 1 h at 80° C. The mixture was concentrated under reduced pressure to give 3-nitrobenzoyl isothiocyanate (3.93 g, crude) as a yellow solid.

[0421] Step 2: 3-Nitro-N-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamothioyl)benzamide

[0422] [ka] A solution of 3-nitrobenzoyl isothiocyanate (3.93 g, 18.88 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (4.10 g, 18.88 mmol) in MeCN (40 mL) was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filter cake was washed with MeCN (20 mL) and water (10 mL). The filter cake was collected to give 3-nitro-N-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamothioyl)benzamide (7.15 g, 16.81 mmol, 89% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.65min, m / z 426.3[M+H] + .

[0423] Step 3: (E)-Methyl N-(3-nitrobenzoyl)-N'-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamimidothioate

[0424] [ka] To a solution of 3-nitro-N-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamothioyl)benzamide (5 g, 11.75 mmol) and CHI (2.50 g, 17.63 mmol) in THF (75 mL) was added KCO (3.25 g, 23.50 mmol), and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was filtered, and the filter cake was washed with water (40 mL). The filter cake was collected to give (E)-methyl N-(3-nitrobenzoyl)-N'-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamimidothioate (2.82 g, 6.42 mmol, 55% yield) as a white solid. LC-MS (ES) + , Method A), 0.71min, m / z 440.1[M+H] + .

[0425] Step 4: 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,2,4-oxadiazol-3-amine

[0426] [ka] To a solution of (E)-methyl N-(3-nitrobenzoyl)-N'-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamimidothioate (2.82 g, 6.42 mmol) in MeOH (60 mL) were added NH2OH.HCl (1.34 g, 19.2 mmol) and TEA (3.90 g, 38.5 mmol), and the reaction solution was stirred at 50 °C for 66 hours. The reaction solution was filtered, and the filter cake was washed with MeOH (20 mL). The filter cake was collected to give 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,2,4-oxadiazol-3-amine (1.5 g, 3.69 mmol, 58% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.63min, m / z 407.1[M+H] + .

[0427] Step 5: 5-(3-aminophenyl)-N-(1H-indazol-5-yl)-1,2,4-oxadiazol-3-amine

[0428] [ka] To a solution of 5-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,2,4-oxadiazol-3-amine (200 mg, 492.13 μmol) in EtOH (5 mL) and HO (0.2 mL) was added SnCl.2HO (555 mg, 2.46 mmol), and the reaction solution was stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to ethyl acetate (30 mL) and sodium bicarbonate solution (10%, 10 mL). The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (19-49% MeCN / HO) to give 5-(3-aminophenyl)-N-(1H-indazol-5-yl)-1,2,4-oxadiazol-3-amine (110 mg, 210.13 μmol, 43% yield) as a white solid. LC-MS (ES) + , Method A), 0.49min, m / z 293.2[M+H] + .

[0429] Compounds prepared in a similar manner to those described above are shown in Table 10 below: [Table 10]

[0430] Schematic Route for the Synthesis of Examples 42-44: [ka]

[0431] Step 1: (Z)-N'-Hydroxy-3-nitrobenzimidamide

[0432] [ka] To a solution of hydroxylamine hydrochloride (14.1 g, 202.6 mmol) in pyridine (100 mL) was added 3-nitrobenzonitrile (5 g, 33.76 mmol) at 0 °C, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (Z)-N'-hydroxy-3-nitrobenzimidamide (6 g, 33.12 mmol, 98% yield) as a yellow solid.

[0433] Step 2: 3-(3-nitrophenyl)-1,2,4-oxadiazol-5-ol

[0434] [ka] To a solution of (Z)-N'-hydroxy-3-nitrobenzimidamide (3.5 g, 19.32 mmol) and dimethyl carbonate (2.61 g, 28.98 mmol) in DMSO (10 mL) was added NaOH (1.16 g, 28.98 mmol). The reaction solution was stirred at room temperature for 16 hours. The reaction was diluted with HO (10 mL), and concentrated HCl (15 mL) was added to the solution, which was then filtered and washed with HO (30 mL). The filter cake was collected to give 3-(3-nitrophenyl)-1,2,4-oxadiazol-5-ol (2.5 g, 12.07 mmol, 62% yield) as a yellow solid.

[0435] Step 3: 5-chloro-3-(3-nitrophenyl)-1,2,4-oxadiazole

[0436] [ka] To a stirred mixture of 3-(3-nitrophenyl)-1,2,4-oxadiazol-5-ol (1 g, 4.83 mmol) in POCl (20 mL) was added Py (572.8 mg, 7.24 mmol). The mixture was heated at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was added dropwise to ice water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5-chloro-3-(3-nitrophenyl)-1,2,4-oxadiazole (940 mg, 4.17 mmol, 86% yield) as a white solid.

[0437] Step 4: 3-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,2,4-oxadiazol-5-amine

[0438] [ka] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (443.03 mg, 2.04 mmol) in DMF (15 mL) was added DIPEA (790.62 mg, 6.12 mmol), and then 5-chloro-3-(3-nitrophenyl)-1,2,4-oxadiazole (460 mg, 2.04 mmol) was added to the mixture. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography eluting with 10-50% EtOAc / Pet. ether to give 3-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,2,4-oxadiazol-5-amine (1.4 g, 3.44 mmol, 84% yield) as a red oil. LC-MS (ES+, Method A), 0.66 min, m / z 407.3 [M+H] + .

[0439] Step 5: 3-(3-aminophenyl)-N-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-amine

[0440] [ka] To a solution of 3-(3-nitrophenyl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1,2,4-oxadiazol-5-amine (400 mg, 984.27 μmol) in EtOH (12 mL) and HO (0.4 mL) was added SnCl.2HO (1.11 g, 4.92 mmol), and the reaction solution was stirred at 80 °C for 2 h. The reaction was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (8-38% MeCN / HO) to give 3-(3-aminophenyl)-N-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-amine (180 mg, 597.34 μmol, 30% yield) as a white solid. LC-MS (ES+, Method A), 0.42 min, m / z 293.1 [M+H] + .

[0441] Compounds prepared in a similar manner to those described above are shown in Table 11 below: [Table 11]

[0442] Schematic Route for the Synthesis of Examples 45-47: [ka]

[0443] Step 1: 1-(6-chloropyridin-2-yl)-3-iodo-1H-indazole

[0444] [ka] A mixture of 3-iodo-1H-indazole (0.2 g, 819.56 μmol), 2-chloro-6-nitro-pyridine (130 mg, 819.56 μmol), and CsCO (534 mg, 1.64 mmol) in DMF (5 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C for 16 h under a N atmosphere. The reaction mixture was partitioned between EtOAc (50 mL) and water (20 mL). The organic phase was separated, washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography eluting with 20–50% EtOAc / Pet. ether to give 1-(6-chloropyridin-2-yl)-3-iodo-1H-indazole (0.25 g, 611.71 μmol, 75% yield) as a white solid. LC-MS(ES + , Method A), 0.87min, m / z 355.8[M+H] + .

[0445] Step 2: 1-(6-chloropyridin-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine

[0446] [ka] To a solution of 1-(6-chloropyridin-2-yl)-3-iodo-1H-indazole (240 mg, 674.99 μmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (147 mg, 674.99 μmol) in dioxane (6 mL), Xantphos (78 mg, 135.00 μmol), Pd(dba) (62 mg, 67.50 μmol), and CsCO (440 mg, 1.35 mmol) were added at room temperature. The reaction was degassed under vacuum, flushed with nitrogen, and stirred at 100 °C for 2 h. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between HO (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-33% EtOAc / Pet. ether to afford 1-(6-chloropyridin-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (220 mg, 494.48 μmol, 73% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.80min, m / z 445.3[M+H] + .

[0447] Step 3: 1-methyl-N-(6-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0448] [ka] To a solution of the resulting 1-(6-chloropyridin-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (200 mg, 449.52 μmol) and 1-methyl-1H-pyrazole-4-carboxamide (84 mg, 674.29 μmol) in dioxane (4 mL), Pd(dba) (41 mg, 44.95 μmol), Xantphos (52 mg, 89.90 μmol), and CsCO (293 mg, 899.05 μmol) were added at room temperature. The reaction was degassed in vacuo, flushed with nitrogen, and stirred at 100 °C for 5 h. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between HO (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-100% EtOAc / Pet. ether to afford 1-methyl-N-(6-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (120 mg, 224.89 μmol, 50% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.65min, m / z 534.2[M+H] + .

[0449] Example 45: N-(6-(3-((1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0450] [ka] To a solution of 1-methyl-N-(6-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (110 mg, 206.15 μmol) in DCM (10 mL) was added TFA (2.31 g, 20.26 mmol) at 0° C. and the reaction was stirred at room temperature for 12 hours. The reaction solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (36-66% MeCN / HO) to give N-(6-(3-((1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (28.40 mg, 48.03 μmol, 23% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.56min, m / z 450.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.30 (s, 1H), 9.14 (d, J = 8.4 Hz, 1H), 8.51 (s, 2H), 8.20 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.95-7.93 (m, 1H), 7.89-7.86 (m, 1H), 7.71-7.68 (m, 2H), 7.63-7.56 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H), no exchangeable NH groups observed.

[0451] Compounds prepared in a similar manner to those described above are shown in Table 12 below: [Table 12]

[0452] Schematic Route for the Synthesis of Examples 48-49: [ka]

[0453] Step 1: 4-Methyl-2-(tributylstannyl)oxazole

[0454] [ka] To a solution of 4-methyloxazole (2 g, 24.07 mmol) in 2-MeTHF (80 mL) at -78 °C under nitrogen, n-BuLi (9.63 mL, 24.07 mmol, 2.5 M) was slowly added, and the reaction was stirred at -78 °C for 0.5 h. Tributyltin chloride (7.84 g, 24.07 mmol) was then added. The reaction was allowed to warm to room temperature and stirred under nitrogen for 1 h. The reaction mixture solvent was removed under reduced pressure. The residue was then suspended in petroleum ether (60 mL). The resulting precipitate was filtered, and the filtrate was evaporated under reduced pressure to give 4-methyl-2-(tributylstannyl)oxazole (8 g, 21.5 mmol, 89% yield) as a colorless liquid.

[0455] Step 2: 2-(4-methyloxazol-2-yl)isonicotinic acid

[0456] [ka] To a solution of methyl 2-chloroisonicotinate (461 mg, 2.69 mmol) and 4-methyl-2-(tributylstannyl)oxazole (5 g, 13.44 mmol) in dioxane (25 mL) was added Pd(PPh3)4 (311 mg, 268.72 μmol) at room temperature. The reaction was degassed under vacuum, flushed with nitrogen, and stirred at 80 °C for 12 h. The reaction mixture was quenched by the addition of saturated aqueous KF solution (80 mL) at 0 °C, and the aqueous phase was extracted with EtOAc (2 × 80 mL). The combined organics were washed with brine (2 × 100 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-30% EtOAc / Pet. ether to give methyl 2-(4-methyloxazol-2-yl)isonicotinate (40 mg, 183.31 μmol, 6.8% yield) as a white solid. The aqueous phase was purified by reverse-phase flash (30-80% MeCN / HO) to give 2-(4-methyloxazol-2-yl)isonicotinic acid (200 mg, 832.59 μmol, 31% yield) as a white solid. LC-MS (ES) analysis revealed that the 2-(4-methyloxazol-2-yl)isonicotinate was methyl ... + , Method A), 0.28min, m / z 205.1[M+H] + .

[0457] Step 3: Methyl 2-(4-methyloxazol-2-yl)isonicotinate

[0458] [ka] To a solution of 2-(4-methyloxazol-2-yl)isonicotinic acid (200 mg, 1.05 mmol) in MeOH (10 mL) was added thionyl chloride (250 mg, 2.10 mmol) at 0°C, and the reaction was stirred at 70°C for 12 hours. It was then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-35% EtOAc / Pet. ether to give methyl 2-(4-methyloxazol-2-yl)isonicotinate (50 mg, 229.14 μmol, 22% yield) as a white solid. LC-MS (ES) analysis revealed that the methyl 2-(4-methyloxazol-2-yl)isonicotinate was eluted with 22% ethyl acetate (E100) and 22% ethyl acetate (E100).+ , Method A), 0.41min, m / z 219.0[M+H] + .

[0459] Step 4: 2-(4-methyloxazol-2-yl)isonicotinohydrazide

[0460] [ka] To a solution of methyl 2-(4-methyloxazol-2-yl)isonicotinate (90 mg, 412.45 μmol) in MeOH (2 mL) was added hydrazine hydrate (211 mg, 4.12 mmol) in one portion at room temperature. The reaction was stirred at 70° C. for 2 hours. It was then cooled to room temperature, and the solvent was removed under reduced pressure to give 2-(4-methyloxazol-2-yl)isonicotinohydrazide (80 mg, 366.62 μmol, 89% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.24min, m / z 219.0[M+H] + .

[0461] Step 5: N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(2-(4-methyloxazol-2-yl)isonicotinoyl)hydrazinecarboxamide

[0462] [ka] To a solution of 2-(4-methyloxazol-2-yl)isonicotinohydrazide (120 mg, 549.92 μmol) and phenyl(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate (266 mg, 714.90 μmol) in dioxane (10 mL), DIEA (213 mg, 1.65 mmol) was added at room temperature. The reaction was stirred at 50° C. for 5 hours. It was then cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by recrystallization from HO (30 mL) at room temperature to give N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(2-(4-methyloxazol-2-yl)isonicotinoyl)hydrazinecarboxamide (200 mg, 403.29 μmol, 73% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.39min, m / z 496.3[M+H] + .

[0463] Step 6: N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-(2-(4-methyloxazol-2-yl)pyridin-4-yl)-1,3,4-oxadiazol-2-amine

[0464] [ka] To a solution of N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(2-(4-methyloxazol-2-yl)isonicotinoyl)hydrazinecarboxamide (180 mg, 362.96 μmol) in DCM (20 mL) was added TosCl (97 mg, 508.15 μmol) and TEA (110 mg, 1.09 mmol) at 0° C., and the reaction was stirred at 0° C. for 2 hours. It was then warmed to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by recrystallization from MeOH (15 mL) at room temperature to give N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-(2-(4-methyloxazol-2-yl)pyridin-4-yl)-1,3,4-oxadiazol-2-amine (130 mg, 272.02 μmol, 75% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.47min, m / z 478.2[M+H] + .

[0465] Example 48: N-(4-chloro-1H-indazol-5-yl)-5-(2-(4-methyloxazol-2-yl)pyridin-4-yl)-1,3,4-oxadiazol-2-amine

[0466] [ka] To a solution of N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-(2-(4-methyloxazol-2-yl)pyridin-4-yl)-1,3,4-oxadiazol-2-amine (120 mg, 251.10 μmol) was added HCl / dioxane (4 M, 12 mL) at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction solvent was removed under reduced pressure. The crude product was triturated with DMSO (3 mL) and HO (10 mL) at room temperature for 30 minutes to give N-(4-chloro-1H-indazol-5-yl)-5-(2-(4-methyloxazol-2-yl)pyridin-4-yl)-1,3,4-oxadiazol-2-amine (13.10 mg, 32.60 μmol, 13% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.39min, m / z 394.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.36 (s, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.87 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 2.21 (s, 3H).

[0467] Compounds prepared in a similar manner to those described above are shown in Table 13 below: [Table 13]

[0468] Schematic Route for the Synthesis of Examples 50-51: [ka]

[0469] Step 1: Methyl 3-(oxazol-2-yl)benzoate

[0470] [ka] To a solution of 2-(tributylstannyl)oxazole (10 g, 27.92 mmol) and methyl 3-iodobenzoate (2.44 g, 9.31 mmol) in dioxane (80 mL) was added Pd(PPh3)4 (1.08 g, 930.67 μmol) at room temperature. The reaction was stirred at 90 °C for 12 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between HO (110 mL) and EtOAc (90 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 90 mL). The combined organics were washed with brine (100 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-15% EtOAc / Pet. ether to give methyl 3-(oxazol-2-yl)benzoate (1 g, 4.92 mmol, 53% yield) as a white solid. LC-MS (ES) + , Method A), 0.41min, m / z 204.2[M+H] + .

[0471] Step 2: 3-(Oxazol-2-yl)benzohydrazide

[0472] [ka] To a solution of methyl 3-(oxazol-2-yl)benzoate (500 mg, 2.46 mmol) in MeOH (15 mL) was added hydrazine hydrate (1.23 g, 24.08 mmol) in one portion at room temperature, and the reaction was stirred at 70 °C for 12 h. It was then cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was triturated with MeOH (10 mL) at room temperature to give 3-(oxazol-2-yl)benzohydrazide (230 mg, 1.13 mmol, 46% yield) as a white solid. LC-MS (ES) + , Method A), 0.24min, m / z 204.1[M+H] + .

[0473] Step 3: N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(3-(oxazol-2-yl)benzoyl)hydrazinecarboxamide

[0474] [ka] To a solution of 3-(oxazol-2-yl)benzohydrazide (140 mg, 688.99 μmol) and phenyl (4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)carbamate (307.41 mg, 826.78 μmol) in dioxane (8 mL), DIEA (178.09 mg, 1.38 mmol) was added at room temperature. The reaction was stirred at 80° C. for 5 hours. It was then cooled to room temperature. The mixture was then diluted with HO (15 mL). The reaction mixture was filtered and the filter cake was washed with EtOAc (3 x 10 mL) to give N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(3-(oxazol-2-yl)benzoyl)hydrazinecarboxamide (180 mg, 374.30 μmol, 54% yield) as an off-white solid. LC-MS (ES) + , Method A), 0.48min, m / z 481.2[M+H] + .

[0475] Step 4: N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-(3-(oxazol-2-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0476] [ka] To a solution of N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(3-(oxazol-2-yl)benzoyl)hydrazinecarboxamide (260 mg, 540.65 μmol) in DCM (10 mL) was added TEA (164 mg, 1.62 mmol) and TosCl (144 mg, 756.91 μmol) at 0° C., and the reaction was stirred at 0° C. for 4 hours. It was then warmed to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by recrystallization from MeOH (10 mL) at room temperature to give N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-(3-(oxazol-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (122 mg, 263.56 μmol, 49% yield) as an off-white solid. LC-MS (ES) + , Method A), 0.69min, m / z 462.9[M+H] + .

[0477] Example 50: N-(4-chloro-1H-indazol-5-yl)-5-(3-(oxazol-2-yl)phenyl)-1,3,4-oxadiazol-2-amine

[0478] [ka] To a solution of N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-(3-(oxazol-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (90 mg, 194.43 μmol) was added HCl / dioxane (4 M, 4 mL) at room temperature, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was filtered, the filter cake was washed with MeCN (30 mL), and the filter cake was lyophilized to give N-(4-chloro-1H-indazol-5-yl)-5-(3-(oxazol-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (65.40 mg, 170.94 μmol, 88% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.51min, m / z 379.2[M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 8.14-8.13 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), no exchangeable NH groups observed.

[0479] Compounds prepared in a similar manner to those described above are shown in Table 14 below: [Table 14]

[0480] Synthesis of Example 52: [ka]

[0481] Step 1: Methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0482] [ka] To a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (4.98 g, 21.46 mmol) and KCO (5.93 g, 42.93 mmol) in DMF (50 mL), MeI (4.57 g, 32.19 mmol) was slowly added at 25 °C, and the mixture was stirred at 35 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (600 mL) and then washed with water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (5.2 g, 21.13 mmol) as an off-white solid.

[0483] Step 2: 5-Bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide

[0484] [ka] To a solution of methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1 g, 4.06 mmol) in MeOH (10 mL), NH.HO (1.04 g, 20.32 mmol) was added in one portion at 25 °C, and the mixture was then stirred at 70 °C for 4 h. The reaction solution was diluted with methanol (30 mL) and concentrated under reduced pressure to give 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide (950 mg, 3.86 mmol, 95% yield) as a yellow solid. LC-MS (ES) + , Method D), 0.17min, m / z 246.0[M+H] + .

[0485] Step 3: 2-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)hydrazinecarboxamide

[0486] [ka] To a solution (12 mL) of 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide (395 mg, 1.61 mmol) and phenyl N-(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)carbamate (596.9 mg, 1.61 mmol) in dioxane, DIPEA (415 mg, 3.21 mmol) was added in one portion at room temperature, and the reaction mixture was stirred at 80° C. for 16 hours. The mixture was diluted with water (15 mL), filtered, and the filter cake was washed with ethyl acetate (3×10 mL). The filter cake was collected to give 2-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)hydrazinecarboxamide (430 mg, 820.98 μmol, 51% yield) as an off-white solid. LC-MS (ES) + , Method A), 0.46min, m / z 525.3[M+H] + .

[0487] Step 4: 3-Bromo-5-(5-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methylpyridin-2(1H)-one

[0488] [ka] To a solution of 2-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)hydrazinecarboxamide (430 mg, 820.98 μmol) in DCM (12 mL), TosCl (219.12 mg, 1.15 mmol) and TEA (249.22 mg, 2.46 mmol) were added at 0° C., and the reaction solution was stirred at 0° C. for 2 hours. The reaction solution was filtered, the filter cake was washed with DMF (16 mL), and the filter cake was collected to give 3-bromo-5-(5-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methylpyridin-2(1H)-one (180 mg, 355.91 μmol, 43% yield) as an off-white solid. LC-MS (ES) + , Method A), 0.50min, m / z 507.0[M+H] + .

[0489] Step 5: N-(5-(5-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-fluorobenzamide

[0490] [ka] To a mixture of 3-bromo-5-(5-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methylpyridin-2(1H)-one (180 mg, 355.91 μmol) and 2-fluorobenzamide (99 mg, 711.81 μmol) in dioxane (3 mL) was added CsCO (231.9 mg, 711.81 μmol), Xantphos (41.2 mg), and Pd(dba) (32.6 mg, 35.59 μmol) in one portion at room temperature under N, and the mixture was stirred at 100° C. for 16 h under N. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and then washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-(5-(5-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-fluorobenzamide (340 mg, crude) as an off-white solid. LC-MS (ES + , Method A), 0.63min, m / z 564.4[M+H] + .

[0491] Example 52: N-(5-(5-((4-chloro-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-fluorobenzamide

[0492] [ka] To a solution of N-(5-(5-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-fluorobenzamide (320 mg, 567.41 μmol) in DCM (5 mL), TFA (7.70 g, 67.53 mmol) was added in one portion, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (5 mL) and then concentrated under reduced pressure to give the crude product. The crude product was purified by recrystallization from acetonitrile (10 mL) at 80 °C to give N-(5-(5-((4-chloro-1H-indazol-5-yl)amino)-1,3,4-oxadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-fluorobenzamide (31.40 mg, 62.17 μmol, 75% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.48min, m / z 480.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.77 (d, J = 11.2 Hz, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.12-8.00 (m, 3H), 7.93 (s, 1H), 7.73-7.67 (m, 1H), 7.48-7.39 (m, 4H), 3.65 (s, 3H).

[0493] Synthesis of Example 53: [ka]

[0494] Step 1: N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(2-nitropyridin-4-yl)-1H-indazol-3-amine

[0495] [ka] To a mixture of 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (281.26 mg, 1.12 mmol) and 3-iodo-1-(2-nitropyridin-4-yl)-1H-indazole (450 mg, 1.23 mmol) in dioxane (20 mL) was added Xantphos (129.31 mg, 223.48 μmol), Pd(dba) (102.32 mg, 111.74 μmol), and CsCO (910.17 mg, 2.79 mmol) at room temperature. The reaction was degassed under vacuum, flushed with nitrogen, and stirred at 105 °C for 4 h. It was cooled to room temperature and partitioned between HO (30 mL) and EtOAc (40 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organics were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-25% EtOAc / Pet. ether to afford N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(2-nitropyridin-4-yl)-1H-indazol-3-amine (350 mg, 714.41 μmol, 64% yield) as a red solid. LC-MS (ES) + , Method A), 0.60min, m / z 490.2[M+H] + .

[0496] Step 2: 1-(2-aminopyridin-4-yl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine

[0497] [ka] To a solution of N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(2-nitropyridin-4-yl)-1H-indazol-3-amine (150 mg, 306.18 μmol) in EtOH (8 mL) and water (2 mL) was added NH4Cl (163.78 mg, 3.06 mmol) and Fe (51.30 mg, 918.53 μmol) at room temperature. The reaction was stirred at 80° C. for 2 h. The reaction mixture was filtered and the filter cake was washed with MeOH (50 mL). The solvent of the filtrate was removed under reduced pressure. The crude product was triturated with HO (20 ml) at room temperature for 10 min. The mixture was filtered and the filter cake was washed with HO (10 mL) to give 1-(2-aminopyridin-4-yl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (110 mg, 239.17 μmol, 78% yield) as an off-white solid. LC-MS (ES) + , Method A), 0.50min, m / z 460.1[M+H] + .

[0498] Step 3: N-(4-(3-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0499] [ka] To a solution of 1-(2-aminopyridin-4-yl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (100 mg, 217.42 μmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (55 mg, 434.85 μmol) in pyridine (5 mL) was added EDCI (104 mg, 543.56 μmol) at room temperature, and the reaction was stirred at room temperature for 48 hours. The residue was partitioned between HO (20 mL) and DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2×20 mL). The combined organics were washed with brine (2×30 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase flash (0-33% MeCN / HO) to give N-(4-(3-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 156.68 μmol, 72% yield) as a brown solid. LC-MS (ES) + , Method A), 0.53min, m / z 568.2[M+H] + .

[0500] Example 53: N-(4-(3-((4-chloro-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0501] [ka] To a solution of N-(4-(3-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (95 mg, 167.25 μmol) was added HCl / dioxane (4 M, 4 mL) at room temperature. The reaction was stirred at room temperature for 12 hours. The reaction mixture was filtered and the filter cake was washed with MeCN (30 mL). The crude product was purified by recrystallization from MeCN (15 mL) at 45 °C to give N-(4-(3-((4-chloro-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (20.30 mg, 41.53 μmol, 25% yield) as a green solid. LC-MS (ES) + , Method A), 0.47min, m / z 484.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.13 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.34-8.28 (m, 3H), 8.24 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.75-7.71 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 3.93 (s, 3H), no exchangeable NH groups observed.

[0502] Synthesis of Example 54: [ka]

[0503] Step 1: 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0504] [ka] To a solution of 3-bromo-5-nitropyridine (3 g, 14.78 mmol) in dioxane (100 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.51 g, 29.56 mmol), Pd(dppf)Cl2 (540 mg, 738.94 μmol), and AcOK (4.35 g, 44.34 mmol). The reaction was degassed in vacuo, flushed with nitrogen, and stirred at 90 °C for 12 h. The reaction was cooled to room temperature, and the mixture was partitioned between HO (100 mL) and EtOAc (75 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 75 mL). The combined organics were washed with brine (2 × 75 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-20% EtOAc / Pet. ether to give 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g, 14.00 mmol, 94.5% yield) as a yellow solid.

[0505] Step 2: 3-Iodo-1-(5-nitropyridin-3-yl)-1H-indazole

[0506] [ka] To a solution of 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 2.00 mmol) and 3-iodo-1H-indazole (488 mg, 2.00 mmol) in MeCN (80 mL) was added pyridine (316 mg, 4.00 mmol), Cu(OAc) (545 mg, 3.00 mmol), boric acid (247 mg, 4.00 mmol), and 200 mg of 4 Å molecular sieves. The reaction was purged with air and stirred at 60 °C for 12 h. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between HO (200 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-15% EtOAc / Pet. ether to give 3-iodo-1-(5-nitropyridin-3-yl)-1H-indazole (270 mg, 737.48 μmol, 37% yield) as a yellow solid. LC-MS (ES) + , Method A), 0.58min, m / z 367.0[M+H] + .

[0507] Step 3: N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(5-nitropyridin-3-yl)-1H-indazol-3-amine

[0508] [ka] To a solution of 3-iodo-1-(5-nitropyridin-3-yl)-1H-indazole (260 mg, 710.16 μmol) and 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (179 mg, 710.16 μmol) in dioxane (6 mL), Xantphos (82 mg, 142.03 μmol), CsCO (463 mg, 1.42 mmol), and Pd(dba) (65 mg, 71.02 μmol) were added at room temperature. The reaction was degassed under vacuum, flushed with nitrogen, and stirred at 100 °C for 2 h. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between HO (20 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was loaded onto silica and purified by column chromatography eluting with 0-20% EtOAc / Pet. ether to afford N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(5-nitropyridin-3-yl)-1H-indazol-3-amine (270 mg, 551.12 μmol, 78% yield) as a red solid. LC-MS (ES) + , Method A), 0.66min, m / z 490.1[M+H] + .

[0509] Step 4: 1-(5-aminopyridin-3-yl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine

[0510] [ka] To a solution of N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(5-nitropyridin-3-yl)-1H-indazol-3-amine (200 mg, 314.34 μmol) in EtOH (16 mL) and HO (4 mL) was added NHCl (168 mg, 3.14 mmol) and Fe (53 mg, 943.02 μmol) at room temperature, and the reaction was stirred at 80° C. for 2 h. The reaction mixture was then filtered, and the filter cake was washed with MeOH (70 mL). The solvent of the filtrate was removed under reduced pressure, and the crude product was triturated with HO (20 mL) at room temperature for 10 min. The mixture was filtered and the filter cake was washed with HO (10 mL) to give 1-(5-aminopyridin-3-yl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (120 mg, 260.91 μmol, 83% yield) as a red solid. LC-MS (ES) + , Method A), 0.46min, m / z 460.2[M+H] + .

[0511] Step 5: N-(5-(3-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0512] [ka] To a solution of 1-(5-aminopyridin-3-yl)-N-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-indazol-3-amine (200 mg, 434.85 μmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (165 mg, 1.30 mmol) in pyridine (10 mL) was added EDCI (333 mg, 1.74 mmol) at room temperature, and the reaction was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase flash (0-60% MeCN / HO) to give N-(5-(3-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 176.05 μmol, 40% yield) as a red solid. LC-MS (ES) + , Method A), 0.48min, m / z 568.4[M+H] + .

[0513] Example 54: N-(5-(3-((4-chloro-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0514] [ka] To a solution of N-(5-(3-((4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide (90 mg, 158.44 μmol), HCl / dioxane (4 M, 6 mL) was added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by recrystallization from MeOH (10 mL) at room temperature to give N-(5-(3-((4-chloro-1H-indazol-5-yl)amino)-1H-indazol-1-yl)pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide (42.90 mg, 85.73 μmol, 54% yield) as a brown solid. LC-MS(ES + , Me...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof (In the formula, R １ is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; R ２ is hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl; X is CR ７ or N, Y is CR ８ or N, Z is CR ９ or N, R ３ is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; A is, 【Chemistry 2】 and R ４ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ５ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R ４ and R ５ together with the atom to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; B is aryl, heterocyclyl, heteroaryl, or carbocyclyl; Each R ６ are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR Ａ , -N ３ , -N(R Ａ ) ２ , -SR Ａ , -CN, -SCN, -C(=NR Ａ )R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )N(R Ａ ) ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)N(R Ａ ) ２ , -NO ２ , -NR Ａ C(=O)R Ａ , -NR Ａ C(=O)OR Ａ , -NR Ａ C(=O)N(R Ａ ) ２ , -NR Ａ C (=NR Ａ )N(R Ａ ) ２ , -OC(=O)R Ａ , -OC(=O)OR Ａ , -OC(=O)N(R Ａ ) ２ , -NR Ａ S(O) ２ R Ａ , -OS(O) ２ R Ａ , or -S(O) ２ R Ａ and n is 1, 2, 3, 4, or 5; Each R ７ , R ８ , and R ９ are independently hydrogen, halogen, —CN, or substituted or unsubstituted alkyl; R １０ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Ａ each instance of R is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetaralkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; or Ａ The groups are linked to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring.

2. R １ is hydrogen or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

3. R ２ is hydrogen, halogen, or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

4. R ３ is hydrogen or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

5. X is CR ７ 2. The compound of claim 1, wherein:

6. Y is CR ８ 2. The compound of claim 1, wherein:

7. Z is CR ９ 2. The compound of claim 1, wherein:

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein B is aryl, heterocyclyl, or heteroaryl.

9. 9. The compound of claim 8, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein B is phenyl or pyridinyl.

10. 9. The compound of claim 8, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein B is pyridinyl.

11. 2. The compound of claim 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, wherein n is 1 or 2.

12. Each R ６ are independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, oxo, -OR Ａ , -N(R Ａ ) ２ , -CN, -C(=NR Ａ )R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )N(R Ａ ) ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)N(R Ａ ) ２ , -NR Ａ C(=O)R Ａ , -NR Ａ C(=O)OR Ａ , -NR Ａ C(=O)N(R Ａ ) ２ , -NR Ａ C (=NR Ａ )N(R Ａ ) ２ , -OC(=O)R Ａ , -OC(=O)OR Ａ , -OC(=O)N(R Ａ ) ２ , -NR Ａ S(O) ２ R Ａ , -OS(O) ２ R Ａ , or -S(O) ２ R Ａ 2. The compound of claim 1, wherein:

13. Each R ６ are independently oxo, —CH ３ , -OCH ３ , -F, 【Chemistry 3-1】 【Chemistry 3-2】 2. The compound of claim 1, wherein:

14. A is, 【Chemistry 4】 2. The compound of claim 1, wherein:

15. A is, 【Chemistry 5】 2. The compound of claim 1, wherein:

16. A is, 【Chemistry 6】 2. The compound of claim 1, wherein:

17. A is, 【Chemistry 7】 2. The compound of claim 1, wherein:

18. A is, 【Chemistry 8】 2. The compound of claim 1, wherein:

19. The compound has the formula 【Chemistry 9-1】 【Chemistry 9-2】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

20. The compound has the formula 【Chemistry 10】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

21. The compound has the formula 【Chemistry 11】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

22. The compound has the formula 【Chemistry 12】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

23. The compound has the formula 【Chemistry 13】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

24. The compound has the formula 【Chemistry 14】 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

25. The compound is 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 【Chemistry 15-5】 【Chemistry 15-6】 【Chemistry 15-7】 【Chemistry 15-8】 【Chemistry 15-9】 【Chemistry 15-10】 【Chemistry 15-11】 【Chemistry 15-12】 【Chemistry 15-13】 【Chemistry 15-14】 【Chemistry 15-15】 【Chemistry 15-16】 【Chemistry 15-17】 【15-18】 【Chemistry 15-19】 【15-20】 【Chemistry 15-21】 【Chemistry 15-22】 【Chemistry 15-23】 【15-24】 【15-25】 【15-26】 【15-27】 【15-28】 【Chemistry 15-29】 【15-30】 【Chemistry 15-31】 10. The compound of claim 1, wherein:

26. 26. A pharmaceutical composition comprising the compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, and a pharmaceutically acceptable excipient.

27. 27. The pharmaceutical composition of claim 26 for use in the treatment or prevention of a disease or disorder associated with ROCK2.

28. The diseases or disorders associated with ROCK2 include fibrotic disorders, autoimmune diseases, inflammatory conditions, edema, eye diseases, cardiovascular diseases, central nervous system disorders, cancer, pulmonary fibrosis, cystic pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, previous myocardial infarction, arterial stiffness, atherosclerosis, restenosis, arthrofibrosis, Crohn's disease, myelofibrosis, and pneumococcal infarction. Ronnie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, mediastinal fibrosis, keloids and hypertrophic scars, glial scars, renal fibrosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Batten disease, dementia, spinal muscular atrophy, motor neuron disease, spinocerebellar ataxia, acute or chronic pain, dementia, neurodegeneration, spinal cord injury, cerebral hemorrhage Vasospasm, glaucoma, asthma, cardiovascular inflammation, renal inflammation, arteriosclerosis, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral arterial disease, peripheral circulatory disorders, cerebral cavernous malformation, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, acute respiratory distress syndrome (ARDS), erectile dysfunction, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, atopic dermatitis, eczema, or graft-versus-host disease (GV) 28. The pharmaceutical composition for use according to claim 27, wherein the edema is selected from the group consisting of inflammatory edema, cystoid macular edema, Irvine-Gass syndrome, diabetic macular edema, lymphedema, lymphedema caused by at least a parasitic disease, angioedema, cerebral edema, CHAPLE syndrome, cardiac edema, hydrops fetalis, inflammatory edema, macular edema, myxedema, pulmonary edema, peripheral edema, periorbital edema, skin edema, hereditary angioedema, cystoid macular edema, Irvine-Gass syndrome, diabetic macular edema, and paw edema.

29. An effective amount of A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof; or A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, and a pharmaceutically acceptable excipient. An in vitro method for inhibiting ROCK2, comprising contacting ROCK2 with

30. 26. A method of screening a library of compounds, comprising conducting an assay for a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, and an additional compound, wherein the additional compound is different from the compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof.

31. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof; or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, and a pharmaceutically acceptable excipient; and Instructions for using the compound, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched compound, or prodrug thereof, or a pharmaceutical composition thereof. Includes a kit.

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