Compounds, compositions, and methods of use thereof

Abstract

The present disclosure provides, in part, compounds of Formula (I): and pharmaceutically acceptable salts thereof, and compositions comprising said compounds or salts thereof and a pharmaceutically acceptable excipient. In some embodiments, the compounds or salts thereof and compositions disclosed herein are effective at inhibiting CDK2 activity. In some embodiments, the compounds or salts thereof and compositions disclosed herein are selective at inhibiting CDK2 over other CDKs. Thus, also provided herein are uses of the compounds or salts thereof and compositions in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders mediated by CDK2, such as cancer.

Description

Attorney Docket No.00007.001.1801 COMPOUNDS, COMPOSITIONS, AND METHODS OF USE THEREOF CROSS REFERENCE

[0001] The present application claims priority to and benefit of U.S. Provisional Patent Application No.63 / 680,288 filed on August 7, 2024, which is incorporated herein by reference in its entirety. SUMMARY

[0002] Disclosed herein, in some embodiments, are compounds of Formula (I), and pharmaceutically acceptable salts thereof, compositions comprising said compounds or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient, and uses thereof such as in treating, preventing, or reducing the risk or severity of certain diseases or disorders (e.g., cancer).

[0003] In some embodiments, provided herein are compounds of Formula (I): or a pharmaceutically acceX is N or CH; A2is phenyl or 5-6 membered heteroaryl; A4is aryl, heteroaryl, C3-12carbocyclyl, or 4-12 membered heterocyclyl; L1is -O-, -S-, or -NH-; L2is -NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, -C(=O)C(R8)2-, - or -heteroaryl, -(C1-6 alkylene)-(C3-10 carbocyclyl), -(C1-6 alkylene)-(4-12 memberedAttorney Docket No.00007.001.1801 heterocyclyl), -(C1-6alkylene)-(phenyl), -(C1-6alkylene)-(5-12 membered heteroaryl), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-5 R11; R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, -NHCOR9, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6alkylsulfonyl, aryl, or heteroaryl, wherein R2is each independently optionally substituted by 1-4 R11; R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, -NHCOR9, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, or C1-6 alkylsulfonyl, wherein R3is each independently optionally substituted by 1-4 R11; R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7R10, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkylsulfonyl, SO2N(R7)2, or phenyl, or any two occurrences of R4s on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4s are attached, form a saturated, partially unsaturated, or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(=O)0-2, P(=O)R5, N, and NR10, wherein R4is each independently optionally substituted by 1-4 R11; R5is each independently H, C1-6 alkyl, C1-6 alkoxy, hydroxy, or -N(R7)2; R6is each independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3 alkylene)-(C3-6 cycloalkyl), (C1-3 alkylene)- (4-6 membered heterocycloalkyl), C1-6acyl, aroyl, or heteroaroyl; R7is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, (C1-3alkylene)-(C3-6 cycloalkyl), or (C1-3 alkylene)-(4-6 membered heterocycloalkyl), or two R7s are taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR12, O, and S(=O)0-2; R8is each independently H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3alkylene)-(C3-6cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), 2Attorney Docket No.00007.001.1801 or two R8s taken together with the C atom to which they are attached form a 4-7 membered ring comprising 0-1 heteroatom selected from O, S(=O)0-2, P(=O)R5, and NR12, wherein R8is optionally substituted by 1-3 R11; R9is each independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, (C1-3 alkylene)-(C3-6 cycloalkyl), (C1-3 alkylene)- (4-6 membered heterocycloalkyl), C1-6acyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-3 R11; R10is each independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, (C1-3 alkylene)-(C3-6 cycloalkyl), (C1-3 alkylene)- (4-6 membered heterocycloalkyl), C1-6acyl, C1-6alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1-3 R11, or R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from O, S(=O)0-2, P(=O)R5, and NR6; R11is each independently H, halo, hydroxy, cyano, oxo, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3 alkylene)-(C3-6 cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), C6-10 aryl, 5-12 membered heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2; R12is each independently H, C1-6 alkyl, C1-6 alkoxy, hydroxy, C1-6 acyl, or C1-6 alkylsulfonyl; m is an integer 0, 1 or 2; n is an integer 0, 1, 2, or 3; and p is an integer 0, 1, 2, or 3, provided that the A1ring and the L1linker are on contiguous C atoms of the A2ring, whereas L1and L2are not situated on contiguous atoms of the A3ring.

[0004] In some embodiments, provided herein are pharmaceutical compositions, comprising: a) a compound described herein, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.

[0005] In some embodiments, provided herein are methods of inhibiting CDK2 in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. 3Attorney Docket No.00007.001.1801

[0006] In some embodiments, provided herein are methods of treating a disease or disorder characterized by overexpression or amplification of cyclin E in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the cyclin E is CCNE1 or CCNE2.

[0007] In some embodiments, provided herein are methods of treating a disease or disorder characterized by overexpression or amplification of cyclin A in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0008] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0009] In some embodiments, the cancer is associated with amplification or overexpression of cyclin E or cyclin A. In some embodiments, the cancer is breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, melanoma, lung cancer, pancreatic cancer, stomach cancer, esophageal cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, prostate cancer, renal cancer, hepatic cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, lymphoma, or leukemia.

[0010] In some embodiments, provided herein are methods of treating an autoimmune disorder or disease in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the autoimmune disorder or disease is associated with amplification or overexpression of cyclin E or cyclin A. In some embodiments, the autoimmune disorder or disease is rheumatoid arthritis, Lupus, Crohn’s Disease, Addison disease, celiac disease, dermatomyositis, Graves’ disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or pemphigus vulgaris.

[0011] In some embodiments, provided herein are methods of treating an inflammatory disease or disorder in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the inflammatory disease or disorder is associated with amplification or overexpression of cyclin E or cyclin A. In some embodiments, the inflammatory disease or 4Attorney Docket No.00007.001.1801 disorder is asthma, chronic peptic ulcers, psoriasis, inflammatory bowel disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

[0012] In some embodiments, provided herein are methods of treating a neurodegenerative disease or disorder in a subject in need thereof, the methods comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the neurodegenerative disease or disorder is associated with amplification or overexpression of cyclin E or cyclin A. In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, or cerebellar degeneration.

[0013] In some embodiments, provided herein are conjugates, comprising a compound described herein, or a pharmaceutically acceptable salt thereof, bound to CDK2.

[0014] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims. DETAILED DESCRIPTION

[0015] The present disclosure provides, in some embodiments, compounds of Formula (I), and pharmaceutically acceptable salts thereof, and compositions comprising said compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. In some embodiments, the compounds or pharmaceutically acceptable salts thereof and compositions disclosed herein are effective at inhibiting or reducing the activity of cyclin-dependent kinase 2 (CDK2). In some embodiments, the compounds or pharmaceutically acceptable salts thereof and compositions disclosed herein are selective at inhibiting CDK2 over other cyclin-dependent kinases (CDKs), such as CDK1. In some embodiments, also provided herein are uses of the compounds or pharmaceutically acceptable salts thereof and compositions disclosed herein in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders mediated by unwanted activity of CDK2 or over-expression of cyclin E or cyclin A2, such as but not limited to, cancer. Definitions

[0016] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. 5Attorney Docket No.00007.001.1801 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0017] As used herein the specification, “a” or “an” may mean one or more. As used herein, when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one. As used herein “another” may mean at least a second or more. Still further, the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the disclosure may consist of or consist essentially of one or more elements, method steps, and / or methods of the disclosure. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein.

[0018] “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[0019] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0020] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. When describing the disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term 6Attorney Docket No.00007.001.1801 “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0021] When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0022] As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1–6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. In some embodiments, “alkyl” is unsubstituted or substituted with one or more substituents as described herein.

[0023] As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon– carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20 alkenyl”). In some embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). 7Attorney Docket No.00007.001.1801 Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. In some embodiments, “alkenyl” is unsubstituted or substituted with one or more substituents as described herein.

[0024] As used herein, “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon– carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20 alkynyl”). In some embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1– butynyl). Examples of C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1– propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. In some embodiments, “alkynyl” is unsubstituted or substituted with one or more substituents as described herein.

[0025] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be unsubstituted or substituted with one or more substituents as described herein. 8Attorney Docket No.00007.001.1801

[0026] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. In some embodiments, “aryl” is unsubstituted or substituted with one or more substituents as described herein.

[0027] As used herein, “heteroaryl” refers to a radical of an aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic). Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl tricyclic ring systems can include one or more heteroatoms in one or two or all three rings. Heteroaryl tetracyclic ring systems can include one or more heteroatoms in one or two or three or all four rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is 9Attorney Docket No.00007.001.1801 fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2– indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). In some embodiments, “heteroaryl” is unsubstituted or substituted with one or more substituents as described herein.

[0028] In some embodiments, a heteroaryl group is a 5–12 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–12 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0029] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one 10Attorney Docket No.00007.001.1801 heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0030] Examples of representative heteroaryls include the following:, , , , d RNNis independently hydrogen, C1-8 alkyl, C3-10 carbocyclyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl.

[0031] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non– aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3–14 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3–12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3–10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocycyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6 carbocyclyl”). In 11Attorney Docket No.00007.001.1801 some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10 carbocyclyl”). Exemplary C3–6carbocyclyl groups include, without limitation, cyclopropyl (C3),cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8carbocyclyl groups include, without limitation, the aforementioned C3–6 carbocyclyl groups as well as 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. Exemplary C3–10carbocyclyl groups include, without limitation, the aforementioned C3–8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. In some embodiments, “carbocyclyl” is unsubstituted or substituted with one or more substituents as described herein.

[0032] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-12cycloalkyl,” “C3-10cycloalkyl,” “C3-8cycloalkyl,” “C4-8cycloalkyl,” or “C4-6cycloalkyl,” respectively, derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. In some embodiments, “cycloalkyl” is unsubstituted or substituted with one or more substituents as described herein.

[0033] The term “cycloalkenyl” refers to a monovalent cyclic, bicyclic, or bridged cyclic (e.g., norbornenyl) hydrocarbon group containing at least one C=C of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-12cycloalkenyl,” “C3-10cycloalkenyl,” “C3-8cycloalkenyl,” “C4-8cycloalkenyl,” or “C4-6cycloalkenyl,” respectively, derived from a cycloalkene. In some embodiments, “cycloalkenyl” is unsubstituted or substituted with one or more substituents as described herein. 12Attorney Docket No.00007.001.1801

[0034] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 12–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–12 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” “heterocyclic radical,” and “heterocycloalkyl” may be used interchangeably. In some embodiments, “heterocyclyl” is unsubstituted or substituted with one or more substituents as described herein.

[0035] In some embodiments, a heterocyclyl group is a 4-12 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-12 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is 13Attorney Docket No.00007.001.1801 independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5– dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8– membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0037] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, 14Attorney Docket No.00007.001.1801 pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached.

[0038] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0039] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In some embodiments, the halo group is either fluoro or chloro.

[0040] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. For the group C1-4haloalkyl-O-C1-4alkyl, the point of attachment occurs on the alkyl moiety which is halogenated.

[0041] The term “alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (–O(alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy.

[0042] The term “alkoxyalkyl” refers to an alkyl group substituted with one or more (e.g., one or two) alkoxy groups. Exemplary alkoxyalkyls include, for example, C1-2- alkylene-O-(C1-4alkyl) and C1-2-alkylene-O-(C1-2alkylene)-O-(C1-4alkyl).

[0043] The term “alkenoxy,” as used herein, refers to an alkenyl group which is attached to another moiety via an oxygen atom (–O(alkenyl)).

[0044] The term “alkynoxy,” as used herein, refers to an alkynyl group which is attached to another moiety via an oxygen atom (–O(alkynyl)).

[0045] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHCF2or –OCF3. 15Attorney Docket No.00007.001.1801

[0046] As used herein, “amino” refers to -NH2.

[0047] As used herein, “alkylamino” refers to -NHRaa, wherein Raais an alkyl group. For example, “C1-6alkylamino” refers to -NHRaa, wherein Raais an unsubstituted or substituted C1-6alkyl group.

[0048] As used herein, “dialkylamino” refers to -NRaaRbb, wherein Raaand Rbbare each independently an alkyl group. For example, “C1-6dialkylamino” refers to – NRaaRbb, wherein Raaand Rbbare each independently unsubstituted or substituted C1-6alkyl group.

[0049] As used herein, “alkylthio” refers to an alkyl group which is attached to another moiety via a sulfur atom (-S(alkyl)).

[0050] As used herein, “alkenylthio” refers to an alkenyl group which is attached to another moiety via a sulfur atom (-S(alkenyl)).

[0051] As used herein, “alkylsulfonyl” refers to an alkyl group which is attached to another moiety via a sulfonyl (-SO2(alkyl)).

[0052] As used herein, “alkenylsulfonyl” refers to an alkenyl group which is attached to another moiety via a sulfonyl (-SO2(alkenyl)).

[0053] As used herein, “acyl” refers to –C(=O)Rcc, wherein Rccis an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl group. For example, "C1-6 acyl” refers to – C(=O)Rccwherein Rccis an unsubstituted or substituted C1-6alkyl, C2-6 alkenyl, or C2-6alkynyl group.

[0054] As used herein, “aroyl” refers to –C(=O)Rdd, wherein Rddis an aryl group as defined herein. For example, "C6 aroyl” refers to –C(=O)Rddwherein Rddis an unsubstituted or substituted phenyl ring.

[0055] As used herein, “heteroaroyl” refers to –C(=O)Ree, wherein Reeis a heteroaryl group as defined above. For example, "monocyclic heteroaroyl” refers to –C(=O)Reewherein Reeis an unsubstituted or substituted 5- or 6-membered heteroaryl group.

[0056] As used herein, “heterocycloacyl” refers to –C(=O)Rff, wherein Rffis a heterocyclyl group as defined above. For example, "C3-6 monocyclic heterocycloacyl” refers to –C(=O)Rffwherein Rffis an unsubstituted or substituted 3-6 membered heterocyclyl group.

[0057] As used herein, “cyano” refers to -CN.

[0058] As used herein, “nitro” refers to -NO2. 16Attorney Docket No.00007.001.1801

[0059] As used herein, “azido” refers to -N=N=N.

[0060] As used herein, “oxo” refers to refers to an oxygen atom doubly bonded to a carbon atom (=O).

[0061] As used herein, “oxa” refers to refers to an oxygen atom singly bonded to two different atoms in a chain or ring.

[0062] As used herein, “aza” refers to refers to a nitrogen atom bonded to at least two other atoms in a chain or ring.

[0063] As used herein, “thiono” refers to refers to an sulfur atom doubly bonded to a carbon atom (=S).

[0064] As used herein, “thia” refers to refers to an sulfur atom of formal oxidation state zero singly bonded to two different atoms in a chain or ring.

[0065] As used herein, “sulfinyl” refers to refers to an S=O group singly bonded to two different atoms in a chain or ring.

[0066] As used herein, “sulfonyl” refers to refers to an S(=O)2 group singly bonded to two different atoms in a chain or ring.

[0067] As used herein, “sulfonamido” and “aminosulfonyl” refer to refers to an - S(=O)2-NRgg- group singly bonded to two different atoms in a chain or ring wherein Rggis a hydrocarbyl group such as alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0068] As used herein, the term “hydroxy” or “hydroxyl” refers to -OH group.

[0069] As used herein, the term “hydroxyalkyl” refers to an alkyl group substituted with a hydroxy group.

[0070] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this disclosure, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.

[0071] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. 17Attorney Docket No.00007.001.1801

[0072] Certain compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure.

[0073] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0074] All configurational isomers of the compounds of the present disclosure are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present disclosure embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0075] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present disclosure. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present disclosure.

[0076] The present disclosure also includes isotopically-labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, 18Attorney Docket No.00007.001.1801 phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,11C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds of the present disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure.

[0077] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0078] As used herein, “pharmaceutically acceptable excipient” refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s). 19Attorney Docket No.00007.001.1801 Exemplary pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability. They may also assist in product identification or enhance the overall safety or function of the product during storage or use.

[0079] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non- human animal. The terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms require the active supervision of medical personnel.

[0080] Disease, disorder, and condition are used interchangeably herein.

[0081] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or reverses or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).

[0082] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. A “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit (e.g., treating, preventing, and / or ameliorating cancer in a subject, or inhibiting protein-protein interactions mediated by CDK2 in a subject, at a reasonable benefit / risk ratio applicable to any medical treatment) in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic 20Attorney Docket No.00007.001.1801 efficacy of another therapeutic agent. A “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. A “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.

[0083] An “anti-cancer agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of anti-cancer agents include, but are not limited to: alkylating agents, antimetabolites, anti-hormone therapies, endocrine therapies, immunomodulatory agents, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Anti-cancer agents include compounds used in targeted therapy and conventional chemotherapy. Exemplary anti-cancer agents include proteasome inhibitors such as bortezomib (e.g., VELCADE®), carfilzomib (e.g., KYPROLIS®) and ixazomib (e.g., NINLARO®). Other examples include immunomodulatory agents such as lenalidomide (e.g., REVLIMID®) and pomalidomide (e.g., POMALYST®). Other exemplary anti-cancer agents include inhibitors of B-cell receptor targets such as BTK, Bcl-2 and JAK inhibitors and include, for example, venetoclax (e.g., VENCLEXTA®) and ibrutinib (e.g., IMBRUVICA®). Additional anti- cancer agents include, for example, abemaciclib (e.g., VERZENIO®); abiraterone (e.g., ZYTIGA®, YONSA®); aclarubicin; acivicin; acodazole; acronine; actinomycin; acylfulvene; adecypenol; adozelesin; adriamycin; aldesleukin; altretamine; ambamustine; ambomycin; ametantrone; amidox; amifostine; aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; antarelix; anthramycin; aphidicolin glycinate; apurinic acid; ARRY-300; arabinoside; asperlin; asulacrine; atamestane; atrimustine; azasetron; azatoxin; azatyrosine; azacitidine; selumetinib (AZD6244); AZD8330 (2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-1,5- dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide); azetepa; azotomycin; balanol; batimastat; bendamustine; benzochlorins; benzodopa; benzoylstaurosporine; beta-alethine; betaclamycin B; betulinic acid; bicalutamide; binimetinib; bisantrene; bisaziridinylspermine; bisnafide; bistratene; bleomycin; busulfan; bizelesin; breflate; bortezomib; brequinar; 21Attorney Docket No.00007.001.1801 bropirimine; budotitane; buthionine; bryostatin; cactinomycin; calusterone; calcipotriol; calphostin C; camptothecin; capecitabine (e.g., XELODA®); caracemide; carbetimer; carboplatin; carboquone; carmust ine; carubicin; carzelesin; castanospermine; celecoxib; cetrorelix; cetuximab (e.g., ERBITUX®); chloroquinoxaline; cicaprost; chlorambucil; chlorofusin; cisplatin; cladribine; clomifene; clotrimazole; crisnatol; crisnatol; cypemycin; cyclophosphamide; cytarabine; cytostatin; dacarbaz ine; dactinomycin; daratumamab; daunorubicin; decarbazine; dacliximab; dasatinib; decitabine; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; dexormaplatin; dezaguanine; diaziquone; dihydrotaxol; docosanol; dolasetron; docetaxel; doxorubicin; doxifluridine; droloxifene; dromostanolone; dronabinol; duazomycin; ebselen; ecomustine; edelfosine; edrecolomab; edatrexate; eflomithine; elemene; emitefur; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin; epristeride; erbulozole; erlotinib (e.g., TARCEVA®); esorubicin; estramustine; etanidazole; etoposide; etoprine; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; floxuridine; fludarabine; fludarabine; fluorodaunorubicin; forfenimex; formestane; fluorouracil; floxouridine; flurocitabine; fosquidone; fostriecin; fotemustine; fulvestrant (e.g., FASLODEX®); gadolinium; gallium; galocitabine; ganirelix; gemcitabine; geldanamycin; gefitinib; gossyphol; hydroxyurea; hepsulfam; heregulin; ibandronate; ibrutinib; idarubicin; idelalisib (e.g., ZYDELIG®), ifosfam ide; canfosfamide; ilmofosine; iproplatin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib mesylate (e.g., GLEEVEC®); imiquimod; iobenguane; iododoxorubicin; ipomeanol; irinotecan; itasetron; iimofosine; lanreotide; lapatinib (e.g., TYKERB®); leinamycin; lenograstim; lentinan; leptolstatin; letrozole; leuprorelin; levamisole; liarozole; lobaplatin; lombricine; lometrexol; lonidamine; lonafamib (e.g., SARASAR®); losoxantrone; lovastatin; loxoribine; lurtotecan; lapatinib; leucovorin; lometrexol; lomustine; maitansine; marimastat; masoprocol; maspin; menogaril; merbarone; meterelin; methioninase; metoclopramide; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitonafide; mitoxantrone; mofarotene; molgramostim; mopidamol; maytansine; megestrol acetate; melengestrol acetate; melphalan; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitinmitomycin; mitosper; mitotane; mitoxantrone; mycophenolic acid; nafarelin; nagrestip; napavin; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; oblimersen (e.g., GENASENSE®); octreotide; okicenone; onapristone; ondansetron; ormaplatin; oxisuran; oxaloplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palbociclib (e.g., IBRANCE®); panitumumab (e.g., VECTIBIX®); panomifene; pegaspargase; picibanil; pirarubicin; 22Attorney Docket No.00007.001.1801 piritrexim; prednisone; prednisolone, paclitaxel; nab-paclitaxel (e.g., ABRAXANE®); prednimustine; procarbazine; puromycin; raltitrexed; ramosetron; rapamycin (e.g., RAPAMUNE®); rhizoxin; ribociclib (e.g., KISQALI®), rituximab; rogletimide; rohitukine; romurtide; roquinimex; romidepsin; safingol; saintopin; sargramostim; semustine; sizofiran; sobuzoxane; sorafenib (e.g., NEXAVAR®); suniti nib; spiromustine; squalamine; suradista; suramin; swainsonine; spiroplatin; streptonigrin; streptozocin; sulofenur; tallimustine; tamoxifen; tauromustine; tazarotene; tellurapyrylium; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thrombopoietin; thymalfasin; thymotrinan; tirapazamine; toremifene; tretinoin; trimetrexate; triptorelin; tropisetron; talisomycin; taxotere; teroxirone; testolactone; thiamiprine; thiotepa; tirapazamine; toremifene; trastuzumab; trastuzumab emtansine; trestolone acetate; triciribine phosphate; trimetrexate; uracil mustard; vandetanib (e.g., CAPRELSA®); variolin B; velaresol; veramine; verteporfin; vemurafenib; vinorelb ine; vinxaltine; vitaxin; vinblastine; vincristine; vindesine; vinepidine; vinglycinate; vinleurosine; vinorelb ine; vinrosidine; vinzolidine; vorozole; wortmannin; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer; zinostatin; and zorubicin. In some embodiments, the anti- cancer agent includes, for example, idelalisib (e.g., ZYDELIG®), docetaxel, fluorouracil, gemcitabine (e.g., GEMZAR®), cisplatin, cis-diamine, carboplatin, paclitaxel, nab-paclitaxel, trastuzumab (e.g., HERCEPTIN®), temozolomide, tamoxifen, 4-hydroxytamoxifen, and doxorubicin.

[0084] Also included in the definition of anti-cancer agent are: (i) anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018 ([6-hydroxy- 2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone), onapristone, and toremifine citrate; (ii) selective estrogen receptor modulators (SERDs) such as brilanestrant, GDC-0927 ((2S)-2-[4-[2-[3-(fluoromethyl)azetidinedin-1-yl]ethoxy]phenyl]- 3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol), giredestrant (GDC-9545), AZ9496 ((E)-3- [3,5-difluoro-4-[(1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]phenyl]prop-2-enoic acid), camizestrant (AZ9833), GNE-274 ((S)-3-(3- hydroxyphenyl)-4-methyl-2-(4-((1-propylazetidin-3-yl)methoxy)phenyl)-2H-chromen-6-ol), and fulvestrant (e.g., FASLODEX®); (iii) aromatase inhibitors such as, for example, 4(5)- imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, and anastroz ole; (iv) anti-androgens such as apalutamide, abiraterone, enzalutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin. Further included in the definition of anti-cancer agents are: (v) MEK inhibitors such as cobimetinib; 23Attorney Docket No.00007.001.1801 (vi) lipid kinase inhibitors, such as taselisib; (vii) antisense oligonucleotides such as oblimersen; (viii) ribozymes such as VEGF expression inhibitors such as angiozyme; (ix) vaccines such as gene therapy vaccines, for example, velimogene aliplasmid (allovectin), plasmid DNA / lipid complex comprised of a plasmid DNA expression vector encoding human interleukin (IL)-2 complexed in a 5:1 mass ratio with DMRIE / DOPE lipid (leuvectin), and anti-idiotype naked DNA vaccine (vaxid); (x) topoisomerase 1 inhibitors such as lurtotecan; abarelix; and (xi) anti-angiogenic agents such as bevacizumab. In some embodiments herein, the anti-cancer agent is a therapeutic antibody such as atezolizumab, nivolumab, daratumumab, pembrolizumab, alemtuzumab, bevacizumab; cetuximab; panitumumab, rituximab, pertuzumab, trastuzumab, trastuzumab emtansine, or tositumomab.

[0085] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products. CDK2 Inhibition

[0086] Cyclin-dependent kinases (CDKs) are important cellular enzymes that perform essential functions in regulating cell division and proliferation. The CDK catalytic units are activated by binding to regulatory subunits, known as cyclins, followed by phosphorylation. The cyclins are divided into four general classes, G1, G2 / S, S and M cyclins, whose expression levels vary at different points in the cell cycle.

[0087] In particular, CDK2 becomes active when cyclin E or cyclin A binds at the active site of the kinase. The cyclin E / CDK2 complex plays an important role in regulation of the G1 / S transition, histone biosynthesis, and centrosome duplication. Progressive phosphorylation of retinoblastoma (Rb) by cyclin D / Cdk4 / 6 and cyclin E / CDK2 releases the G1 transcription factor, E2F, and promotes S-phase entry. Activation of cyclin A / CDK2 during early S-phase promotes phosphorylation of endogenous substrates that permit DNA replication and inactivation of E2F, for S-phase completion.

[0088] CDK2 is critical to the abnormal growth processes of certain disease or disorders such as cancer. The CCNE1 gene which produces cyclin E is frequently overexpressed in various cancers, causing the cells to become dependent on Cdk2 and cyclin E. In addition, abnormal expression of cyclin A2 is associated with chromosomal instability and tumor proliferation. However, Cyclin A also binds CDK1 during the late S / G2 phase. 24Attorney Docket No.00007.001.1801 CDK1 is an essential cyclin dependent kinase in the cell cycle, and its inhibition could lead to undesired toxicity. Thus, there is a need for CDK2 inhibitors that are selective for CDK2 over CDK1.

[0089] In addition, CDK2 has been implicated in regulatory events in autoimmune diseases, such as pemphigus vulgaris, inflammation, and neurodegenerative diseases or disorders. Thus, inhibitors of CDK2 are viable candidates for the methods of treating, preventing, or reducing the risk or severity of certain autoimmune diseases or disorders, inflammatory diseases or disorders, and neurodegenerative diseases or disorders.

[0090] The present disclosure provides, in some embodiments, compounds of Formula (I) and pharmaceutically acceptable salts thereof, compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which inhibit the activity of CDK2, thereby effecting biological processes mediated by unwanted activity of CDK2. In some embodiments, the compounds and compositions disclosed herein are selective against CDK2 (e.g., have a lower inhibitory constant, KI or IC50 for CDK2) relative to other enzymatic targets of CDK such as CDK1. Compounds that are selective against CDK2 may provide improved safety profile, improved dosing schedule, and / or enhanced overall efficacy. Similarly selective inhibitors of CDK2 may have reduced risk of certain toxicities linked to inhibition of other CDKs. In some embodiments, the compounds and compositions disclosed herein are selective against CDK2 relative to CDK1. Compounds

[0091] In some embodiments, provided herein are compounds of Formula I: or a pharmaceutically acceX is N or CH; 25Attorney Docket No.00007.001.1801 A2is phenyl or 5-6 membered heteroaryl; A4is aryl, heteroaryl, C3-12carbocyclyl, or 4-12 membered heterocyclyl; L1is -O-, -S-, or -NH-; L2is -NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, -C(=O)C(R8)2-, - C(=O)O-, -OC(=O)-, -C(R8)2O-, -OC(R8)2-, -C(=O)NR7-, -NR7C(=O)-, -C(R8)2NR7-, - NR7C(R8)2-, -C(R8)2S(=O)0-2-, -S(=O)0-2C(R8)2-, -C(R8)2S(=O)NR7-, S(=O)NR7C(R8)2-, or - C(R8)2C(R8)2-; R1is C3-12carbocyclyl, 4-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -(C1-6 alkylene)-(C3-10 carbocyclyl), -(C1-6 alkylene)-(4-12 membered heterocyclyl), -(C1-6alkylene)-(phenyl), -(C1-6alkylene)-(5-12 membered heteroaryl), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-5 R11; R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, -NHCOR9, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6 alkylsulfonyl, aryl, or heteroaryl, wherein R2is each independently optionally substituted by 1-4 R11; R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, -NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, or C1-6 alkylsulfonyl, wherein R3is each independently optionally substituted by 1-4 R11; R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7R10, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, SO2N(R7)2, or phenyl, or any two occurrences of R4s on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4s are attached, form a saturated, partially unsaturated, or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(=O)0-2, P(=O)R5, N, and NR10, wherein R4is each independently optionally substituted by 1-4 R11; R5is each independently H, C1-6alkyl, C1-6alkoxy, hydroxy, or -N(R7)2; R6is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-4-6 membered heterocycloalkyl, C1-6 acyl, aroyl, or heteroaroyl; 26Attorney Docket No.00007.001.1801 R7is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, C1-3alkylene-C3-6 cycloalkyl, or C1-3 alkylene-4-6 membered heterocycloalkyl, or two R7s are taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR12, O, and S(=O)0-2; R8is each independently H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-4-6 membered heterocycloalkyl, or two R8s taken together with the C atom to which they are attached form a 4-7 membered ring comprising 0-1 heteroatom selected from O, S(=O)0-2, P(=O)R5, and NR12, wherein R8is optionally substituted by 1-3 R11; R9is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-4-6 membered heterocycloalkyl, C1-6 acyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-3 R11; R10is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-4-6 membered heterocycloalkyl, C1-6acyl, C1-6alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1-3 R11, or R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from O, S(=O)0-2, P(=O)R5, and NR6; R11is each independently H, halo, hydroxy, cyano, oxo, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene- 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2; R12is each independently H, C1-6alkyl, C1-6alkoxy, hydroxy, C1-6acyl, or C1-6alkylsulfonyl; m is an integer 0, 1 or 2; n is an integer 0, 1, 2, or 3; and p is an integer 0, 1, 2, or 3, 27Attorney Docket No.00007.001.1801 provided that the A1ring and the L1linker are on contiguous C atoms of the A2ring, whereas L1and L2are not situated on contiguous atoms of the A3ring.

[0092] In some embodiments of Formula (I), A2is phenyl or 5-6 membered heteroaryl. In some embodiments of Formula (I), A2is 5-6 membered heteroaryl. In some embodiments of Formula (I), A2is phenyl or 6-membered heteroaryl. In some embodiments of Formula (I), A2is phenyl or pyridyl. In some embodiments of Formula (I), A2is phenyl. In some embodiments of Formula (I), A2is pyridyl.

[0093] In some embodiments, the compound is of Formula (I-A):or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4are each CH or N, provided that no more than two of X1, X2, X3, and X4are N, and the hydrogen of CH may be optionally substituted by R2.

[0094] In some embodiments of Formula (I-A), two of X1, X2, X3, and X4are N and the remaining of X1, X2, X3, and X4are CH. In some embodiments of Formula (I-A), one of X1, X2, X3, and X4is N and the remaining of X1, X2, X3, and X4are CH.

[0095] In some embodiments of Formula (I) or (I-A), L1is -O- or -NH-. In some embodiments of Formula (I) or (I-A), L1is -NH-. In some embodiments of Formula (I) or (I- A), L1is -O-. In some embodiments of Formula (I) or (I-A), L1is -S-.

[0096] In some embodiments, the compound is of Formula (I-B1) or (I-B2):Attorney Docket No.00007.001.1801or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4are each CH or N, provided that no more than two of X1, X2, X3, and X4are N, and the hydrogen of CH may be optionally substituted by R2.

[0097] In some embodiments of Formula (I-B1) or (I-B2), two of X1, X2, X3, and X4are N and the remaining of X1, X2, X3, and X4are CH. In some embodiments of Formula (I- B1) or (I-B2), one of X1, X2, X3, and X4is N and the remaining of X1, X2, X3, and X4are CH.

[0098] In some embodiments of Formula (I), (I-A), (I-B1), or (I-B2), L2is -NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, -C(=O)C(R8)2-, -C(=O)O-, -OC(=O)-, - C(R8)2O-, -OC(R8)2-, or -C(=O)NR7-. In some embodiments of Formula (I), (I-A), (I-B1), or (I-B2), L2is -NR7SO2-. In some embodiments of Formula (I), (I-A), (I-B1), or (I-B2), R7is H or C1-6alkyl. In some embodiments of Formula (I), (I-A), (I-B1), or (I-B2), R7is H or methyl.

[0099] In some embodiments of Formula (I), (I-A), (I-B1), or (I-B2), X is N. In other embodiments of Formula (I), (I-A), (I-B1), or (I-B2), X is CH. [000100] In some embodiments, the compound is of Formula (I-C1), (I-C2), (I-C3), or (I-C4):Attorney Docket No.00007.001.1801or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4are each CH or N, provided that no more than two of X1, X2, X3, and X4are N, and the hydrogen of CH may be optionally substituted by R2. [000101] In some embodiments of Formula (I-C1), (I-C2), (I-C3), or (I-C4), two of X1, X2, X3, and X4are N and the remaining of X1, X2, X3, and X4are CH. In some embodiments of Formula (I-C1), (I-C2), (I-C3), or (I-C4), one of X1, X2, X3, and X4is N and the remaining of X1, X2, X3, and X4are CH. [000102] In some embodiments of Formula (I-C1), (I-C2), (I-C3), or (I-C4), L2is - NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, -C(=O)C(R8)2-, -C(=O)O-, - OC(=O)-, -C(R8)2O-, -OC(R8)2-, or -C(=O)NR7-. In some embodiments of Formula (I-C1), 30Attorney Docket No.00007.001.1801 (I-C2), (I-C3), or (I-C4), L2is -NR7SO2-. In some embodiments of Formula (I-C1), (I-C2), (I- C3), or (I-C4), R7is H or C1-6alkyl. In some embodiments of Formula (I-C1), (I-C2), (I-C3), or (I-C4), R7is H or methyl. [000103] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), A4is aryl or heteroaryl. In some embodiments of Formula (I), (I-A), (I-B1), (I- B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is aryl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is heteroaryl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is C3-12carbocyclyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is 4-12 membered heterocyclyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is phenyl, naphthyl, 5-12 membered heteroaryl, C3-10 carbocyclyl, or 4-12 membered heterocyclyl. In some embodiments of Formula (I), (I-A), (I- B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is phenyl, naphthyl, or 5-12 membered heteroaryl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is phenyl, naphthyl, or 5-6 membered heteroaryl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is phenyl or naphthyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), A4is phenyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), A4is naphthyl. [000104] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is C3-12carbocyclyl, 4-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -(C1-6 alkylene)-(C3-10 carbocyclyl), -(C1-6 alkylene)-(4-12 membered heterocyclyl), -(C1-6alkylene)-(phenyl), -(C1-6alkylene)-(5-12 membered heteroaryl), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is C3-12 carbocyclyl, 4-12 membered heterocyclyl, -(C1-6alkylene)-OR9, or -(C1-6alkylene)- NR7R10, wherein R1is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is C6-10carbocyclyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -(C1-6alkylene)-(C3-10carbocyclyl), -(C1-6alkylene)-(4-8 membered heterocyclyl), -(C1-6alkylene)-(5-6 membered heteroaryl), - (C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I- C4), R1is C6-10carbocyclyl, 4-8 membered heterocyclyl, -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-2 R11. 31Attorney Docket No.00007.001.1801 [000105] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is C6-10carbocyclyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -(C1-6alkylene)-(C3-10carbocyclyl), -(C1-6alkylene)-(4-8 membered heterocyclyl), - (C1-6alkylene)-(5-6 membered heteroaryl), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1 R11. [000106] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is C6-10carbocyclyl, 4-8 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of O, S, and N, -(C1-6alkylene)-(C3-10carbocyclyl), -(C1-6alkylene)-(4-8 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of O, S, and N), -(C1-6alkylene)-(5-6 membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O, S, and N), -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is C6-10carbocyclyl, 4-8 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of O, S, and N, -(C1-3alkylene)-(4-6 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of O, S, and N), -(C1-3alkylene)-(5-6 membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O, S, and N), -(C1- 6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1 R11. [000107] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is cyclohexyl, piperidinyl, tetrahydrofuranyl, or oxetanyl, wherein R1is optionally substituted with 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is cyclohexyl optionally substituted with 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is piperidinyl, tetrahydrofuranyl, or oxetanyl, each optionally substituted with 1 R11. [000108] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is –(C1-4alkylene)-OR9optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is -(C1-4alkylene)-OR9optionally substituted with 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R9is H or C1-6alkyl. [000109] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is –(C1-3alkylene)-OR9optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is – (C1-3alkylene)-OR9optionally substituted by 1 R11. In some embodiments of Formula (I), (I- A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R9is H or C1-6 alkyl. 32Attorney Docket No.00007.001.1801 [000110] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is -(C1-4alkylene)-NR7R10optionally substituted with 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is -(C1-4alkylene)-NR7R10optionally substituted with 1 R11. In some embodiments of Formula (I), (I- A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R7is H or C1-6 alkyl and R10is C1-6 alkylsulfonyl. [000111] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is -(C1-3alkylene)-NR7R10optionally substituted with 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R1is -(C1-3alkylene)-NR7R10optionally substituted with 1 R11. In some embodiments of Formula (I), (I- A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R7is H or C1-6 alkyl and R10is C1-6 alkylsulfonyl. [000112] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is -(C1-3alkylene)-(4-6 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of O, S, and N) optionally substituted by 1 R11. [000113] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R1is -(C1-3alkylene)-(5-6 membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O, S, and N) optionally substituted by 1 R11. [000114] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R11is each independently H, halo, hydroxy, cyano, oxo, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3alkylene-4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2. In some embodiments of Formula (I), (I-A), (I- B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R11is each independently H, halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R11is each independently H, halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, or N(R7)2. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R11is each independently selected from N(R7)2, C1-6alkyl, and C1-6hydroxyalkyl. In 33Attorney Docket No.00007.001.1801 some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R11is each independently selected from NH2, C1-4alkyl, and C1-4hydroxyalkyl. [000115] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6 alkenylthio, C1-6 alkylsulfonyl, aryl, or heteroaryl, wherein R2is each independently optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, -NHCOR9, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C2-6alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, aryl, or heteroaryl, wherein R2is each independently optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, -NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, or C2-6 alkenylthio, C1-6 alkylsulfonyl, wherein R2is each independently optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R2is each independently halogen or C1-6 alkyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I- C2), (I-C3), or (I-C4), R2is each independently halogen. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R2is each independently F. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), m is 0 or 1. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I- C4), m is 0. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), m is 1. [000116] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6alkenylthio, or C1-6alkylsulfonyl, wherein R3is each independently optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I- C2), (I-C3), or (I-C4), R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, 34Attorney Docket No.00007.001.1801 COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6alkenylthio, or C1-6alkylsulfonyl, wherein R3is each independently optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I- C2), (I-C3), or (I-C4), R3is each independently H, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, C3-8 cycloalkyl, or C3-8 cycloalkenyl, wherein R3is each independently optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R3is each independently halogen or C1-6alkyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I- C2), (I-C3), or (I-C4), R3is each independently halogen. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R3is each independently F. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), n is 0, 1 or 2. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I- C4), n is 0 or 1. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), n is an integer 1 or 2. In some embodiments, n is 0. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), n is 1. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), n is 2. [000117] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7R10, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, SO2N(R7)2, or phenyl, wherein R4is each independently optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7R10, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, C1-6alkylsulfonyl, SO2N(R7)2, or phenyl, wherein R4is each independently optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-C3), or (I-C4), R4is each independently H, halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, COR9, CO2R9, CONR7R10, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, or C3-8cycloalkenyl, wherein R4is each independently optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I- B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R4is each independently halogen or C1-6alkyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), 35Attorney Docket No.00007.001.1801 R4is each independently halogen or methyl. In some embodiments of Formula (I), (I-A), (I- B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R4is each independently F, Cl, or methyl. [000118] In other embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), two occurrences of R4s on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4s are attached, form a saturated, partially unsaturated, or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(=O)0-2, P(=O)R5, N, and NR10. [000119] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), p is 0, 1, or 2. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-C3), or (I-C4), p is an integer 1, 2, or 3. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), p is 0 or 1. In some embodiments, p is 0. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I- C4), p is 1. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), p is 2. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), p is 3. [000120] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R5is each independently H, C1-6 alkyl, or hydroxy. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R5is each independently H or C1-2alkyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R5is H or methyl. [000121] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R6is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, or C1-6acyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R6is each independently H or C1-6alkyl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-C3), or (I-C4), R6is each independently H or methyl. [000122] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R7is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, (C1-3 alkylene)-(C3-6 cycloalkyl), or (C1-3 alkylene)-(4-6 membered heterocycloalkyl). In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R7is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, or 5-12 membered heteroaryl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), 36Attorney Docket No.00007.001.1801 or (I-C4), R7is each independently H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R7is each independently H or C1-6alkyl. In other embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), two R7s are taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR12, O, and S(=O)0-2. [000123] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R8is each independently H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C2-6cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3alkylene)-(C3-6cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), wherein R8is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I- C2), (I-C3), or (I-C4), R8is each independently H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein R8is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-C3), or (I-C4), R8is each independently H or C1-6 alkyl. [000124] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R9is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C4-10heterocycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-C4-6heterocycloalkyl, C1-6acyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R9is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, (C1-3alkylene)-(C3-6cycloalkyl), (C1-3alkylene)-(4-6 membered heterocycloalkyl), C1-6 acyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-C3), or (I-C4), R9is H, C3-10 cycloalkyl, C4-10 heterocycloalkyl, phenyl, or 5-12 membered heteroaryl, wherein R9is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R9is each independently H or C1-6alkyl, wherein R9is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R9is H or C1-6alkyl. [000125] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R10is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10 heterocycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C4-6 heterocycloalkyl, C1-6 37Attorney Docket No.00007.001.1801 acyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R10is H or C1-6alkyl, wherein the R10is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R10is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- 10 membered heterocycloalkyl, (C1-3alkylene)-(C3-6cycloalkyl), (C1-3alkylene)-(4-6 membered heterocycloalkyl), C1-6 acyl, C1-6 alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R10is each independently H, C1-6 alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein R10is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R10is H or C1-6alkyl, wherein the R10is optionally substituted by 1 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R10is H or C1-6alkyl. [000126] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from O, S(=O)0-2, P(=O)R5, and NR6, wherein R10is optionally substituted by 1-2 R11. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I- C4), R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from O, S(=O)0-2, P(=O)R5, and NR6. [000127] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R11is each independently H, halo, hydroxy, cyano, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2. In some embodiments of Formula (I), (I-A), (I- B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R11is each independently H, halo, C1-6alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, CON(R7)2, or N(R7)2. In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R11is each independently H, halo, C1-6alkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, CON(R7)2, or N(R7)2. [000128] In some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I- C3), or (I-C4), R12is each independently H, C1-6 alkyl, C1-6 acyl, or C1-6 alkylsulfonyl. In 38Attorney Docket No.00007.001.1801 some embodiments of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4), R12is each independently H or C1-6alkyl. [000129] In some embodiments, a compound described herein is a compound depicted in Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Compound Structure Number39Attorney Docket No.00007.001.1801 5Attorney Docket No.00007.001.1801 10Attorney Docket No.00007.001.1801 15Attorney Docket No.00007.001.1801 20Attorney Docket No.00007.001.1801 [000130] Also provided herein, in some embodiments, is a conjugate, comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, bound to CDK2. Pharmaceutical Compositions [000131] Compounds provided in accordance with the present disclosure, in some embodiments, are administered in the form of pharmaceutical compositions. This disclosure therefore provides pharmaceutical compositions that comprise, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. In some embodiments, the pharmaceutical compositions are administered in combination with other therapeutic agents. [000132] Provided herein, in some embodiments, are pharmaceutical compositions, comprising: a) a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient. [000133] In some embodiments, the pharmaceutical compositions are administered in a single dose by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. In some embodiments, the pharmaceutical compositions are administered in multiple doses. [000134] One mode for administration is parenteral, for example by injection. Administration by injection comprises, in some embodiments, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection. In some embodiments, compositions suitable for injection comprise ethanol, glycerol, propylene glycol, liquid polyethylene glycol, or the like (and suitable mixtures thereof), cyclodextrin derivatives, or vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought 44Attorney Docket No.00007.001.1801 about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, or the like. [000135] Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [000136] Oral administration is another route for administration of compounds in accordance with the disclosure. Oral administration includes, for example, capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is, in some embodiments, diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments comprising the active compound, soft and hard gelatin capsules, sterile injectable solutions, or sterile packaged powders. [000137] The compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. 45Attorney Docket No.00007.001.1801 [000138] The compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [000139] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [000140] In some embodiments, the tablets or pills of the present disclosure are coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [000141] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or 46Attorney Docket No.00007.001.1801 powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Methods of Use [000142] Provided herein, in some embodiments, are compounds of Formula (I), (I-A), (I-B1), (I-B2), (I-C1), (I-C2), (I-C3), or (I-C4) for use in therapy. [000143] Also provided herein, in some embodiments, are methods of inhibiting CDK2 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000144] Also provided herein, in some embodiments, are methods of reducing CDK2 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000145] Also provided herein, in some embodiments, are methods of treating a disease or disorder characterized by overexpression or amplification of cyclin E in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000146] In some embodiments, the cyclin E is CCNE1 or CCNE2. [000147] In some embodiments, provided herein are methods of treating a disease or disorder characterized by overexpression or amplification of cyclin A in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000148] Also provided herein, in some embodiments, are methods of preventing a disease or disorder characterized by overexpression or amplification of cyclin E in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000149] In some embodiments, the cyclin E is CCNE1 or CCNE2. [000150] In some embodiments, provided herein are methods of preventing a disease or disorder characterized by overexpression or amplification of cyclin A in a subject in need thereof, administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. 47Attorney Docket No.00007.001.1801 [000151] Also provided herein, in some embodiments, are methods of reducing the risk or severity a disease or disorder characterized by overexpression or amplification of cyclin E in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000152] In some embodiments, the cyclin E is CCNE1 or CCNE2. [000153] In some embodiments, provided herein are methods of reducing the risk or severity of a disease or disorder characterized by overexpression or amplification of cyclin A in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000154] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000155] In some embodiments, the cancer is associated with amplification or overexpression of cyclin E. In some embodiments, the cyclin E is CCNE1 or CCNE2. In some embodiments, the cancer is associated with amplification or overexpression of cyclin A. [000156] In some embodiments, the cancer is breast cancer, ovary cancer, cervix cancer, prostate cancer, testis cancer, genitourinary tract cancer, esophagus cancer, larynx cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell cancer, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, buccal cavity cancer, naso-pharyngeal cancer, pharynx cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colon-rectum cancer, large intestine cancer, rectum cancer, bronchial cancer, hepatocellular cancer, gastric cancer, endometrial cancer, melanoma, renal cancer, urinary bladder cancer, uterine corpus cancer, or uterine cervix cancer. [000157] In some embodiments, the cancer is squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver 48Attorney Docket No.00007.001.1801 cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer. [000158] In some embodiments, the cancer is breast cancer. The breast cancer can be Stage I, II, III, or IV as understood in the art. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In another embodiment, the breast cancer is Her2 negative breast cancer. [000159] In some embodiments, the cancer is breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, melanoma, lung cancer, pancreatic cancer, stomach cancer, esophageal cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, prostate cancer, renal cancer, hepatic cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, lymphoma, and leukemia. [000160] In some embodiments, provided herein are methods of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000161] In some embodiments, the hematological malignancy is associated with amplification or overexpression of cyclin E. In some embodiments, the cyclin E is CCNE1 or CCNE2. In some embodiments, the hematological malignancy is associated with amplification or overexpression of cyclin A. [000162] In some embodiments, hematological malignancy is lymphoma, lymphocytic leukemia (acute (ALL) and chronic (CLL), multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), or non-Hodgkin lymphoma. In some embodiments,, the methods herein include treatment of lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD). [000163] In some embodiments, the methods described herein further comprise administering an anti-cancer agent. [000164] In some embodiments, the methods provided herein further comprises administering to the subject an additional therapeutic agent(s) selected from the group consisting of an anti-inflammatory agent, a corticosteroid, an immunomodulatory agent, anti- cancer agent as described herein, an apoptosis-enhancer, a neurotropic factor, an agent for 49Attorney Docket No.00007.001.1801 treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, an agent for treating metabolic disorders, an agent for treating autoimmune disorders, an agent for treating immunodeficiency disorders, and combinations thereof. In some embodiments, the additional therapeutic agent is a corticosteroid, a proteasome inhibitor, an IMiD, an antibody, or a combination thereof. In some embodiments, the additional therapeutic agent is a proteasome inhibitor (e.g. carfilzomib, bortezomib, or ixazomib). In some embodiments, the additional therapeutic agent is an IMiD (e.g. lenalidomide or pomalidomide). In some embodiments, the additional therapeutic agent is an antibody (e.g., an anti-CD38 antibody, an anti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-interleukin-6 antibody). In some embodiments, the additional therapeutic agent is a corticosteroid (e.g., dexamethasone). In some embodiments, the method further comprises radiotherapy. [000165] Also provided herein are methods of treating an autoimmune disorder or disease in a subject in need thereof, administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000166] In some embodiments, the autoimmune disorder or disease is associated with amplification or overexpression of cyclin E. In some embodiments, the cyclin E is CCNE1 or CCNE2. In some embodiments, the autoimmune disorder or disease is associated with amplification or overexpression of cyclin A. [000167] Exemplary autoimmune disorder or disease contemplated in the methods provided herein includes, but not limited to, rheumatoid arthritis, Lupus, Crohn’s Disease, Addison disease, celiac disease, dermatomyositis, Graves’ disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, pemphigus vulgaris, diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE), Sjogren’s syndrome, Churg-Strauss Syndrome, Hashimoto’s thyroiditis, idiopathic thrombocytopenic purpura, or rheumatoid arthritis. [000168] Also provided herein are methods of treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000169] In some embodiments, the inflammatory disease or disorder is associated with amplification or overexpression of cyclin E. In some embodiments, the cyclin E is CCNE1 or 50Attorney Docket No.00007.001.1801 CCNE2. In some embodiments, the inflammatory disease or disorder is associated with amplification or overexpression of cyclin A. [000170] Exemplary inflammatory disease or disorder contemplated in the methods provided herein includes, but not limited to, asthma, chronic peptic ulcers, psoriasis, inflammatory bowel disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, hepatitis chronic prostatitis, glomerulonephritis, hypersensitivities, pelvic inflammatory disease, reperfusion injury, transplant rejection, or vasculitis. [000171] Also provided herein are methods of treating a neurodegenerative disease or disorder in a subject in need thereof, administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition disclosed herein. [000172] In some embodiments, the neurodegenerative disease or disorder is associated with amplification or overexpression of cyclin E. In some embodiments, the cyclin E is CCNE1 or CCNE2. In some embodiments, the neurodegenerative disease or disorder is associated with amplification or overexpression of cyclin A. [000173] Exemplary neurodegenerative disease or disorder contemplated in the methods provided herein includes, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, cerebellar degeneration, Alexander’s disease, Alper’s disease, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSF), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington’s disease, HIV-associated dementia, Kennedy’s disease, Krabbe’s disease, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Pelizaeus-Merzbacher Disease, Pick’s disease, Primary lateral sclerosis, Prion diseases, Refsum’s disease, Sandhoffs disease, Schilder’s disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele- Richardson- Olszewski disease, or Tabes dorsalis. [000174] Also provided herein, in some embodiments, are methods of killing a cell over-expressing cyclin E in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, also disclosed herein are methods of killing a cell over-expressing or amplifying cyclin E, comprising 51Attorney Docket No.00007.001.1801 contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [000175] In some embodiments, the cyclin E is CCNE1 or CCNE2. [000176] Also provided herein, in some embodiments, are methods of killing a cell over-expressing cyclin A in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, also disclosed herein are methods of killing a cell over-expressing or amplifying cyclin A, comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [000177] Also provided herein, in some embodiments, are methods of inhibiting CDK2 in a cell over-expressing cyclin E in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, also disclosed herein are methods of inhibiting CDK2 in cell over-expressing or amplifying cyclin E, comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [000178] In some embodiments, the cyclin E is CCNE1 or CCNE2. [000179] Also provided herein, in some embodiments, are methods of inhibiting CDK2 in a cell over-expressing cyclin A in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, also disclosed herein are methods of inhibiting CDK2 in a cell over-expressing or amplifying cyclin A, comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [000180] Also provided herein, in some embodiments, are methods of killing a cell over-expressing or amplifying cyclin E, comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [000181] Also provided herein, in some embodiments, are methods of killing a cell over-expressing or amplifying cyclin A, comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 52Attorney Docket No.00007.001.1801 Dosage Regimens [000182] Dosage regimens may be adjusted to provide the optimum desired response. The skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure. [000183] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein. [000184] The amount of the compound of the disclosure administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. Kits 53Attorney Docket No.00007.001.1801 [000185] In another aspect provided herein are kits, comprising materials useful for the treatment or prevention of the diseases and disorders described above. In some embodiments, the kit comprises a container comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container can be formed from a variety of materials such as glass or plastic. The container can hold a compound of Formula (I), or a composition thereof which is effective for treating or preventing the condition and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The label or package insert indicates that the composition is used for treating the condition of choice. The label or package insert can also indicate that the composition can be used to treat other disorders. Alternatively, or additionally, the article of manufacture can further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. [000186] The kit can further comprise directions for the administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof and a second pharmaceutical formulation, the kit can further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof. [000187] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. 54Attorney Docket No.00007.001.1801 [000188] In some embodiments, a kit comprises (a) a first container with a compound of Formula (I), or a pharmaceutically acceptable salt thereof contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein. Alternatively, or additionally, the kit can further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. [000189] In some embodiments wherein the kit comprises a composition of Formula (I), or a pharmaceutically acceptable salt thereof and a second therapeutic agent, the kit can comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions can also be contained within a single, undivided container. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. EXAMPLES [000190] Selected abbreviations: ACN: acetonitrile; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; PE: petroleum ether; THF: tetrahydrofuran; TLC: thin layer chromatography. Example 1. Synthetic Methods Method A. 55Attorney Docket No.00007.001.1801of skill in the art, such as that illustrated above. A Suzuki coupling between 4,6- dichlopyrimidine and a 2-fluoropyridyl-3-boronic acid forms a 6-chloro-4-(2-fluoro-3- pyridyl)pyrimidine. The 4-chloro is displaced by the C2 amine, which may contain a suitably protected primary or secondary amine substituent under mildly basic conditions, whereas under more strongly basic conditions the phenoxide derived from an appropriately substituted 4-aminophenol can displace the 2-fluoro from the pyridyl ring, to form a 4-aminophenyl ether. The aniline amino group can be sulfonated with a suitable sulfonyl halide, such as the chloride, to give a 4-sulfonamidophenoxy ether product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. This intermediate may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings before the SNAr reaction to link the A2and A3rings, or the SNAr reaction may be carried out to link the A2and A3rings before the Suzuki-Miyauri biaryl coupling to link the A1and A2rings. Method B. 56Attorney Docket No.00007.001.1801[0001 amiliar to oneof skill in the art, such as that illustrated above. A Suzuki coupling between 4,6- dichlopyrimidine and a 2-fluoropyridyl-3-boronic acid forms a 4-chloro-4-(2-fluoro-3- pyridyl)pyrimidine. The 4-chloro is displaced by the C2 amine, which may contain a suitably protected primary or secondary amine substituent under mildly basic conditions, whereas under strongly acidic conditions weakly nucleophilic anilines such as 4-nitroanilines may then displace the fluorine atom from the 2-pyridyl position. If R1had a protected amine, it is likely that it will have to be reprotected after this step. Reduction of the nitro group, followed by sulfonation of the aniline amino group with a suitable sulfonyl halide, such as the chloride, will give a 4-sulfonamidophenylamino-biaryl product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. This intermediate may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings before the SNAr reaction to link the A2and A3rings if the amine and nitro functionalities are exchanged, or the SNAr reaction may be carried out to link the A2and A3rings before the Suzuki-Miyauri biaryl coupling to link the A1and A2rings. 57Attorney Docket No.00007.001.1801 Method C.of skill in the art, such as that illustrated above. A Stille coupling between a 4-amino-6- chlopyrimidine, which may contain a suitably protected primary or secondary amine substituent, and a 4-fluoro-3-stannyl pyridine forms a 6-amino-4-(4-fluoro-3- pyridyl)pyrimidine. Under strongly basic conditions, preferably in the presence of DMAP catalyst, the phenoxide derived from an appropriately substituted 4-aminophenol can displace the 4-fluoro from the pyridyl ring, to form a 4-aminophenyl pyridyl ether. The aniline amino group can be sulfonated with a suitable sulfonyl halide, such as the chloride, to give a 4- sulfonamidophenoxybiaryl product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. This intermediate may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings before the SNAr reaction to link the A2and A3rings, or the SNAr reaction may be carried out to link the A2and A3rings before the Suzuki-Miyauri biaryl coupling to link the A1and A2rings. 58Attorney Docket No.00007.001.1801 Method D.of skill in the art, such as that illustrated above. A Stille coupling between a 4-amino-6- chlopyrimidine, which may contain a suitably protected primary or secondary amine substituent, and a 4-fluoro-3-stannyl pyridine forms a 6-amino-4-(4-fluoro-3- pyridyl)pyrimidine. whereas under strongly acidic conditions weakly nucleophilic anilines such as 4-notroanilines may then displace the fluorine atom from the 2-pyridyl position. If R1had a protected amine, it is likely that it will have to be reprotected after this step. Reduction of the nitro group, followed by sulfonation of the aniline amino group with a suitable sulfonyl halide, such as the chloride, will give a 4-sulfonamidophenylamino-biaryl product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. This entity may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings before the SNAr reaction to link the A2and A3rings if the amine and nitro functionalities are exchanged, or the SNAr reaction may be carried out to link the A2and A3rings before the Suzuki-Miyauri biaryl coupling to link the A1and A2rings. Method E. 59Attorney Docket No.00007.001.1801of skill in the art, such as that illustrated above. A-3-amino-2-bromopyridine displaces a 4- fluorine atom from a suitably substituted 4-fluoronitrobenzene, and then the bromide is converted to an aryl stannane under standard conditions. A Stille coupling between this moiety and a 4-amino-6-chlopyrimidine, which may contain a suitably protected primary or secondary amine substituent, forms a 6-amino-4-(2-(4-nitroanilino)-3-pyridyl)pyrimidine, which can be reduced to the corresponding amine, and sulfonated under standard conditions. This species can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. The resultant compound may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, the Stille coupling to link the A1and A2rings may be done before the SNAr reaction to link the A2and A3rings, or the insertion of the R1amine by chloride displacement may be carried out only after the Stille coupling assembles the Ar1-Ar2-Ar3moiety. Method F. 60Attorney Docket No.00007.001.1801[ ] ompoun s o genera ormu a can e synt es ze y routes am ar to one of skill in the art, such as that illustrated above. A Suzuki coupling between a 4-amino-2- chlorotriazine, which may contain a suitably protected primary or secondary amine substituent, and a 2-fluoropyrid-3-yl boronic acid forms a 4-amino-2-(2-fluoro-3- pyridyl)(1,3,5)triazine. Under strongly basic conditions, preferably in the presence of DMAP catalyst, the phenoxide derived from an appropriately substituted 4-aminophenol can displace the 2-fluoro from the pyridyl ring, to form a 4-aminophenyl pyridyl ether. The aniline amino group can be sulfonated with a suitable sulfonyl halide, such as the chloride, to give a 4- sulfonamidophenoxy biaryl product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. This intermediate may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings before the SNAr reaction to link the A2and A3rings, or the SNAr reaction may be carried out to link the A2and A3rings before the Suzuki-Miyauri biaryl coupling to link the A1and A2rings. Method G. 61Attorney Docket No.00007.001.1801of skill in the art, such as that illustrated above. Displacement of fluorine by 4- methoxybenzyl thiol from a suitably substituted 4-fluoronitrobenzene give a protected thiophenol species, where the nitro group can be reduced to an amine, and then be N- sulfonated with a suitable sulfonyl halide, such as the chloride, to give a 4- sulfonamidophenylthio product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. A Suzuki coupling between a 4-amino-2-chlorotriazine, which may contain a suitably protected primary or secondary amine substituent, and a 2- fluoropyrid-3-yl boronic acid forms a 4-amino-2-(2-fluoro-3-pyridyl)(1,3,5)triazine. Reaction of this biaryl fluoride with the anion derived from the deprotected thioether will give a a diaryl sulfide containing the desired substituents. This compound may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings after the SNAr reaction to link the A2and A3rings, or the SNAr reaction may be carried out to link the A2and A3rings before the Suzuki-Miyauri biaryl coupling to link the A1and A2rings. 62Attorney Docket No.00007.001.1801 Method H.of skill in the art, such as that illustrated above. A Stille coupling between a 4-amino-2- chlorotriazine, which may contain a suitably protected primary or secondary amine substituent, and a 4-fluoro-3-stannylpyridine forms a 4-amino-2-(4-fluoro-3- pyridyl)(1,3,5)triazine. Sulfonylation of an appropriately substituted 4-nitroaniline derivative with a suitable sulfonyl halide, such as the chloride, to give a 4-sulfonamidophenoxy biaryl product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired, and then the nitro can be reduced to an amino function. Under strongly acidic conditions, this aniline can be coupled with the 2-fluorobiaryl species produced earlier. This intermediate may not require a final deprotection of a C2-side chain amine to give the final product, as the acidic conditions will remove many protecting groups. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, the starting nitroaniline could be monoalkylated before sulfonylation. Method I. 63Attorney Docket No.00007.001.1801art, such as that illustrated above. A Stille coupling between a 4-amino-2-chlorotriazine, which may contain a suitably protected primary or secondary amine substituent, and a 4- fluoro-3-stannylpyridine forms a 4-amino-2-(4-fluoro-3-pyridyl)(1,3,5)triazine. Under strongly basic conditions, preferably in the presence of DMAP catalyst, the phenoxide derived from an appropriately substituted 4-aminophenol can displace the 2-fluoro from the pyridyl ring, to form a 4-aminophenyl pyridyl ether. The aniline amino group can be sulfonated with a suitable sulfonyl halide, such as the chloride, to give a 4- sulfonamidophenoxy biaryl product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. This intermediate may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, a sulfonamide bond may be formed to link the A3and A4rings before the SNAr reaction to link the A2and A3rings, or the SNAr reaction may be carried out to link the A2and A3rings before the Stille biaryl coupling to link the A1and A2rings. Method J. 64Attorney Docket No.00007.001.1801of skill in the art, such as that illustrated above. Displacement of fluorine by a suitable 2- aminophenyl boronate species from a suitably substituted 4-fluoronitrobenzene give a diarylaminel species, where the nitro group can be reduced to an amine, and then be N- sulfonated with a suitable sulfonyl halide, such as the chloride, to give a 4- sulfonamidophenylthio product, which can be N-alkylated on the sulfonamide nitrogen under strongly basic conditions, if desired. A Suzuki coupling between a 4-amino-2-chlorotriazine, which may contain a suitably protected primary or secondary amine substituent, and this 2- (4-sulfonamidoanilino boronate derivative forms a compound which may require a final deprotection of a C2-side chain amine to give the final product. Timing of individual steps may also vary depending on the chemistry needed to incorporate various substituents. For example, Suzuki-Miyauri biaryl coupling to link the A1and A2rings may be carried out prior to nitro reduction and sulfonylation, or even prior to the SNAr fluoride displacement. [000200] Using techniques similar to those described above, as well as other reactions well known to those of skill in the art, other compounds of this invention, such as those illustrated below can be made. 65Attorney Docket No.00007.001.180166Attorney Docket No.00007.001.1801Example 2. Syntheses of Compounds 1-24 Synthesis of Intermediates Intermediate 1: tert-Butyl ((1R,4R)-4-((4-chloro-1,3,5-triazin-2- yl)amino)cyclohexyl)carbamate [000201] To a solution of 2,g, 6.67 mmol) in DCM (30 mL) were added tert-butyl N-(4-aminocyclohexyl)carbamate (1.35 g, 6.34 mmol, 0.95 eq) and N,N-diisopropylethylamine (1.51 mL, 8.67 mmol, 1.3 eq), and then the reaction mixture was stirred at -30oC for 1 h and then at 0oC for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (2.04 g, 77% purity) which was used for the next reaction without purification; ESI-MS: m / z = 328 [M+H]+.Intermediate 2: tert-Butyl ((1R,4R)-4-((4-(2-fluoropyridin-3-yl)-1,3,5-triazin-2- yl)amino)cyclohexyl)carbamate 67Attorney Docket No.00007.001.1801 [000202] To a solution of t chloro-1,3,5-triazin-2- yl)amino)cyclohexyl)carbamate,Intermediate 1 (1.00 g, 3.06 mmol) in dioxane (13 mL) and H2O (7 mL) were added (2-fluoropyridin-3-yl)boronic acid (0.52 g, 3.67 mmol, 1.2 eq), K3PO4(2.60 g, 12.2 mmol, 4 eq) and Pd(PPh3)2Cl2(107 mg, 0.15 mmol, 0.05 eq). The reaction mixture was irradiated in a microwave reactor at 150°C for 10 min. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (0.91 g, 77% purity) which was used for the next reaction without purification; ESI-MS: m / z = 389 [M+H]+. Intermediate 3: tert-butyl ((1R,4R)-4-((4-(2-(4-Amino-2-fluorophenoxy)pyridin-3-yl)- 1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate [000203] To a solution of te(2-fluoropyridin-3-yl)-1,3,5-triazin- 2-yl)amino)cyclohexyl)carbamate (410 mg, 1.06 mmol, 77% purity) in DMF (10 mL) was added 4-amino-2-fluorophenol (147 mg, 1.16 mmol, 1.1 eq), DMAP (26 mg, 0.21 mmol, 0.2 eq), and Cs2CO3(516 mg, 1.59 mmol, 1.5 eq). The reaction mixture was irradiated in a microwave reactor at 120°C for 30 min. The resulting mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), and then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was then purified by silica gel flash column chromatography (50% to 100% EtOAc in Hex) to afford the title compound (163 mg, 0.33 mmol, 40% yield) as an off white solid.1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.30 – 7.95 (m, 2H), 7.19 (ddd, J = 12.6, 7.5, 4.9 Hz, 1H), 6.83 (td, J = 8.9, 7.2 Hz, 1H), 6.71 (dd, 68Attorney Docket No.00007.001.1801 J = 11.5, 8.1 Hz, 1H), 6.47 – 6.27 (m, 2H), 5.23 (d, J = 6.4 Hz, 2H), 3.78 – 3.65 (m, 1H), 3.17 (d, J = 4.8 Hz, 1H), 1.95 – 1.67 (m, 4H), 1.36 (s, 13H); ESI-MS: m / z = 496 [M+H]+. Intermediate 4: 4-fluoro-3-(tributylstannyl)pyridine [000204] To a solution of 3-bromo- pyridine (5 g, 28.4 mmol) andhexabutylditin (19.5 g, 36.9 mmol, 1.3 eq) in dioxane (70 mL) were added Pd(OAc)2 (0.64 g, 2.84 mmol, 0.1 eq) and PCy3( 1.59 g, 5.68 mmol, 0.2 eq). The reaction mixture was heated at 100°C for 4 d under nitrogen. The resulting mixture was then filtered through a pad of Celite and concentrated under reduced pressure to give a crude material, which was purified by silica gel flash column chromatography (0% to 5% EtOAc in Hex) to afford the title compound (6.12 g, 15.9 mmol, 56% yield) as a clear oil. ESI-MS m / z = 388 [M+H]+. Intermediate 5: tert-butyl ((1R,4R)-4-((4-(4-fluoropyridin-3-yl)-1,3,5-triazin-2- yl)amino)cyclohexyl)carbamate [000205] To a solution of techloro-1,3,5-triazin-2- yl)amino)cyclohexyl)carbamate, Intermediate 1 (800 mg, 2.45 mmol) and 4-fluoro-3- (tributylstannyl)pyridine, Intermediate 7 (944 mg, 2.45 mmol, 1 eq) in DMF (12 mL) were added CuI (93 mg, 0.49 mmol, 0.2 eq) and Pd(PPh3)4(282 mg, 0.25 mmol, 0.1 eq). The reaction mixture was heated at 40°C overnight under nitrogen. The resulting mixture was concentrated under reduced pressure to give a crude material, which was purified by silica gel flash column chromatography (0% to 10% MeOH in EtOAc) to afford the title compound (294 mg, 0.76 mmol, 31% yield) as a yellow solid.1H NMR (500 MHz, Chloroform-d) δ 9.33 (dd, J = 36.6, 10.1 Hz, 1H), 8.76 – 8.57 (m, 1H), 7.76 – 7.30 (m, 1H), 7.15 (dt, J = 10.9, 5.6 Hz, 1H), 5.53 (s, 1H), 4.43 (s, 1H), 3.92 (s, 1H), 3.49 (s, 1H), 2.27 – 1.95 (m, 4H), 1.46 (s, 9H), 1.40 – 1.20 (m, 4H); ESI-MS m / z = 389 [M+H]+. 69Attorney Docket No.00007.001.1801 Intermediate 6: tert-butyl ((1R,4R)-4-((4-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)- 1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate [000206] This compound w the procedure described inIntermediate 3, using Intermediate 5. ESI-MS m / z = 496 [M+H]+. Intermediate 7: 2-chloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide [000207] To a solution of 2 .50 g, 9.61 mmol) in THF (50 mL)was added NaH (845 mg, 21.1 mmol, 2.2 eq, 60% in mineral oil) at 0°C and the solution was stirred for 15 min at the same temperature.2-Chlorobenzenesulfonyl chloride (2.23 g, 10.6 mmol, 1.1 eq) was added and the reaction mixture was stirred at rt for 1 h. The resulting mixture was quenched with sat. NH4Cl (50 mL), diluted with H2O (50 mL), and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material, which was purified by silica gel flash column chromatography (10% to 30% EtOAc in Hex) to afford the title compound (2.14 g, 6.48 mmol, 67% yield) as a brown solid.1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.12 (dd, J = 10.5, 2.6 Hz, 1H), 8.07 – 8.03 (m, 1H), 8.03 – 7.99 (m, 1H), 7.71 – 7.64 (m, 2H), 7.58 – 7.50 (m, 2H); ESI-MS m / z = 348 [M+ H2O]+. Intermediate 8: 2-chloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide [000208] This compound wthe procedure described in Intermediate 7, using 2-methylbenzenesulfonyl chloride. ESI-MS m / z = 328 [M+H2O]+. Intermediate 9: 2-chloro-N-(2-fluoro-4-nitrophenyl)-N-methylbenzenesulfonamide 70Attorney Docket No.00007.001.1801 [000209] To a solution of 2- itrophenyl)benzenesulfonamide, Intermediate 7 (257 mg, 0.78 mmol) in DMF (4 mL) was added NaH (38 mg, 0.94 mmol, 1.2 eq, 60% in mineral oil) at 0°C and the solution was stirred for 15 min at the same temperature. Iodomethane (74 μL, 1.17 mmol, 1.5 eq) was added and the reaction mixture was stirred at rt for 3 h. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material (266 mg, 0.77 mmol, 99% yield), which was used for the next reaction without purification. ESI- MS m / z = 362 [M+ H2O]+. Intermediate 10: N-(2-fluoro-4-nitrophenyl)-N,2-dimethylbenzenesulfonamide [000210] This compound wthe procedure described in Intermediate 9. ESI-MS m / z = 342 [M+ H2O]+. Intermediate 11: N-(4-amino-2-fluorophenyl)-2-chlorobenzenesulfonamide [000211] To a solution of 2-itrophenyl)benzenesulfonamide, Intermediate 7 (0.69 g, 2.09 mmol) in EtOAc (20 mL) was added tin(II) chloride dihydrate (1.93 g, 10.5 mmol, 5 eq). The reaction mixture was heated at 70oC overnight, cooled to rt, quenched with sat. NaHCO3 slowly (100 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material (0.62 g, 2.07 mmol, 99% yield) which was used for the next reaction without purification. ESI-MS m / z = 301 [M+H]+. 71Attorney Docket No.00007.001.1801 Intermediate 12: N-(4-amino-2-fluorophenyl)-2-methylbenzenesulfonamide [000212] This compound w ediate 8 according to the procedure described in Intermediate 11. ESI-MS m / z = 281 [M+H]+. Intermediate 13: N-(4-amino-2-fluorophenyl)-2-chloro-N-methylbenzenesulfonamide [000213] This compound wa ediate 9 according to the proceduredescribed in Intermediate 11.1H NMR (500 MHz, DMSO-d6) δ 7.78 (dd, J = 7.9, 1.6 Hz, 1H), 7.69 (dd, J = 8.0, 1.2 Hz, 1H), 7.63 (td, J = 7.7, 1.6 Hz, 1H), 7.45 (td, J = 7.9, 1.3 Hz, 1H), 6.76 (t, J = 8.9 Hz, 1H), 6.28 – 6.21 (m, 2H), 5.58 (s, 2H), 3.23 (s, 3H); ESI-MS m / z = 315 [M+H]+. Intermediate 14: N-(4-amino-2-fluorophenyl)-N,2-dimethylbenzenesulfonamide [000214] This compound wediate 10 according to the procedure described in Intermediate 11. ESI-MS m / z = 295 [M+H]+. Intermediate 15: 4-chloro-N-(tetrahydrofuran-3-yl)-1,3,5-triazin-2-amine [000215] This compound was pg to the procedure described in Intermediate 1, using tetrahydrofuran-3-amine. ESI-MS m / z = 201 [M+H]+. 72Attorney Docket No.00007.001.1801 Intermediate 16: 4-(4-fluoropyridin-3-yl)-N-(tetrahydrofuran-3-yl)-1,3,5-triazin-2- amine N F O [000216] This compound was p g to the procedure described in Intermediate 5, using Intermediate 15. ESI-MS m / z = 262 [M+H]+. Intermediate 17: 3-fluoro-4-nitro-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)aniline [000217] To a solution of 2- 3,2-dioxaborolan-2-yl)aniline (2.0 g,9.13 mmol) and 2,4-difluoro-1-nitrobenzene (2.18 g, 13.7 mmol, 1.5 eq) in DMF (15 mL) was added diisopropylethylamine (1.92 mL, 11.0 mmol, 1.2 eq). The reaction mixture was heated at 110oC overnight, cooled to rt, diluted with water (100 mL), and then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material (2.73 g, 7.63 mmol, 84% yield) which was used for the next reaction without purification.1H NMR (500 MHz, Chloroform-d) δ 8.24 (dd, J = 9.4, 6.1 Hz, 1H), 7.86 (dd, J = 7.4, 1.4 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.19 – 7.13 (m, 1H), 7.05 (dd, J = 11.6, 2.6 Hz, 1H), 6.49 (dd, J = 9.5, 7.1 Hz, 1H), 1.32 (s, 12H); ESI-MS m / z = 359 [M+H]+. Intermediate 18: 3-Fluoro-N1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzene-1,4-diamine 73Attorney Docket No.00007.001.1801 [000218] This compound wa o the procedure described in Intermediate 11, using Intermediate 17. ESI-MS m / z = 329 [M+H]+. Intermediate 19: 2-chloro-N-(2-fluoro-4-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)amino)phenyl)benzenesulfonamide [000219] Pyridine (3 equ on of 3-fluoro-N1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzene-1,4-diamine (1 equivalent) and 2- chlorobenzenesulfonyl chloride (1.2 equivalents) in DCM (5 mL) The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash column chromatography (30% to 100% EtOAc in Hex) to afford the title compound. ESI-MS m / z = 503 [M+H]+. Intermediate 20: 4-chloro-N-(oxetan-3-yl)-1,3,5-triazin-2-amine [000220] This compound was png to the procedure described in Intermediate 1, using 3-aminooxetane. ESI-MS m / z = 187 [M+H]+. Intermediate 21: N-(2-((4-chloro-1,3,5-triazin-2-yl)amino)ethyl)-N- methylmethanesulfonamidemine 74Attorney Docket No.00007.001.1801 [000221] This compound w the procedure described in Intermediate 1, using N-(2-aminoethyl)-N-methylmethanesulfonamide hydrochloride. ESI- MS m / z = 266 [M+H]+. Intermediate 22: tert-butyl (S)-3-((4-chloro-1,3,5-triazin-2-yl)amino)piperidine-1- carboxylate [000222] This compound wa to the procedure described inIntermediate 1, using tert-butyl (S)-3-aminopiperidine-1-carboxylate. ESI-MS m / z = 314 [M+H]+. Intermediate 23: tert-butyl ((1R,4R)-4-((6-chloropyrimidin-4- yl)amino)cyclohexyl)carbamate [000223] This compound wthe procedure described in Intermediate 1, using 4,6-dichloropyrimidine. ESI-MS m / z = 327 [M+H]+. Intermediate 24: 4-(4-fluoropyridin-3-yl)-N-(oxetan-3-yl)-1,3,5-triazin-2-amine N O [000224] This compound was png to the procedure described in Intermediate 5, using Intermediate 20. ESI-MS m / z = 248 [M+H]+. 75Attorney Docket No.00007.001.1801 Intermediate 25: tert-butyl ((1R,4R)-4-((6-(2-fluoropyridin-3-yl)pyrimidin-4- yl)amino)cyclohexyl)carbamate [000225] This compound w the procedure described inIntermediate 2, using Intermediate 23. ESI-MS m / z = 388 [M+H]+. Intermediate 26: tert-butyl ((1R,4R)-4-((6-(2-(4-amino-2-fluorophenoxy)pyridin-3- yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000226] This compound w the procedure described inIntermediate 3, using Intermediate 25. ESI-MS m / z = 495 [M+H]+. Intermediate 27 : tert-butyl ((1R,4R)-4-((6-(4-((3-fluoro-4-nitrophenyl)amino)pyridin-3- yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000227] To a solution of t4-fluoropyridin-3-yl)pyrimidin-4- yl)amino)cyclohexyl)carbamate, Intermediate 35 (900 mg, 2.33 mmol) and 3-fluoro-4- nitroaniline (726 mg, 4.66 mmol, 2 eq) in nitromethane (23 mL) was added trifluoromethanesulfonic acid (1.23 mL, 14.0 mmol, 6 eq). The reaction mixture was heated at 100oC overnight, cooled to rt, and then concentrated under reduced pressure to give a residue which was then dissolved in THF (30 mL). Boc2O (560 mg, 2.56 mmol, 1.1 eq) and N,N-diisopropylethylamine (4.06 mL, 23.3 mmol, 10 eq) were added and the reaction mixture 76Attorney Docket No.00007.001.1801 was stirred at rt for 4 h and then diluted with water (100 mL) and extreacted with EtOAc (100 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material, which was then recrystallized with DCM and diethyl ether to afford the title compound (219 mg, 0.42 mmol, 18% yield) as a yellow solid. ESI-MS m / z = 524 [M+H]+. Intermediate 28: tert-butyl ((1R,4R)-4-((6-(4-((4-amino-3-fluorophenyl)amino)pyridin-3- yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000228] To a solution of t 4-((3-fluoro-4-nitrophenyl)amino)pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate, Intermediate 27 (184 mg, 0.35 mmol) in THF (7 mL) and water (7 mL) were added zinc (138 mg, 2.10 mmol, 6 eq) and ammonium chloride (113 mg, 2.10 mmol, 6 eq). The reaction mixture was stirred at rt overnight and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material (140 mg) which was used for the next reaction without purification. ESI-MS m / z = 494 [M+H]+. Intermediate 29: 2-bromopyridin-3-amine [000229] This compound was preding to the procedure described in Intermediate 11, using 2-bromo-3-nitropyridine. ESI-MS m / z = 173 [M+H]+. Intermediate 30: 2-bromo-N-(3-fluoro-4-nitrophenyl)pyridin-3-amineAttorney Docket No.00007.001.1801 [000230] To a solution of 2-bromopyridin-3-amine, Intermediate 29 (2.0 g, 11.6 mmol) in THF (60 mL) was added 1 M LiHMDS (19.7 mL, 19.7 mmol, 1.7 eq) at 0°C and the solution was stirred for 15 min at the same temperature.2,4-Difluoro-1-nitrobenzene (1.84 g, 11.6 mmol, 1 eq) was added and the reaction mixture was stirred at rt overnight. The resulting mixture was quenched with sat. NH4Cl (50 mL), diluted with H2O (50 mL), and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (2.84 g, 9.13 mmol, 79% yield). ESI-MS m / z = 312 [M+H]+. Intermediate 31: N-(3-fluoro-4-nitrophenyl)-2-(tributylstannyl)pyridin-3-amine [000231] To a solution of 2- itrophenyl)pyridin-3-amine (2.0 g,6.43 mmol) in hexabutylditin (6.40 g, 11.6 mmol, 1.8 eq) were added Pd(OAc)2(144 mg, 0.64 mmol, 0.1 eq) and PCy3 ( 360 mg, 1.28 mmol, 0.2 eq). The reaction mixture was heated at 100°C for 20 h under nitrogen. The resulting mixture was then filtered through a pad of Celite and concentrated under reduced pressure to give a crude material, which was purified by neutral alumina flash column chromatography (0% to 10% EtOAc in Hex) to afford the title compound (524 mg, 1.00 mmol, 16% yield) as a clear oil. ESI-MS m / z = 524 [M+H]+. Intermediate 32: tert-butyl ((1R,4R)-4-((6-(3-((3-fluoro-4-nitrophenyl)amino)pyridin-2- yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000232] This compound wthe procedure described in Intermediate 4, using Intermediate 31 and Intermediate 23 with XPhos-Pd-G2 catalyst.1H NMR (500 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.37 (d, J = 4.0 Hz, 1H), 8.23 (dd, J = 9.4, 6.0 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.45 (dd, J = 8.2, 4.5 Hz, 1H), 7.23 (s, 1H), 7.11 (dd, J = 78Attorney Docket No.00007.001.1801 11.3, 2.4 Hz, 1H), 6.69 (ddd, J = 9.5, 7.3, 2.5 Hz, 1H), 3.87 (s, 1H), 3.36 (m, 1H), 2.07 (s, 2H), 1.98 (s, 2H), 1.45 (s, 9H), 1.40 – 1.33 (m, 4H); ESI-MS m / z = 524 [M+H]+. Intermediate 33: tert-butyl ((1R,4R)-4-((6-(3-((4-amino-3-fluorophenyl)amino)pyridin-2- yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000233] This compound w the procedure described inIntermediate 28, using Intermediate 32. ESI-MS m / z = 494 [M+H]+. [000234] The following compounds were made using Method A. 1. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-2-yoxy]-2- fluorophenyl] 2-chlorobenzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((6-(2-(4-((2-chlorophenyl)sulfonamido)-2- fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000235] This compoundhe procedure described in Compound 10, using Intermediate 26 and 2-chlorobenzene sulfonyl chloride.1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.47 (s, 2H), 8.11 – 8.03 (m, 2H), 7.65 (dd, J = 4.2, 2.3 Hz, 2H), 7.54 (ddd, J = 8.5, 5.6, 3.2 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.21 (dt, J = 12.0, 3.8 Hz, 3H), 7.02 (dd, J = 12.0, 2.5 Hz, 1H), 6.98 – 6.92 (m, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.71 (s, 1H), 3.17 (s, 1H), 1.89 (d, J = 10.5 Hz, 2H), 1.74 (s, 2H), 1.34 (s, 9H), 1.19 (m, 4H); ESI-MS m / z = 669 [M+H]+. 79Attorney Docket No.00007.001.1801 N-(4-((3-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3- fluorophenyl)-2-chlorobenzenesulfonamide [000236] This compound he procedure described in 1Compound 10. H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.37 (s, 1H), 8.76 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 4.9 Hz, 1H), 8.17 (d, J = 5.4 Hz, 2H), 8.12 – 8.07 (m, 1H), 7.69 – 7.62 (m, 2H), 7.55 (ddd, J = 8.4, 5.9, 2.8 Hz, 1H), 7.38 – 7.29 (m, 2H), 7.23 (s, 1H), 7.04 (dd, J = 11.9, 2.5 Hz, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H), 3.95 – 3.86 (m, 1H), 3.01 (s, 1H), 1.98 (m, 4H), 1.47 (m, 2H), 1.35 (m, 2H); ESI-MS m / z 569 [M+H]+. 2. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-2-yloxy]-3- fluorophenyl] naphthalene-1-sulfonamide. O-tert-butyl N-((1R,4R)-4-((6-(2-(2-fluoro-4-(naphthalene-1- sulfonamido)phenoxy)pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000237] This compound was pdure described in Compound 10, using Intermediate 26 and naphtha-1-yl sulfonyl chloride. ESI-MS m / z = 685 [M+H]+. N-(4-((3-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3- fluorophenyl)naphthalene-1-sulfonamide 80Attorney Docket No.00007.001.1801 [000238] This compoun procedure described in Compound 10.1H NMR (500MHz, DMSO-d6) δ 11.14 (s, 1H), 9.34 (s, 1H), 8.76 – 8.70 (m, 2H), 8.30 – 8.23 (m, 3H), 8.18 (dd, J = 6.7, 3.2 Hz, 2H), 8.09 (d, J = 8.1 Hz, 1H), 7.75 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.66 (dt, J = 12.9, 7.7 Hz, 2H), 7.30 (dd, J = 7.6, 4.9 Hz, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.00 (dd, J = 11.9, 2.5 Hz, 1H), 6.91 (dd, J = 8.9, 2.4 Hz, 1H), 3.89 (s, 1H), 3.00 (s, 1H), 1.98 (m, 4H), 1.47 (m, 2H), 1.34 (m, 2H); ESI-MS m / z 585 [M+H]+. 3. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-2-yloxy]-3- fluorophenyl] benzenesulfonamide. O- tert-butyl N-((1R,4R)-4-((6-(2-(2-fluoro-4-(phenylsulfonamido)phenoxy)pyridin-3- yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000239] This compounde procedure described in Compound 10, using Intermediate 26 and benzenesulfonyl chloride. ESI-MS m / z = 635 [M+H]+. N-(4-((3-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-2-yl)oxy)-3- fluorophenyl)benzenesulfonamide 81Attorney Docket No.00007.001.1801 [000240] This compound e procedure described in Compound 10.1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.74 (s, 1H), 8.29 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 4.8 Hz, 1H), 8.16 – 8.02 (m, 2H), 7.82 (d, J = 7.7 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.32 (q, J = 9.8, 7.6 Hz, 2H), 7.22 (s, 1H), 7.06 (dd, J = 11.9, 2.5 Hz, 1H), 6.97 (dd, J = 8.8, 2.4 Hz, 1H), 3.89 (s, 1H), 3.01 (s, 1H), 1.99 (d, J = 11.0 Hz, 4H), 1.45 (m, 2H), 1.34 (m, 2H); ESI-MS m / z 535 [M+H]+. [000241] The following compound was made using Method C. 4. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-4-yloxy]-3- fluorophenyl] 2-chlorobenzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((6-(4-(4-((2-chlorophenyl)sulfonamido)-2- fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000242] This compounde procedure described in Compound 10, using Intermediate 26 and 2-chlorobenzenesulfonyl chloride. ESI-MS m / z = 669 [M+H]+. N-(4-((3-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-4-yl)oxy)-3- fluorophenyl)-2-chlorobenzenesulfonamide 82Attorney Docket No.00007.001.1801 [000243] This compound he procedure described in Compound 10.1H NMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.55 (s, 1H), 8.93 (s, 1H), 8.79 (s, 1H), 8.61 (d, J = 6.1 Hz, 1H), 8.23 (d, J = 5.6 Hz, 2H), 8.11 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 4.9 Hz, 2H), 7.60 – 7.46 (m, 2H), 7.22 – 7.11 (m, 2H), 7.05 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 6.2 Hz, 1H), 3.94 – 3.89 (m, 1H), 3.03 – 2.93 (m, 1H), 2.10 – 1.84 (m, 4H), 1.61 – 1.26 (m, 4H); ESI-MS m / z = 569 [M+H]+. [000244] The following compound was made using Method D. 5. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-4-ylamino]- 2-fluorophenyl] 2-chlorobenzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((6-(4-((4-((2-chlorophenyl)sulfonamido)-3- fluorophenyl)amino)pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000245] This compoundhe procedure described in Compound 10, using Intermediate 28 and 2-chlorobenzenesulfonyl chloride. ESI-MS m / z = 668 [M+H]+. N-(4-((3-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-4-yl)amino)-2- fluorophenyl)-2-chlorobenzenesulfonamide 83Attorney Docket No.00007.001.1801 [000246] This compound e procedure described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 8.69 (d, J = 4.9 Hz, 1H), 8.66 – 8.59 (m, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.64 – 7.57 (m, 2H), 7.54 (t, J = 8.6 Hz, 1H), 7.45 (ddd, J = 8.6, 6.3, 2.4 Hz, 1H), 7.25 – 7.09 (m, 3H), 7.01 (s, 1H), 4.14 (s, 1H), 3.23 – 3.15 (m, 1H), 2.28 – 2.08 (m, 4H), 1.69 – 1.47 (m, 4H); ESI-MS m / z = 568 [M+H]+. [000247] The following compounds were made using Method E. 6. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-2- ylamino]-2-fluorophenyl] 2-chlorobenzenesulfonamide. 100265 O-tert-butyl N-((1R,4R)-4-((6-(3-((4-((2-chlorophenyl)sulfonamido)-3- fluorophenyl)amino)pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000248] This compoundhe procedure described in Compound 10, using Intermediate 33 and 2-chlorobenzenesulfonyl chloride. ESI-MS m / z = 668 [M+H]+. N-(4-((2-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-3-yl)amino)-2- fluorophenyl)-2-chlorobenzenesulfonamide 84Attorney Docket No.00007.001.1801 [000249] This compound e procedure described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 8.78 (s, 1H), 8.45 (dd, J = 4.5, 1.2 Hz, 1H), 7.91 – 7.84 (m, 1H), 7.58 (m, 2H), 7.53 (d, J = 7.1 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.44 – 7.39 (m, 1H), 6.87 (m, 2H), 6.57 (td, J = 8.4, 2.7 Hz, 1H), 4.27 – 4.16 (m, 1H), 3.17 (s, 1H), 2.17 (m, 4H), 1.57 (m, 4H); ESI-MS m / z = 568 [M+H]+. 7. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-2- ylamino]-2-fluorophenyl] 2-methylbenzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((6-(3-((3-fluoro-4-((2-methylphenyl)sulfonamido)phenyl) amino)pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000250] This compounde procedure described in Compound 10 using Intermediate 33 and 2-methylbenzenesulfonyl chloride. ESI-MS m / z = 648 [M+H]+. N-(4-((2-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-3-yl)amino)-2- fluorophenyl)-2-methylbenzenesulfonamideAttorney Docket No.00007.001.1801 [000251] This compound was prepared according to the procedure described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 8.77 (s, 1H), 8.51 – 8.45 (m, 1H), 7.81 – 7.72 (m, 2H), 7.62 – 7.49 (m, 3H), 7.39 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 6.88 (dd, J = 10.3, 2.6 Hz, 1H), 6.59 – 6.45 (m, 2H), 4.20 (dt, J = 11.0, 5.5 Hz, 1H), 3.16 (dt, J = 11.2, 7.0 Hz, 1H), 2.62 (s, 3H), 2.15 (m, 4H), 1.56 (m, 4H); ESI-MS m / z = 548 [M+H]+. 8. N-[4-[3-[6-[(1r,4r)(4-Aminocyclohexyl)amino]pyrimidin-4-yl]pyridin-2- ylamino]-2-fluorophenyl]-N-methyl 2-methylbenzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((6-(3-((4-((N,2-dimethylphenyl)sulfonamido)-3- fluorophenyl)amino)pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate [000252] This compound e procedure described inIntermediate 9, using the starting material of Compound 7 and K2CO3instead of NaH. ESI- MS m / z = 662 [M+H]+. N-(4-((2-(6-(((1R,4R)-4-aminocyclohexyl)amino)pyrimidin-4-yl)pyridin-3-yl)amino)-2- fluorophenyl)-N,2-dimethylbenzenesulfonamide [000253] This compoundhe procedure described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 8.77 (s, 1H), 8.56 (d, J = 4.3 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.56 (s, 1H), 7.43 (t, J = 7.4 Hz, 2H), 6.85 (dd, J = 10.5, 2.2 Hz, 1H), 6.58 – 6.46 (m, 2H), 4.19 (t, J = 11.0 Hz, 1H), 86Attorney Docket No.00007.001.1801 3.22 (s, 3H), 3.18 – 3.10 (m, 1H), 2.39 (s, 3H), 2.15 (m, 4H), 1.54 (m, 4H); ESI-MS m / z = 562 [M+H]+. [000254] The following compounds were made using Method F. 9. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-2- yloxy]-3-fluorophenyl] benzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((4-(2-(2-fluoro-4-(phenylsulfonamido)phenoxy)pyridin-3-yl)- 1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate [000255] This compound e procedure described inCompound 10, using Intermediate 3 and benzenesulfonyl chloride. ESI-MS m / z = 636 [M+H]+. N-(4-((3-(4-(((1R,4R)-4-aminocyclohexyl)amino)-1,3,5-triazin-2-yl)pyridin-2-yl)oxy)-3- fluorophenyl)benzenesulfonamide [000256] This compoundhe procedure described in Compound 10.1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.65 (s, 1H), 8.49 (d, J = 6.4 Hz, 1H), 8.20 (dd, J = 9.3, 3.9 Hz, 2H), 7.81 (t, J = 8.1 Hz, 2H), 7.68 – 7.52 (m, 3H), 7.31 – 7.22 (m, 1H), 7.17 (q, J = 8.9 Hz, 1H), 7.10 – 7.00 (m, 1H), 6.96 (d, J = 9.8 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 2.94 (d, J = 5.6 Hz, 1H), 2.03 – 1.86 (m, 4H), 1.49 – 1.29 (m, 4H); ESI-MS m / z 536 [M+H]+. 87Attorney Docket No.00007.001.1801 10. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-2- yloxy]-3-fluorophenyl] 2-chlorobenzenesulfonamide. O-tert-butyl N-((1R,4R)-4-((4-(2-(4-((2-chlorophenyl)sulfonamido)-3- fluorophenoxy)pyridin-3-yl)-1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate [000257] To a solution of -(4-Amino-2-fluorophenoxy)pyridin-3-yl)-1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate (269 mg, 0.54 mmol), Intermediate 3, and 2-chlorobenzenesulfonyl chloride (138 mg, 0.65 mmol, 1.2 eq) in DCM (5 mL) was added pyridine (0.13 mL, 1.62 mmol, 3 eq). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel flash column chromatography (30% to 100% EtOAc in Hex) to afford the title compound (242 mg, 0.36 mmol, 67% yield) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.57 (s, 1H), 8.36 – 7.91 (m, 4H), 7.64 (t, J = 6.3 Hz, 2H), 7.59 – 7.48 (m, 1H), 7.29 – 7.19 (m, 1H), 7.12 (dd, J = 16.3, 8.4 Hz, 1H), 6.99 (dd, J = 11.9, 8.6 Hz, 1H), 6.92 (t, J = 6.3 Hz, 1H), 6.69 (dd, J = 21.2, 8.0 Hz, 1H), 3.67 (ddt, J = 32.6, 7.8, 4.1 Hz, 1H), 3.15 (t, J = 9.8 Hz, 1H), 1.95 – 1.59 (m, 4H), 1.55 – 0.90 (m, 13H); ESI-MS: m / z = 670 [M+H]+. N-(4-((3-(4-(((1R,4R)-4-aminocyclohexyl)amino)-1,3,5-triazin-2-yl)pyridin-3-yl)oxy)-3- fluorophenyl)-2-chlorobenzenesulfonamide 88Attorney Docket No.00007.001.1801 [000258] To a solution o -tert-butyl-2-[4-[(2- chlorophenyl)sulfonamido]-2-fluorophenoxy]phenyl]pyrimidin-2-yl]amino]cyclohexyl] carbamate (67 mg, 0.10 mmol) in DCM (2 mL) was added 4 N HCl in dioxane (0.13 mL, 0.50 mmol, 5 eq). The reaction mixture was stirred at room temperature for 2 h to give a precipitate, which was then filtered, washed with DCM (20 mL), and dried to afford the title compound (51 mg, 0.090 mmol, 90% yield) as a white solid.1H NMR (500 MHz, Methanol- d4) δ 8.77 – 8.55 (m, 2H), 8.30 (t, J = 5.9 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 3.2Hz, 2H), 7.51 – 7.41 (m, 1H), 7.40 – 7.30 (m, 1H), 7.20 (td, J = 8.6, 2.7 Hz, 1H), 7.08 (dt, J = 11.7, 3.8 Hz, 1H), 7.02 (dd, J = 8.7, 2.8 Hz, 1H), 4.18 – 4.06 (m, 1H), 3.16 (t, J = 7.5 Hz, 1H), 2.32 – 2.00 (m, 4H), 1.58 (t, J = 9.4 Hz, 4H); ESI-MS: m / z = 570 [M+H]+. 11. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-2- yloxy]-3-fluorophenyl] naphthalene-1-sulfonamide. O-tert-butyl N-((1R,4R)-4-((4-(2-(2-fluoro-4-(naphthalene-1- sulfonamido)phenoxy)pyridin-3-yl)-1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate [000259] This compounprocedure described in Compound 10 using Intermediate 3 and naphthalene-1-sulfonyl chloride. ESI-MS m / z = 686 [M+H]+. N-(4-((3-(4-(((1R,4R)-4-aminocyclohexyl)amino)-1,3,5-triazin-2-yl)pyridin-2-yl)oxy)-3- fluorophenyl)naphthalene-1-sulfonamide 89Attorney Docket No.00007.001.1801 [000260] This compoun procedure described in Compound 10.1H NMR (500MHz, DMSO-d6) δ 11.05 (s, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 8.26 (p, J = 6.0 Hz, 2H), 8.15 (t, J = 6.0 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.75 (t, J = 7.7 Hz, 1H), 7.66 (dt, J = 16.3, 7.8 Hz, 2H), 7.28 – 7.19 (m, 1H), 7.10 (td, J = 9.0, 4.4 Hz, 1H), 7.02 – 6.93 (m, 1H), 6.87 (dd, J = 14.7, 8.2 Hz, 1H), 3.74 (t, J = 5.8 Hz, 1H), 2.94 (dd, J = 10.6, 5.3 Hz, 1H), 1.93 (dd, J = 16.9, 12.5 Hz, 4H), 1.48 – 1.26 (m, 4H); ESI-MS m / z 586 [M+H]+. [000261] The following compound was made using Method G. 12. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin- 4-yloxy]-2-fluorophenyl] 2-chlorobenzenesulfonamide. O- tert-butyl N-((1R,4R)-4-((4-(4-(4-((2-chlorophenyl)sulfonamido)-2- fluorophenoxy)pyridin-3-yl)-1,3,5-triazin-2-yl)amino)cyclohexyl)carbamate [000262] This compounde procedure described in Compound 10, using Intermediate 6 and 2-chlorobenzenesulfonyl chloride. ESI-MS m / z = 670 [M+H]+. N-(4-((3-(4-(((1R,4R)-4-aminocyclohexyl)amino)-1,3,5-triazin-2-yl)pyridin-4-yl)oxy)-3- fluorophenyl)-2-chlorobenzenesulfonamide 90Attorney Docket No.00007.001.1801 [000263] This compound he procedure described in Compound 10.1H NMR (500 MHz, DMSO-d6) δ 11.05 (d, J = 5.5 Hz, 1H), 8.94 (s, 1H), 8.59 (m, 2H), 8.29 (t, J = 8.4 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 4.2 Hz, 2H), 7.56 (dt, J = 7.8, 4.0 Hz, 1H), 7.30 – 7.02 (m, 3H), 6.97 (d, J = 8.9 Hz, 1H), 6.84 (t, J = 6.2 Hz, 1H), 3.74 (s, 1H), 2.95 (s, 1H), 1.92 (m, 4H), 1.50 – 1.14 (m, 4H); ESI-MS m / z 570 [M+H]+. [000264] The following compounds were made using Method H. 13. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-4- ylamino]-2-fluorophenyl] 2-chlorobenzenesulfonamide. [000265] This compoundhe procedure described in Compound 15, using Intermediate 11 and Intermediate 5, followed by a deprotection as described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 9.43 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 3H), 7.45 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 7.07 (d, J = 7.1 Hz, 1H), 3.94 (s, 1H), 3.16 (s, 1H), 2.16 (m, 4H), 1.69 – 1.39 (m, 4H); ESI-MS m / z = 569 [M+H]+. 14. N-[4-[3-[4-[1,3-dihydroxyprop-2-ylamino](1,3,5)-triazin-2-yl]pyridin-4-ylamino]- 2-fluorophenyl] 2-chlorobenzenesulfonamide. 2-chloro-N-(4-((3-(4-((1,3-dihydroxypropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-4- yl)amino)-2-fluorophenyl)benzenesulfonamide 91Attorney Docket No.00007.001.1801 F H N N S l [000266] This compound he procedure described in Compound 15, using Intermediate 24 and Intermediate 11.1H NMR (500 MHz, Methanol-d4) δ 9.32 (s, 1H), 8.64 – 8.56 (m, 1H), 8.19 – 8.12 (m, 1H), 8.00 (d, J = 11.4 Hz, 1H), 7.57 – 7.45 (m, 3H), 7.45 – 7.36 (m, 1H), 7.25 – 7.16 (m, 1H), 7.05 – 6.98 (m, 1H), 6.61 (d, J = 6.0 Hz, 1H), 4.55 – 4.48 (m, 1H), 3.63 (m, 2H), 3.53 (m, 1H), 3.36 (m, 1H); ESI-MS m / z = 546 [M+H]+. 15. N-[4-[3-[4-[(S)-oxolan-3-ylamino](1,3,5)-triazin-2-yl]pyridin-4-ylamino]-2- fluorophenyl] 2-chlorobenzenesulfonamide. [000267] To a solution oftetrahydrofuran-3-yl)-1,3,5- triazin-2-amine, Intermediate 16 (50 mg, 0.19 mmol) and N-(4-amino-2-fluorophenyl)-2- chlorobenzenesulfonamide, Intermediate 11 (58 mg, 0.19 mmol, 1 eq) in nitromethane (2 mL) was added trifluoromethanesulfonic acid (43 μL, 0.48 mmol, 2.5 eq). The reaction mixture was heated at 70oC for 5 min, cooled to rt, and then quenched with sat. NaHCO3 (0.5 mL). The resulting mixture was concentrated under reduced pressure to give a residue which was purified by silica gel flash column chromatography (0% to 10% MeOH in DCM) to afford the title compound (44 mg, 0.081 mmol, 43% yield) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.37 (s, 1H), 8.70 – 8.57 (m, 2H), 8.19 (d, J = 6.0 Hz, 1H), 7.89 (td, J = 7.3, 6.7, 1.5 Hz, 1H), 7.72 – 7.60 (m, 2H), 7.53 – 7.43 (m, 1H), 7.31 – 7.17 (m, 2H), 7.10 (dd, J = 8.6, 2.0 Hz, 1H), 6.85 (d, J = 6.0 Hz, 1H), 4.51 (dt, J = 6.6, 3.2 Hz, 1H), 3.90 – 3.78 (m, 2H), 3.75 – 3.66 (m, 1H), 3.63 (dt, J = 9.0, 4.2 Hz, 1H), 2.25 – 2.10 (m, 1H), 1.97 – 1.84 (m, 1H); ESI-MS m / z = 542 [M+H]+. 92Attorney Docket No.00007.001.1801 16. N-[4-[3-[4-[(S)-oxolan-3-ylamino](1,3,5)-triazin-2-yl]pyridin-4-ylamino]-2- fluorophenyl] 2-methylbenzenesulfonamide. F H N N S [000268] This compound he procedure described inCompound 15, using Intermediate 16 and N-(4-amino-2-fluorophenyl)-2- methylbenzenesulfonamide, Intermediate 12.1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.21 (s, 1H), 9.37 (s, 1H), 8.69 – 8.57 (m, 2H), 8.21 (d, J = 6.0 Hz, 1H), 7.72 (dd, J =11.8, 8.0 Hz, 1H), 7.55 – 7.48 (m, 1H), 7.41 (t, J = 6.9 Hz, 1H), 7.35 – 7.22 (m, 2H), 7.22 – 7.14 (m, 1H), 7.14 – 7.05 (m, 1H), 6.83 (d, J = 6.0 Hz, 1H), 4.51 (m, 1H), 3.85 (m, 2H), 3.76 – 3.60 (m, 2H), 2.63 (s, 3H), 2.26 – 2.11 (m, 1H), 1.97 – 1.84 (m, 1H); ESI-MS m / z = 522 [M+H]+. 17. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-4- ylamino]-2-fluorophenyl]-N-methyl 2-chlorobenzenesulfonamide. [000269] This compoundhe procedure described in Compound 15, using Intermediate 13 and Intermediate 5, followed by a deprotection as described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 9.43 (s, 1H), 8.64 (s, 1H), 8.19 (s, 1H), 7.97 – 7.89 (m, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.50 – 7.42 (m, 1H), 7.37 (t, J = 8.5 Hz, 1H), 7.25 – 7.07 (m, 3H), 4.03 – 3.90 (m, 1H), 3.40 (s, 3H), 3.21 – 3.11 (m, 1H), 2.26 – 2.08 (m, 4H), 1.62 – 1.43 (m, 4H); ESI-MS m / z = 583 [M+H]+. 93Attorney Docket No.00007.001.1801 18. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-4- ylamino]-2-fluorophenyl] 2-methylbenzenesulfonamide. [000270] This compound he procedure described inCompound 15, using Intermediate 13 and Intermediate 5, followed by a deprotection as described in Compound 10.1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.31 (s, 1H), 8.68 (s, 2H), 8.21 (m, 3H), 7.77 (d, J = 7.9 Hz, 1H), 7.62 – 7.26 (m, 5H), 7.20 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 3.78 (s, 1H), 3.00 (s, 1H), 2.64 (s, 3H), 2.00 (m, 4H), 1.42 (m, 4H); ESI- MS m / z = 549 [M+H]+. 19. N-[4-[3-[4-[(S)-oxolan-3-ylamino](1,3,5)-triazin-2-yl]pyridin-4-ylamino]-2- fluorophenyl]-N-methyl 2-methylbenzenesulfonamide. [000271] This compoundhe procedure described in Compound 15, using Intermediates 14 and 15.1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.39 (s, 1H), 8.72 – 8.59 (m, 2H), 8.28 (d, J = 5.9 Hz, 1H), 7.79 (t, J = 8.3 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.23 – 7.14 (m, 1H), 6.99 (d, J = 6.0 Hz, 1H), 4.53 (m, 1H), 3.86 (d, J = 7.3 Hz, 2H), 3.76 – 3.61 (m, 2H), 3.17 (s, 3H), 2.41 (s, 3H), 2.20 (m, 1H), 1.93 (m, 1H); ESI-MS m / z = 536 [M+H]+. [000272] The following compounds were made using Method J. 94Attorney Docket No.00007.001.1801 20. N-[4-[3-[4-[2-(N-Methyl-N-(methylsulfonyl)amino)ethylamino](1,3,5)-triazin-2- yl]pyridin-4-ylamino]-2-fluorophenyl] 2-chlorobenzenesulfonamide. [000273] This compound e procedure described inCompound 22, using Intermediate 19 and Intermediate 21.1H NMR (500 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.37 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 7.7 Hz 1H), 7.51 (q, J = 4.2, 3.3 Hz,1H), 7.43 (d, J = 4.1 Hz, 1H), 7.38 – 7.29 (m, 2H), 7.22 – 7.09 (m, 2H), 6.98 – 6.86 (m, 1H), 6.78 (dd, J = 8.7, 6.0 Hz, 1H), 6.54 (s, 1H), 3.73 (m, 2H), 3.44 (q, J = 6.5 Hz, 2H), 2.94 (s, 3H), 2.85 (s, 3H); ESI-MS m / z = 606 [M+H]+. 21. N-[4-[2-[4-[(S)-piperidin-3-ylamino](1,3,5)-triazin-2-yl]phen-1-ylamino]-2- fluorophenyl] 2-chlorobenzenesulfonamide. O- tert-butyl N-((S)-3- (4-(2-((4-((2-chlorophenyl)sulfonamido)-3- fluorophenyl)amino)phenyl)-1,3,5-triazin-2-yl)amino)piperidine-1-carboxylate [000274] This compoundhe procedure described in Compound 22, using Intermediate 19 and Intermediate 22. ESI-MS m / z = 654 [M+H]+. (S)-2-chloro-N-(2-fluoro-4-((2-(4-(piperidin-3-ylamino)-1,3,5-triazin-2- yl)phenyl)amino)phenyl)benzenesulfonamide 95Attorney Docket No.00007.001.1801 [000275] This compound o the procedure described in Compound 10.1H NMR (500 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.51 – 7.45 (m, 1H), 7.44 – 7.37 (m, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.18 (dd, J = 10.3, 2.7 Hz, 1H), 7.04 (q, J = 7.2 Hz, 1H), 6.77 (m, 1H), 6.64 (m, 1H), 4.52 (m, 1H), 3.66 (m, 1H), 3.36 (t, J = 6.4 Hz, 1H), 3.07 (m, 2H), 2.25 (m, 1H), 2.20 – 2.06 (m, 1H), 1.99 – 1.78 (m, 2H); ESI-MS m / z 554 [M+H]+. 22. N-[4-[2-[4-[Oxetan-3-ylamino](1,3,5)-triazin-2-yl]phen-1-ylamino]-2- fluorophenyl] 2-chlorobenzenesulfonamide. [000276] To a solution o4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)amino)phenyl) 2-chlorobenzenesulfonamide, Intermediate 19 (80 mg, 0.16 mmol) and 4-chloro-N-(oxetan-3-yl)-1,3,5-triazin-2-amine, Intermediate 20 (31 mg, 0.16 mmol, 1 eq) in dioxane (2 mL) and H2O (0.5 mL) were added Cs2CO3 (104 mg, 0.32 mmol, 2 eq) and Pd(dppf)Cl2(13 mg, 0.016 mmol, 0.1 eq). The reaction mixture was heated at 100°C for 2 h under nitrogen. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material, which was purified by silica gel flash column chromatography (20% to 60% EtOAc in Hex) to afford the title compound (45 mg, 0.085 mmol, 53% yield) as a yellow solid.1H NMR (500 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.54 (q, J = 7.8 Hz, 1H), 7.43 (d, J = 3.5 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.25 (d, J = 8.2 96Attorney Docket No.00007.001.1801 Hz, 1H), 7.15 (m, 1H), 6.90 (m, 1H), 6.73 (dd, J = 8.6, 6.1 Hz, 1H), 6.61 – 6.46 (m, 1H), 5.22 (m, 1H), 4.98 (m, 2H), 4.73 (q, J = 8.3, 7.4 Hz, 2H); ESI-MS m / z = 527 [M+H]+. 23. N-[4-[2-[4-[(S)-piperidin-3-ylamino](1,3,5)-triazin-2-yl]phen-1-ylamino]-2- fluorophenyl]-N-methyl 2-chlorobenzenesulfonamide. [000277] To a solution of (2-(4-(piperidin-3-ylamino)-1,3,5-triazin-2-yl)phenyl)amino)phenyl)benzenesulfonamide, Compound 21 (30 mg, 0.054 mmol) in methanol (1 mL) were added 37% formaldehyde (8 μL, 0.108 mmol, 2 eq), a drop of acetic acid and sodium cyanoborohydride (7 mg, 0.108 mmol, 2 eq). The reaction mixture was stirred at rt for 1 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layer was washed with sat. NaHCO3(20 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (27 mg, 0.048 mmol, 89% yield) as a yellow solid.1H NMR (500 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.34 (dd, J = 8.0, 1.3 Hz, 1H), 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.40 – 7.25 (m, 3H), 7.14 (dd, J = 10.9, 2.8 Hz, 1H), 7.08 – 6.96 (m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.77 (dd, J = 8.7, 6.1 Hz, 1H), 6.41 (td, J = 8.4, 2.8 Hz, 1H), 4.18 (m, 1H), 3.01 (s, 1H), 2.81 – 2.70 (m, 1H), 2.29 (s, 3H), 2.02 (m, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (m, 1H); ESI-MS m / z 568 [M+H]+. 24. N-[4-[3-[4-[(1r,4r)(4-Aminocyclohexyl)amino](1,3,5)-triazin-2-yl]pyridin-4- ylamino]-2-fluorophenyl]-N-methyl 2-chlorobenzenesulfonamide. 97Attorney Docket No.00007.001.1801 This compound was prepared a scribed in Compound 15, using Intermediates 14 and 5 (~3:1 tautomer / rotamer mixture. Major species reported)1H NMR (500 MHz, Methanol-d4) δ 9.46 (s, 1H), 8.64 (s, 1H), 8.69 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.58 – 7.48 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.39 – 7.26 (m, 3H), 7.18 (d, J = 7.0 Hz, 1H), 3.99– 3.89 (m, 1H), 3.26 (s, 3H), 3.21 – 3.11 (m, 1H), 2.53 (s, 3H), 2.24 – 2.07 (m, 4H), 1.67 – 1.43 (m, 4H); ESI-MS m / z = 563 [M+H]+. Example 3. Biological Data Surface Plasmon Resonance (SPR) method description [000278] Compound interaction was profiled using a Biacore 8K instrument (Cytiva). Biotinylated N-terminal avi-tagged Cdk2(2-298) or Cdk1(1-297) was immobilized on a series S sensor Chip SA at a capture level between 2500 RU and 3000 RU (Cdk2) or 7000 RU (Cdk1) in buffer (25 mM HEPES, 150 mM NaCl, 0.05% Tween 20, pH 7.5). A compound dilution plate (8 concentrations, 3-fold dilution) in DMSO was prepared (100x assay concentration). From this plate, compound DMSO stock solution was transferred into buffer, yielding a final DMSO concentration of 1% in assay. The remaining buffer was supplemented with 1% DMSO. Compounds were injected in a series of increasing concentrations in multi-cycle kinetics (MCK, “M”) or single-cycle kinetics (SCK, “S”) mode at a flow rate of 30 µl / min for 120 sec and dissociation was profiled for 180 sec (MCK) or 1800 sec (SCK). Data were analyzed using Biacore Insight Evaluation Software (Cytiva). Results for exemplary compounds disclosed herein are summarized in Table 2. [000279] In Table 2 below, “A” indicates a KDof 10 nM or less; “B” indicates a KDof 11-100 nM; “C” indicates a KD of 100-1000 nM; “D” indicates a KD of 1000-5000 nM; “E” indicates a KDof >5000 nM. Table 2. Compound Number Activity rating* M / S (CK)Attorney Docket No.00007.001.1801 3 E S 4 D S B99

Claims

Attorney Docket No.00007.001.1801 CLAIMS 1. A compound of Formula I: or a pharmaceuticaX is N or CH; A2is phenyl or 5-6 membered heteroaryl; A4is aryl, heteroaryl, C3-12carbocyclyl, or 4-12 membered heterocyclyl; L1is -O-, -S-, or -NH-; L2is -NR7SO2-, -C(R8)2SO2-, -NR7SO2-C(R8)2-, -C(R8)2C(=O)-, - C(=O)C(R8) C(=O)O OC(=O) C(R8) O OC(R8) C(=O)NR7- -, - memberedheteroaryl, -(C1-6 alkylene)-(C3-10 carbocyclyl), -(C1-6 alkylene)-(4-12 membered heterocyclyl), -(C1-6alkylene)-(phenyl), -(C1-6alkylene)-(5-12 membered heteroaryl), - (C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-5 R11; R2is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C2-6alkenoxy, C2-6alkynoxy, COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, aryl, or heteroaryl, wherein R2is each independently optionally substituted by 1-4 R11; R3is each independently H, halogen, cyano, nitro, hydroxy, -NR7R10, - NHCOR9, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, COR9, CON(R9)2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-8 100Attorney Docket No.00007.001.1801 cycloalkenyl, C1-6 alkylthio, C2-6 alkenylthio, or C1-6 alkylsulfonyl, wherein R3is each independently optionally substituted by 1-4 R11; R4is each independently H, halogen, cyano, nitro, hydroxy, NR7R10, NHCOR9, NR7CONR7R10, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, COR9, CO2R9, CONR7R10, C1-6 alkoxy, C2-6 alkenoxy, C2-6 alkynoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-8cycloalkyl, C3-8cycloalkenyl, C1-6alkylthio, C2-6alkenylthio, C1-6alkylsulfonyl, SO2N(R7)2, or phenyl, or any two occurrences of R4s on contiguous atoms, taken together with the contiguous atoms to which the two occurrences of R4s are attached, form a saturated, partially unsaturated, or unsaturated 5-7 membered ring comprising 0-2 heteroatoms each independently selected from O, S(=O)0-2, P(=O)R5, N, and NR10, wherein R4is each independently optionally substituted by 1-4 R11; R5is each independently H, C1-6 alkyl, C1-6 alkoxy, hydroxy, or -N(R7)2; R6is each independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3 alkylene)-(C3-6 cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), C1-6 acyl, aroyl, or heteroaroyl; R7is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, C6-10aryl, 5-12 membered heteroaryl, (C1-3 alkylene)-(C3-6 cycloalkyl), or (C1-3 alkylene)-(4-6 membered heterocycloalkyl), or two R7s are taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from NR12, O, and S(=O)0-2; R8is each independently H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, C3-6cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3alkylene)- (C3-6 cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), or two R8s taken together with the C atom to which they are attached form a 4- 7 membered ring comprising 0-1 heteroatom selected from O, S(=O)0-2, P(=O)R5, and NR12, wherein R8is optionally substituted by 1-3 R11; R9is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, (C1-3alkylene)-(C3-6cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), C1-6 acyl, phenyl, or 5- 12 membered heteroaryl, wherein R9is optionally substituted by 1-3 R11; 101Attorney Docket No.00007.001.1801 R10is each independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, 4-10 membered heterocycloalkyl, (C1-3alkylene)-(C3-6cycloalkyl), (C1-3 alkylene)-(4-6 membered heterocycloalkyl), C1-6 acyl, C1-6 alkylsulfonyl, phenyl, or 5-12 membered heteroaryl, wherein R10is optionally substituted by 1-3 R11, or R7and R10on the same N atom may be taken together with the N atom to which they are attached form a 4-7 membered ring comprising an additional 0-1 heteroatoms selected from O, S(=O)0-2, P(=O)R5, and NR6; R11is each independently H, halo, hydroxy, cyano, oxo, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, (C1-3 alkylene)-(C3-6 cycloalkyl), (C1-3alkylene)-(4-6 membered heterocycloalkyl), C6-10aryl, 5-12 membered heteroaryl, SO2R7, S(=O)NR5, SO2N(R7)2, CON(R7)2, or N(R7)2; R12is each independently H, C1-6alkyl, C1-6alkoxy, hydroxy, C1-6acyl, or C1-6alkylsulfonyl; m is an integer 0, 1 or 2; n is an integer 0, 1, 2, or 3; and p is an integer 0, 1, 2, or 3, provided that the A1ring and the L1linker are on contiguous C atoms of the A2ring, whereas L1and L2are not situated on contiguous atoms of the A3ring.

2. The compound of claim 1, wherein A2is phenyl or 6-membered heteroaryl.

3. The compound of claim 1 or 2, wherein A2is phenyl or pyridyl.

4. The compound of claim 1, wherein the compound is a compound of Formula (I-A): (R2)m4)por a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4are each CH or N, provided that no more than two of X1, X2, X3, and X4are N, and the hydrogen of CH may be optionally substituted by R2. 102Attorney Docket No.00007.001.1801 5. The compound of any one of claims 1-4, wherein L1is -NH-.

6. The compound of any one of claims 1-4, wherein L1is -O-.

7. The compound of claim 4, wherein the compound is a compound of Formula (I-B1) or (I-B2): (R2)m24)p4)por a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein X is N.

9. The compound of any one of claims 1-7, wherein X is CH.

10. The compound of claim 7, wherein the compound is a compound of Formula (I-C1), (I-C2), (I-C3), or (I-C4): (R2)m4)pAttorney Docket No.00007.001.1801 (R2)mX2)p)por a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-10, wherein A4is phenyl, naphthyl, or 5-12 membered heteroaryl.

12. The compound of any one of claims 1-11, wherein A4is phenyl or naphthyl.

13. The compound of any one of claims 1-12, wherein L2is -NR7SO2-.

14. The compound of claim 13, wherein R7is H or C1-6 alkyl.

15. The compound of claim 13 or 14, wherein R7is H or methyl.

16. The compound of any one of claims 1-15, wherein R1is C3-12carbocyclyl, 4-12 membered heterocyclyl, -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-2 R11. 104Attorney Docket No.00007.001.1801 17. The compound of any one of claims 1-16, wherein R1is C6-10 carbocyclyl, 4-8 membered heterocyclyl, -(C1-6alkylene)-OR9, or -(C1-6alkylene)-NR7R10, wherein R1is optionally substituted by 1-2 R11.

18. The compound of any one of claims 1-17, wherein R1is: i) cyclohexyl optionally substituted with 1 R11; ii) piperidinyl, tetrahydrofuranyl, or oxetanyl, each optionally substituted with 1 R11; iii) -(C1-4alkylene)-OR9optionally substituted with 1 R11, optionally wherein R9is H or C1-6alkyl; or iv) -(C1-4alkylene)-NR7R10optionally substituted with 1 R11, optionally wherein R7is H or C1-6alkyl and R10is C1-6alkylsulfonyl.

19. The compound of any one of claims 1-18, wherein R11is each independently selected from the group consisting of N(R7)2, C1-6alkyl, and C1-6hydroxyalkyl.

20. The compound of claim 19, wherein R11is each independently selected from the group consisting of NH2, C1-4alkyl, and C1-4hydroxyalkyl.

21. The compound of any one of claims 1-20, wherein m is 0 or 1.

22. The compound of any one of claims 1-21, wherein m is 0.

23. The compound of any one of claims 1-22, wherein R3is each independently halogen or C1-6 alkyl.

24. The compound of any one of claims 1-23, wherein n is 0 or 1.

25. The compound of any one of claims 1-24, wherein n is 0.

26. The compound of any one of claims 1-24, wherein n is 1.

27. The compound of any one of claims 1-26, wherein R4is each independently halogen or C1-6alkyl.

28. The compound of any one of claims 1-27, wherein p is 0 or 1.

29. The compound of any one of claims 1-28, wherein p is 0.

30. The compound of any one of claims 1-28, wherein p is 1.

31. A compound selected from the group consisting of:105Attorney Docket No.00007.001.1801106Attorney Docket No.00007.001.1801107Attorney Docket No.00007.001.1801108Attorney Docket No.00007.001.1801109Attorney Docket No.00007.001.1801 f.ing: a) a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.

33. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in inhibiting CDK2 in a subject in need thereof.

34. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in treating a disease or disorder characterized by overexpression or amplification of cyclin E in a subject in need thereof, optionally wherein the cyclin E is CCNE1 or CCNE2.

35. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in of treating a disease or 110Attorney Docket No.00007.001.1801 disorder characterized by overexpression or amplification of cyclin A in a subject in need thereof.

36. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in of treating cancer in a subject in need thereof, optionally wherein the cancer is associated with amplification or overexpression of cyclin E or cyclin A.

37. The compound or composition for use of claim 36, wherein the cancer is breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, melanoma, lung cancer, pancreatic cancer, stomach cancer, esophageal cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, prostate cancer, renal cancer, hepatic cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, lymphoma, or leukemia.

38. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in of treating an autoimmune disorder or disease in a subject in need thereof, optionally wherein the autoimmune disorder or disease is associated with amplification or overexpression of cyclin E or cyclin A.

39. The compound or composition for use of claim 38, wherein the autoimmune disorder or disease is rheumatoid arthritis, Lupus, Crohn’s Disease, Addison disease, celiac disease, dermatomyositis, Graves’ disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or pemphigus vulgaris.

40. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in of treating an inflammatory disease or disorder in a subject in need thereof, optionally wherein the inflammatory disease or disorder is associated with amplification or overexpression of cyclin E or cyclin A.

41. The compound or composition for use of claim 40, wherein the inflammatory disease or disorder is asthma, chronic peptic ulcers, psoriasis, inflammatory bowel disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

42. A compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 32 for use in of treating a neurodegenerative disease or disorder in a subject in need thereof, optionally wherein the neurodegenerative disease or disorder is associated with amplification or overexpression of cyclin E or cyclin A. 111Attorney Docket No.00007.001.1801 43. The compound or composition for use of claim 42, wherein the neurodegenerative disease or disorder is Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, or cerebellar degeneration. 112

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