WO2020210320A1

WO2020210320A1 - Substituted l,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones

Info

Publication number: WO2020210320A1
Application number: PCT/US2020/027218
Authority: WO
Inventors: Peter Qinhua HUANG; Kevin Duane BUNKER; Brant Clayton Boren; Aditya Krishnan UNNI; Sunny Abraham
Original assignee: Recurium Ip Holdings, Llc
Priority date: 2019-04-11
Filing date: 2020-04-08
Publication date: 2020-10-15
Also published as: WO2020210320A8

Abstract

Compounds of Formula (I) are provided herein. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions, including conditions characterized by excessive cellular proliferation, such as breast cancer.

Description

SUBSTITUTED l,2-DIHYDRO-3H-PYRAZOLO[3,4-D]PYRIMIDIN-3-ONES

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No. 62/832,529, filed April 11, 2019.

Field

[0002] The present application relates to compounds that are WEE1 inhibitors and methods of using them to treat conditions characterized by excessive cellular proliferation, such as cancer.

Description

[0003] WEE1 kinase plays a role in the G2-M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest. Cancer cells often have a deficient Gl-S checkpoint and depend on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various cancer types.

SUMMARY

[0004] Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can include an effective amount of one or more of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0006] Some embodiments described herein relate to a method for ameliorating and/or treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating and/or treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating and/or treating a cancer described herein.

[0007] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. [0008] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0009] Some embodiments described herein relate to a method for inhibiting the activity of WEE1 in a cell (for example, inhibiting the activity of WEE1 in TP53 -mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53 -deficient cells and/or decreasing the overexpression of WEE1 in cells) that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE 1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53 -deficient cells and/or decreasing the overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE 1 (for example, inhibiting the activity of WEE 1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells).

[0010] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells) using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein by inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53- mutated cells, inhibiting the activity of WEE 1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described herein by inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells).

DETAILED DESCRIPTION

[0011] WEE1 is a tyrosine kinase that is a critical component of the ATR- mediated G2 cell cycle checkpoint control that prevents entry into mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which in turn activates WEE1, leading to the selective phosphorylation of cyclin-dependent kinase 1 (CDK1) at Tyrl5, thereby stabilizing the CDKl-cyclin B complex and halting cell-cycle progression. This process confers a survival advantage by allowing tumor cells time to repair damaged DNA prior to entering mitosis. Inhibition of WEE1 abrogates the G2 checkpoint, promoting cancer cells with DNA damage to enter into unscheduled mitosis and undergo cell death via mitotic catastrophe. Therefore, WEE1 inhibition has the potential to sensitize tumors to DNA-damaging agents, such as cisplatin, and to induce tumor cell death.

Definitions

[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0013] Whenever a group is described as being“optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated“optionally substituted” or“substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, an amino, a mono-substituted amine group, a di-substituted amine group and an amine(Ci-C₆ alkyl).

[0014] As used herein,“C_a to C_t>” in which“a” and“b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from“a” to“b”, inclusive, carbon atoms. Thus, for example, a“Ci to C₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH CH₂CH(CH )- and (CH₃)₃C-. If no“a” and“b” are designated, the broadest range described in these definitions is to be assumed.

[0015] If two“R” groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R^a and R^b of an NR^aR^b group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:

[0016] As used herein, the term“alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec -butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as“1 to 30” refers to each integer in the given range; e.g.,“1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted.

[0017] The term“alkenyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2- butenyl and the like. An alkenyl group may be unsubstituted or substituted.

[0018] The term“alkynyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted.

[0019] As used herein,“cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term“fused” refers to two rings which have two atoms and one bond in common. As used herein, the term“bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term“spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Examples of mono cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-lH-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[l.l.l]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0020] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be“aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0021] As used herein,“carbocyclyl” refers to a non-aromatic a mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion, as described herein. Carbocyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A carbocyclyl group may be unsubstituted or substituted. Examples of carbocyclyl groups include, but are in no way limited to, cycloalkyl groups and cycloalkenyl groups, as defined herein, and the non aromatic portions of 1,2,3,4-tetrahydronaphthalene, 2,3 -dihydro- lH-indene, 5, 6,7,8- tetrahydroquinoline and 6,7-dihydro-5H-cyclopenta[b]pyridine.

[0022] As used herein,“aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group or a Ce aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0023] As used herein,“heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

[0024] As used herein,“heterocyclyl” or“heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo- systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term“fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such“heterocyclyl” or“heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5- triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl groups include 2-azaspiro[3.3]heptane, 2- oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.

[0025] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

[0026] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.

[0027] A“heteroalicyclyl(alkyl)” and“heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).

[0028] As used herein, “lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by

substituting both hydrogens on the same carbon with a cycloalkyl group (e.g., ^~C- ).

[0029] As used herein, the term“hydroxy” refers to a -OH group.

[0030] As used herein,“alkoxy” refers to the Formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0031] As used herein,“acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.

[0032] A“cyano” group refers to a“-CN” group.

[0033] The term“halogen atom” or“halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

[0034] A“thiocarbonyl” group refers to a“-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0035] An“0-carbamyl” group refers to a“-OC(=0)N(R_AR_B)” group in which R_A and R_B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0036] An“N-carbamyl” group refers to an“ROC(=0)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0037] An “0-thiocarbamyl” group refers to a “-OC(=S)-N(RAR_B)” group in which RA and R_B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0038] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0039] A“C-amido” group refers to a“-C(=0)N(RAR_B)” group in which RA and R_B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0040] An“N-amido” group refers to a“RC(=0)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

[0041] An“S-sulfonamido” group refers to a“-S0₂N(RAR_B)” group in which RA and R_B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

[0042] An“N-sulfonamido” group refers to a“RS0₂N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0043] An“O-carboxy” group refers to a“RC(=0)0-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0044] The terms“ester” and“C-carboxy” refer to a“-C(=0)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0045] A“nitro” group refers to an“-NO2” group.

[0046] A“sulfenyl” group refers to an“-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.

[0047] A“sulfinyl” group refers to an“-S(=0)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0048] A“sulfonyl” group refers to an“SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0049] As used herein,“haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri- haloalkyl and polyhaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted.

[0050] As used herein,“haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2- fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0051] The term“amino” as used herein refers to a -Nth group. [0052] A“mono-substituted amine” group refers to a“-NHR_A” group in which R_A can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. The R_A may be substituted or unsubstituted. Examples of mono-substituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.

[0053] A“di-substituted amine” group refers to a“-NRAR_B” group in which RA and R_B can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. RA and R_B can independently be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl) (methyl), -N(ethyl) (methyl) and the like.

[0054] As used herein, “amine(alkyl)” group refers to an -(alkylene)-NR’R” radical where R’ and R” are independently hydrogen or alkyl as defined herein. An amine(alkyl) may be substituted or unsubstituted. Examples of amine(alkyl) groups include, but are not limited to, -CH2NH(methyl), -CH2NH(phenyl), -CthCthNHimethyl), -CthCthNHiphenyl), -CH2N(methyl)2, -CthN phenyl) (methyl), -NCH2(ethyl) (methyl), -CH2CH2N(methyl)2, -CH2CH2N(phenyl)(methyl), -NCH2CH2(ethyl)(methyl) and the like.

[0055] Where the number of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example,“haloalkyl” may include one or more of the same or different halogens. As another example,“C₁-C₃ alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0056] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term“radical” can be used interchangeably with the term“group.”

[0057] The term“pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, trifluoroacetic, benzoic, salicylic, 2- oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NFh), the nitrogen-based group can be associated with a positive charge (for example, NFh can become NH3⁺) and the positive charge can be balanced by a negatively charged counterion (such as Cl ).

[0058] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S -configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0059] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium). [0060] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0061] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0062] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0063] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term‘including’ should be read to mean‘including, without limitation,’‘including but not limited to,’ or the like; the term‘comprising’ as used herein is synonymous with‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term‘having’ should be interpreted as‘having at least;’ the term‘includes’ should be interpreted as‘includes but is not limited to;’ the term‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like‘preferably,’‘preferred,’‘desired,’ or‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term“comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.

[0064] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article“a” or“an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Compounds

[0065] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein: R¹ can be selected from hydrogen, halogen and a substituted or unsubstituted C1-C6 alkyl; Ring A can be selected from a substituted or unsubstituted phenyl and a substituted or unsubstituted 5-6 membered monocyclic heteroaryl; Ring B can be selected from a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and a substituted or

(R³)m unsubstituted 5-7 membered monocyclic heterocyclyl; R² can be selected from

can be 0, 1, 2 or 3; R³ can be selected from halogen and a substituted or unsubstituted C1-C6 alkyl; X can be selected from hydrogen, halogen, hydroxy, cyano, a substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, a substituted or unsubstituted amine(Ci-C₆ alkyl), a substituted or unsubstituted -NH-(CH2)i-6-amine, a mono-substituted amine, a di-substituted amine, an amino, a substituted or unsubstituted Ci- Ce alkyl, a substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C3-C6 cycloalkoxy, a substituted or unsubstituted (C1-C6 alkyl)acyl, a substituted or unsubstituted C-amido, a substituted or unsubstituted N-amido, a substituted or unsubstituted C-carboxy, a substituted or unsubstituted O-carboxy, a substituted or unsubstituted O-carbamyl and a substituted or unsubstituted N-carbamyl; Y can be CH or N (nitrogen); Y¹ can be CR^4A or N (nitrogen); Y² can be CR^4B or N (nitrogen); Ring C can be selected from a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted monocyclic 5-10 membered heteroaryl, a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and a substituted or unsubstituted 7- 10 membered bicyclic heterocyclyl; R^4A and R^4B can be independently selected from hydrogen, halogen and an unsubstituted CM alkyl; and R⁵ can be a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl.

[0066] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R¹ can be selected from hydrogen, halogen and a substituted or unsubstituted C1-C6 alkyl; Ring A can be selected from a substituted or unsubstituted phenyl and a substituted or unsubstituted 5-6 membered monocyclic heteroaryl; Ring B can be selected from a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and a substituted or unsubstituted 5-7 membered

monocyclic heterocyclyl; R² can be selected from

can be 0, 1, 2 or 3; R³ can be selected from halogen and a substituted or unsubstituted C1-C6 alkyl; X can be selected from hydrogen, halogen, hydroxy, cyano, a substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, a substituted or unsubstituted amine(Ci-C₆ alkyl), a substituted or unsubstituted -NH-(CH2)i-6-amine, a mono-substituted amine, a di-substituted amine, an amino, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted Ci- Ce alkoxy, a substituted or unsubstituted C3-C6 cycloalkoxy, a substituted or unsubstituted (C1-C6 alkyl)acyl, a substituted or unsubstituted C-amido, a substituted or unsubstituted N- amido, a substituted or unsubstituted C-carboxy, a substituted or unsubstituted O-carboxy, a substituted or unsubstituted O-carbamyl and a substituted or unsubstituted N-carbamyl; Y can be CH or N (nitrogen); Y¹ can be CR^4A or N (nitrogen); Y² can be CR^4B or N (nitrogen); Ring C can be selected from a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted monocyclic 5-10 membered heteroaryl, a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and a substituted or unsubstituted 7-10 membered bicyclic heterocyclyl; and R^4A and R^4B can be independently selected from hydrogen, halogen and an unsubstituted C1-4 alkyl.

[0067] In some embodiments, R¹ can be selected from the group consisting of hydrogen, halogen and a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Ring A can be selected from the group consisting of a substituted or unsubstituted phenyl and a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, Ring B can be selected from the group consisting of a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl. In some embodiments, R² can be selected from the group

In some embodiments, m can be 0, 1, 2 or 3. In some embodiments, R³ can be selected from the group consisting of halogen and a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X can be selected from the group consisting of hydrogen, halogen, hydroxy, cyano, a substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, a substituted or unsubstituted amine(Ci-C₆ alkyl), a substituted or unsubstituted -NH-(CH2)i-6-amine, a mono-substituted amine, a di-substituted amine, an amino, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted Ci- Ce alkoxy, a substituted or unsubstituted C3-C6 cycloalkoxy, a substituted or unsubstituted (C1-C6 alkyl)acyl, a substituted or unsubstituted C-amido, a substituted or unsubstituted N- amido, a substituted or unsubstituted C-carboxy, a substituted or unsubstituted O-carboxy, a substituted or unsubstituted O-carbamyl and a substituted or unsubstituted N-carbamyl. In some embodiments, Y can be CH or N. In some embodiments, Y¹ can be CR^4A or N. In some embodiments, Y² can be CR^4B or N. In some embodiments, Ring C can be selected from the group consisting of a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted monocyclic 5-10 membered heteroaryl, a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and a substituted or unsubstituted 7-10 membered bicyclic heterocyclyl. In some embodiments, R^4A and R^4B are independently selected from the group consisting of hydrogen, halogen and an unsubstituted C_M alkyl.

[0068] In some embodiments, R¹ can be selected from hydrogen, halogen and Ci- Ce alkyl. In some embodiments, R¹ can be hydrogen. In other embodiments, R¹ can be halogen. In some embodiments, R¹ can be fluoro. In still other embodiments, R¹ can be an unsubstituted Ci-CY alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, t-butyl, pentyl (straight chain or branched) or hexyl (straight chain or branched)). In some embodiments, R¹ can be an unsubstituted methyl. In some embodiments, R¹ can be a substituted C1-C6 alkyl, such as those described herein. In some embodiments, R¹ can be an unsubstituted C1-C6 haloalkyl (such as a C1-C6 fluoroalkyl, a C1-C6 chloroalkyl or a C1-C6 chlorofluoroalkyl). In some embodiments, R¹ can be -CHF2, -CF3, -CF2CH3 or -CH2CF3.

[0069] In some embodiments, Ring A can be selected from a substituted or unsubstituted phenyl and a substituted or unsubstituted 5-6 membered monocyclic heteroaryl.

[0070] In some embodiments, Ring A can be a substituted phenyl. In other embodiments, Ring A can be an unsubstituted phenyl.

[0071] In some embodiments, Ring A can be a substituted 5-6 membered monocyclic heteroaryl. In some embodiments, Ring A can be an unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, Ring A can be selected from a substituted or unsubstituted pyrrole, a substituted or unsubstituted furan, a substituted or unsubstituted thiophene, a substituted or unsubstituted imidazole, a substituted or unsubstituted pyrazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazine, a substituted or unsubstituted pyrimidine and a substituted or unsubstituted pyridazine.

[0072] When substituted, Ring A can be substituted with one or more substituents selected from halogen, an unsubstituted C₁-C₄ haloalkyl and an unsubstituted C₁-C₄ alkyl. In some embodiments, Ring A is mono-substituted with a halogen (for example, fluoro).

wherein each of the aforementioned groups

are substituted or unsubstituted. In some embodiments,

can be a substituted or

unsubstituted

. In some embodiments,

can be a substituted or

unsubstituted

, wherein the Ring A is unsubstituted. In other embodiments,

can be selected from a substituted or unsubstituted

substituted or unsubstituted

[0074] In some embodiments, Ring B can be selected from a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl.

[0075] In some embodiments, Ring B can be a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl. In some embodiments, Ring B can be a substituted or unsubstituted monocyclic 5 membered carbocyclyl. In other embodiments, Ring B can be a substituted or unsubstituted monocyclic 6 membered carbocyclyl. In still other embodiments, Ring B can be a substituted or unsubstituted monocyclic 7 membered carbocyclyl.

[0076] In some embodiments,

can be selected from:

wherein each of the aforementioned groups are substituted or unsubstituted.

[0077] In some embodiments, Ring B can be a substituted or unsubstituted monocyclic 5-7 membered heterocyclyl. In some embodiments, Ring B can be a substituted or unsubstituted monocyclic 5 membered heterocyclyl. In other embodiments, Ring B can be a substituted or unsubstituted monocyclic 6 membered heterocyclyl. In still other embodiments, Ring B can be a substituted or unsubstituted monocyclic 7 membered heterocyclyl.

aforementioned groups are substituted or unsubstituted, including any -NH group. [0079] In some embodiments, Ring B can be selected from

wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group. In some embodiments, Ring B can be

a substituted or unsubstituted

[0080] In some embodiments, when Ring B is substituted, Ring B can be substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy, amino, an unsubstituted N-linked amido (for example, -NHC(0)Ci-C₆ alkyl), an unsubstituted C1-C6 haloalkyl (such as those described herein) and a substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, when Ring B is substituted, Ring B can be substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy, amino, an unsubstituted N-linked amido (for example, -NHC(0)Ci-C₆ alkyl) and a substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, Ring B can be substituted with 1, 2 or 3 substituents independently selected from fluoro, hydroxy, amino, an unsubstituted -NHC(0)Ci-C₆ alkyl, an unsubstituted C1-C6 haloalkyl (such as those described herein) and an unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, Ring B can be substituted with 1 or 2 substituents independently selected from fluoro, hydroxy,

-CF3, -CHF2, -CF2CH3, an unsubstituted methyl, an unsubstituted ethyl and -NHC(0)CH .

aforementioned groups are substituted or unsubstituted, including any -NH group. [0082] In some embodiments,

can be selected from:

aforementioned groups are substituted or unsubstituted. In some embodiments,

can

wherein each of the aforementioned groups are substituted or unsubstituted. In some embodiments,

can be a substituted or unsubstituted

In some embodiments,

can be a substituted

[0083] Both Ring A and Ring B can be substituted or unsubstituted. In some embodiments, Ring A and Ring B

can be independently substituted or unsubstituted. In some embodiments, Ring A and Ring

can be both unsubstituted.

some embodiments, Ring A and Ring

can be both independently substituted. In some embodiments, Ring

can be substituted and

Ring

can be unsubstituted. In some embodiments, Ring

can be unsubstituted and Ring

can be substituted. In some embodiments, Ring A of

can be unsubstituted and Ring

can be substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy and a substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, Ring

can

be unsubstituted and Ring

can be substituted with 1, 2 or 3 substituents independently selected from fluoro, hydroxy, amino, an unsubstituted N-linked amido (for example, -NHC(0)Ci-C₆ alkyl), an unsubstituted C1-C6 haloalkyl (such as those described herein) and an unsubstituted C1-C6 alkyl (such as those described herein). In some

embodiments, Ring

can be unsubstituted and Ring

can be substituted with 1 or 2 substituents independently selected from fluoro, hydroxy, amino,

-CF₃, -CHF₂, -CF₂CH₃, an unsubstituted methyl, an unsubstituted ethyl and

-NHC(0)CH .

[0084] In some embodiments, R² can be selected from

In some embodiments, R² can

some embodiments, R² can be

[0085] In some embodiments, Y can be CH or N (nitrogen). In some embodiments, Y can be CH. In some embodiments, Y can be N (nitrogen).

[0086] In some embodiments, R³ can be selected from halogen and a substituted or unsubstituted C1-C6 alkyl (such as those described herein). In some embodiments, R³ can be halogen. In some embodiments, R³ can be a substituted C1-C6 alkyl (such as those described herein). In some embodiments, R³ can be an unsubstituted C1-C6 alkyl (such as those described herein). [0087] In some embodiments, m can be 0, 1, 2 or 3. In some embodiments, m can be 0. In some embodiments, m can be 1. In some embodiments, m can be 2. In some embodiments, m can be 3. When m is 2 or 3, the R³ groups can be the same or different from each other.

[0088] In some embodiments, X can be selected from hydrogen, halogen, hydroxy, cyano, a substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, a substituted or unsubstituted amine(Ci-C₆ alkyl), a substituted or unsubstituted -NH-(CH2) 1-6- amine, a mono-substituted amine, a di-substituted amine, an amino, a substituted or unsubstituted C1-C6 alkyl (such as those described herein), a substituted or unsubstituted Ci- Ce alkoxy (such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec- butoxy, t-butoxy, pentoxy (straight chain or branched) or hexoxy (straight chain or branched)), a substituted or unsubstituted C3-C6 cycloalkoxy (such as cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy), a substituted or unsubstituted (C1-C6 alkyl)acyl, a substituted or unsubstituted C-amido, a substituted or unsubstituted N-amido, a substituted or unsubstituted C-carboxy, a substituted or unsubstituted O-carboxy, a substituted or unsubstituted O-carbamyl and a substituted or unsubstituted N-carbamyl.

[0089] In some embodiments, X can be hydrogen. In other embodiments, X can be halogen. In some embodiments, X can be fluoro. In some embodiments, X can be chloro. In still other embodiments, X can be hydroxy. In yet still other embodiments, X can be cyano. In some embodiments, X can be an amino.

[0090] In some embodiments, X can be an unsubstituted C₁-C₆ alkyl (such as those described herein). In some embodiments, X can be an unsubstituted methyl, an unsubstituted ethyl or an unsubstituted iso-propyl. In some embodiments, X can be a substituted C₁-C₆ alkyl (such as those described herein). In some embodiments, X can be an unsubstituted C₁-C₆ haloalkyl (such as a C₁-C₆ fluoroalkyl, a C₁-C₆ chloroalkyl or a C₁-C₆ chlorofluoroalkyl). In some embodiments, X can be selected from -CHF₂, -CF₃, -CF₂CH₃ and -CH₂CF₃. In some embodiments, X can be an unsubstituted C₁-C₆ hydroxyalkyl (such as a C₁-C₆ mono-hydroxyalkyl or a C₁-C₆ di-hydroxyalkyl). In some embodiments, X can be selected from -CH₂OH, -CH₂CH₂OH, -CH(OH)CH and -C(OH)(CH )₂. In some embodiments, X can be an unsubstituted C₁-C₆ cyanoalkyl (such as a C₁-C₆ mono-cyanoalkyl or a C₁-C₆ di-cyanoalkyl). In some embodiments, X can be selected from

and

. In some embodiments, X can be an unsubstituted C₁-C₆ alkoxyalkyl (such as a C₁-C₆ mono-alkoxyalkyl or a C₁-C₆ di-alkoxyalkyl). In some embodiments, X can be selected from

, . In some embodiments,

X can be a substituted C₁-C₆ alkyl selected from

,

[0091] In some embodiments, X can be an unsubstituted C₁-C₆ alkoxy (such as those described herein). In some embodiments, X can be an unsubstituted methoxy, an unsubstituted ethoxy or an unsubstituted iso-propoxy. In some embodiments, X can be a substituted C₁-C₆ alkoxy (such as those described herein). In some embodiments, X can be a C₁-C₆ alkoxy substituted with 1, 2 or 3 substituents independently selected from halogen, an amino, a mono-substituted amine (such as those described herein) and a di-substituted amine (such as those described herein). In some embodiments, X can be a C₁-C₆ alkoxy substituted with 1 substituent selected from halogen, an amino, a mono-substituted amine (such as those described herein) and a di-substituted amine (such as those described herein).

[0092] In some embodiments, X can be selected from

[0093] In some embodiments, X can be a substituted C₃-C₆ cycloalkoxy (such as those described herein). In some embodiments, X can be an unsubstituted C₃-C₆ cycloalkoxy (such as those described herein).

[0094] In some embodiments, X can be a substituted (C₁-C₆ alkyl)acyl, such as a substituted -(CO)-CH₃. In some embodiments, X can be an unsubstituted (C₁-C₆ alkyl)acyl, such as an unsubstituted -(CO)-CH₃.

[0095] In some embodiments, X can be a substituted 4-6 membered monocyclic heterocyclyl. In some embodiments, X can be an unsubstituted 4-6 membered monocyclic heterocyclyl. In some embodiments, X can be selected from azetidine, oxetane, diazetidine, azaoxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine and dioxane; wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group. . In some embodiments,

X can be selected from

; wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group.

[0096] In some embodiments, X can be a 4-6 membered monocyclic heterocyclyl (such as those described herein) substituted with 1 or 2 substituents independently selected from halogen, a substituted or unsubstituted C1-C6 alkyl (such as those described herein), a mono-substituted amine (such as those described herein), a di-substituted amine (such as those described herein), an amino, substituted or unsubstituted amine(Ci-C₆ alkyl) and a substituted or unsubstituted (C1-C6 alkyl)acyl. In some embodiments, X can be a 4-6 membered monocyclic heterocyclyl substituted with 1 or 2 substituents independently selected from fluoro, an unsubstituted methyl, an unsubstituted ethyl, an unsubstituted iso- propyl, -CH2OH and -N(CH3)2. In some embodiments, X can be selected from

,

[0097] In some embodiments, X can be a substituted amine(Ci-C6 alkyl). In some embodiments, X can be an unsubstituted amine(Ci-C6 alkyl). In some embodiments, X can be selected from ‘^NH₂

and

wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group. .

[0098] In some embodiments, X can be a substituted -NH-(CH2) 1-6-amine. In some embodiments, X can be an unsubstituted -NH-(CH2) 1-6-amine. In some embodiments, X can be selected from

wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group.

[0099] In some embodiments, X can be a mono-substituted amine. In some embodiments, the substituent of the mono-substituted amine is an unsubstituted C₁-C₆ alkyl (such as those as described herein) or an unsubstituted C₃-C₆ cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).

[0100] In some embodiments, X can be a di-substituted amine. In some embodiments, the two substituents of the di-substituted amine are independently selected from an unsubstituted C₁-C₆ alkyl (such as those as described herein) and an unsubstituted C₃-C₆ cycloalkyl (such as those as described herein).

H

[0101] In some embodiments, X can be selected from

[0102] In some embodiments, X can be a substituted or unsubstituted C-amido. In some embodiments, X can be a substituted or unsubstituted N-amido. In some embodiments, X can be a substituted or unsubstituted C-carboxy. In some embodiments, X can be a substituted or unsubstituted O-carboxy. In some embodiments, X can be a substituted or unsubstituted O-carbamyl. In some embodiments, X can be a substituted or unsubstituted N-carbamyl. In some embodiments, X can be mono-substituted with an unsubstituted C₁-C₆ hydroxyalkyl (such as those described herein).

[0103] In some embodiments, Y¹ can be CR^4A or N (nitrogen). In some embodiments, Y¹ can be CR^4A. In some embodiments, Y¹ can be N (nitrogen).

[0104] In some embodiments, Y² can be CR^4B or N (nitrogen). In some embodiments, Y² can be CR^4B. In some embodiments, Y² can be N (nitrogen).

[0105] In some embodiments, Y¹ and Y² can each be N (nitrogen). In some embodiments, Y¹ can be CR^4A and Y² can be CR^4B. In some embodiments, Y¹ can be CR^4A and Y² can be N (nitrogen). In some embodiments, Y¹ can be N (nitrogen) and Y² can be CR^4B.

[0106] In some embodiments, R^4A can be hydrogen. In some embodiments, R^4A can be halogen. In some embodiments, R^4A can be an unsubstituted CM alkyl (such as those described herein).

[0107] In some embodiments, R^4B can be hydrogen. In some embodiments, R^4B can be halogen. In some embodiments, R^4B can be an unsubstituted Ci-₄ alkyl (such as those described herein).

[0108] In some embodiments, R^4A and R^4B can each be hydrogen. In some embodiments, R^4A and R^4B can each be halogen (wherein the halogens can be the same or different from each other). In some embodiments, R^4A and R^4B can each be an unsubstituted Ci-₄ alkyl (such as those described herein, and wherein the Ci-₄ alkyls can be the same or different from each other). In some embodiments, one of R^4A and R^4B can be hydrogen and the other of R^4A and R^4B can be halogen. In some embodiments, one of R^4A and R^4B can be hydrogen and the other of R^4A and R^4B can be an unsubstituted Ci-₄ alkyl (such as those described herein). In some embodiments, one of R^4A and R^4B can be halogen and the other of R^4A and R^4B can be an unsubstituted Ci-₄ alkyl (such as those described herein).

[0109] In some embodiments, R² can

For example, R² can be

some embodiments, R⁵ can be a substituted 5-7 membered monocyclic heterocyclyl. In other embodiments, R⁵ can be an unsubstituted 5-7 membered monocyclic heterocyclyl. Examples of R⁵ groups include a substituted or unsubstituted piperidinyl, a substituted or unsubstituted pyrrolidinyl and a substituted or unsubstituted azepanyl. When substituted the R⁵ group, possible substituents include an unsubstituted Ci-₄ alkyl, halogen, hydroxy and unsubstituted Ci-₄ haloalkyl.

[0110] In some embodiments, Ring C can be selected from a substituted or unsubstituted C₆-C₁₀ aryl, a substituted or unsubstituted monocyclic 5-10 membered heteroaryl, a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and a substituted or unsubstituted 7- 10 membered bicyclic heterocyclyl.

[0111] In some embodiments, Ring C can be a substituted C6-C10 aryl. In some embodiments, Ring C can be an unsubstituted C6-C10 aryl. In some embodiments, Ring C can be a substituted Ce aryl. In some embodiments, Ring C can be an unsubstituted Ce aryl.

[0112] In some embodiments, Ring C can be a substituted 5-10 membered heteroaryl. In some embodiments, Ring C can be an unsubstituted 5-10 membered heteroaryl. In some embodiments, Ring C can be a substituted 5-6 membered heteroaryl. In some embodiments, Ring C can be an unsubstituted 5-6 membered heteroaryl. In some embodiments, Ring C can be selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, benzimidazole, indole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, quinoline, isoquinoline, quinazoline and quinoxaline; wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group.

[0113] In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 5 membered carbocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 6 membered carbocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted monocyclic 7 membered carbocyclyl.

[0114] In some embodiments, Ring C can be a Ring C can be a substituted or unsubstituted 5 membered monocyclic heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 6 membered monocyclic heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 7 membered monocyclic heterocyclyl. In some embodiments, Ring C can be selected from imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidone, pyrazoline, pyrazolidine, tetrahydropyran, azepine, oxepine and diazepine; wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group.

[0115] In some embodiments, Ring C can be a substituted or unsubstituted 7 membered bicyclic heterocyclyl (for example, a fused, a bridged or a spiro heterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 8 membered bicyclic heterocyclyl, such as, a fused, a bridged or a spiro heterocyclyl. In some embodiments, Ring C can be a substituted or unsubstituted 9 membered bicyclic heterocyclyl (for example, a fused, a bridged or a spiro heterocyclyl). In some embodiments, Ring C can be a substituted or unsubstituted 10 membered bicyclic heterocyclyl, such as, a fused, a bridged or a spiro heterocyclyl. In some embodiments, Ring C can be selected from pyrrolizidine, indoline, 1,2, 3, 4 tetrahydroquinoline, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2- azaspiro[3.4]octane; wherein each of the aforementioned groups are substituted or unsubstituted, including any -NH group.

[0116] In some embodiments, Ring C can be substituted with one or more substituents independently selected from an unsubstituted C1-C6 alkyl (as described herein) and an unsubstituted (C1-C6 alkyl) acyl. In some embodiments, Ring C can be substituted with one substituent selected from an unsubstituted C1-C6 alkyl (as described herein) and an unsubstituted (C1-C6 alkyl) acyl.

[0117] In some embodiments, R² can be selected

wherein each of the aforementioned groups can be substituted or unsubstituted.

[0118] Examples of a compound of Formula (I) include:

foregoing.

[0119] Additional examples of a compound of Formula (I) include:

pharmaceutically acceptable salt of any of the foregoing.

Synthesis

[0120] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein. For example, in an embodiment, compounds of Formula (I) can be prepared in accordance with General Scheme 1 as shown herein. Those skilled in the art understand that appropriate adjustment of the reagents and conditions are described in the Examples. Any preliminary reaction steps required to form starting compounds of the general Formulae A and B, or other precursors, can be carried out by those skilled in the art. As shown in General Scheme 1, an alkyne halide, Formula B, can be added to Formula A using a base, such as sodium hydride. General Scheme 1

Pharmaceutical Compositions

[0121] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0122] The term“pharmaceutical composition” refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0123] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.

[0124] As used herein, a“carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0125] As used herein, a“diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0126] As used herein, an“excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and/or a metal chelating agent. A“diluent” is a type of excipient.

[0127] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0128] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0129] Multiple techniques of administering a compound, salt and/or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally. [0130] One may also administer the compound, salt and/or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue- specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0131] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Uses and Methods of Treatment

[0132] Some embodiments described herein relate to a method for ameliorating and/or treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating and/or treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating and/or treating a cancer described herein.

[0133] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0134] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0135] Some embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE 1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53- deficient cells and/or decreasing the overexpression of WEE1 in cells) that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE 1 (for example, inhibiting the activity of WEE1 in TP53 -mutated cells, inhibiting the activity of WEE1 in TP53 wild- type cells, inhibiting the activity in WEE1 p53 -deficient cells and/or decreasing the overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells). Some embodiments described herein relate to a method for inhibiting the activity of WEE 1 (for example, inhibiting the activity of WEE 1 in TP53 -mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE 1 in cells) that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53- mutated cells, inhibiting the activity of WEE 1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE 1 in cells) that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting the activity of WEE 1.

[0136] Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells) using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating or treating a cancer described herein by inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53- mutated cells, inhibiting the activity of WEE 1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for ameliorating or treating a cancer described herein by inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53-deficient cells and/or decreasing the overexpression of WEE1 in cells). Some embodiments described herein relate to a method for ameliorating or treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53-mutated cells, inhibiting the activity of WEE 1 in TP53 wild-type cells, inhibiting the activity in WEE1 p53- deficient cells and/or decreasing the overexpression of WEE 1 in cells).

[0137] Some embodiments disclosed herein relate to a method for inhibiting the activity of WEE1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein. Other embodiments disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1. Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of WEE1.

[0138] Examples of suitable cancers include, but are not limited to: brain cancers, cervicocerebral cancers, esophageal cancers, thyroid cancers, small cell cancers, non small cell cancers, breast cancers, lung cancers (for example non-small cell lung cancer and small cell lung cancer), stomach cancers, gallbladder/bile duct cancers, liver cancers, pancreatic cancers, colon cancers, rectal cancers, ovarian cancers, choriocarcinomas, uterus body cancers, uterocervical cancers, renal pelvis/ureter cancers, bladder cancers, prostate cancers, penis cancers, testicular cancers, fetal cancers, Wilms' cancer, skin cancers, malignant melanoma, neuroblastomas, osteosarcomas, Ewing's tumors, soft part sarcomas, acute leukemia, chronic lymphatic leukemias, chronic myelocytic leukemias, polycythemia vera, malignant lymphomas, multiple myeloma, Hodgkin's lymphomas, and non-Hodgkin’s lymphomas.

[0139] As described herein, a cancer can become resistant to one or more anti cancer agents. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a cancer that has become resistant to one or more anti-cancer agents (such as one or more WEE1 inhibitors). Examples of anti-cancer agents that a subject may have developed resistance to include, but are not limited to, WEE1 inhibitors (such as AZD1775). In some embodiments, the cancer that has become resistant to one or more anti-cancer agents can be a cancer described herein.

[0140] Several known WEE1 inhibitors can cause one or more undesirable side effects in the subject being treated. Examples of undesirable side effects include, but are not limited to, thrombocytopenia, neutropenia, anemia, diarrhea, vomiting, nausea, abdominal pain, and constipation. In some embodiments, a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can decrease the number and/or severity of one or more side effects associated with a known WEE1 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a severity of a side effect (such as one of those described herein) that is 25% less than compared to the severity of the same side effect experienced by a subject receiving a known WEE1 inhibitor (such as AZD1775, formally known as MK1775 (CAS No.: 955365-80-7, 2-allyl- l-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin- l-yl)phenylamino)-l,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is 25% less than compared to the number of side effects experienced by a subject receiving a known WEE1 inhibitor (for example, AZD1775). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a severity of a side effect (such as one of those described herein) that is less in the range of about 10% to about 30% compared to the severity of the same side effect experienced by a subject receiving a known WEE1 inhibitor (such as AZD1775) In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that is in the range of about 10% to about 30% less than compared to the number of side effects experienced by a subject receiving a known WEE1 inhibitor (for example, AZD1775).

[0141] The one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used to treat, ameliorate and/or inhibit the growth of a cancer wherein inhibiting the activity of WEE1 is beneficial is provided in any of the embodiments described in paragraphs [0065] -[0119], under the heading titled“Compounds.” [0142] As used herein, a“subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and/or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult.

[0143] As used herein, the terms“treat,”“treating,”“treatment,”“therapeutic,” and“therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0144] The terms“therapeutically effective amount” and“effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0145] For example, an effective amount of a compound, or radiation, is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (such as non- small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain. As another example, an effective amount, or a therapeutically effective amount of an WEE1 inhibitor is the amount which results in the reduction in WEE1 activity and/or phosphorylation (such as phosphorylation of CDC2). The reduction in WEE1 activity is known to those skilled in the art and can be determined by the analysis of WEE1 intrinsic kinase activity and downstream substrate phosphorylation.

[0146] The amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.

[0147] In general, however, a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between. The compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form.

[0148] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. [0149] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine)

[0150] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0151] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0152] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.

EXAMPLES

[0153] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

Intermediate 1

l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-l- yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0154] To a solution of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4- d]pyrimidin-3-one (450 mg, 2.02 mmol), 2-chloro-7-ethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-7-ol (517 mg, 2.62 mmol), Cul (384 mg, 2.02 mmol) and K2CO3 (390 mg, 2.83 mmol) in 1,4-dioxane (30 mL), AW-Dimcthylcthylcncdiaminc (0.43 mL, 4.02 mmol) was added at 80 °C. The suspension was heated at 95 °C for 18 h. The mixture was cooled to room temperature (rt), diluted with aq. NH4OH (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried (NaiSCL) and evaporated to dryness. The residue was purified by flash chromatography (S1O2, 40% EtOAc/pet ether) to afford 2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl)-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (280 mg, 36%) as a pale yellow oil. MS (ESI) 384.5 [M+H]⁺.

[0155] To a 0 °C solution of 2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl)-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4.5 g, 1 E7 mmol) in toluene (90 mL) was added m-CPBA (3.7 g, 12.9 mmol). The ice bath was removed and the reaction was stirred for 30 min. After completion by TLC, 4-(4- methylpiperazin-l-yl)aniline (2.9 g, 15.2 mmol) and DIPEA (10.9 mL, 61.05 mmol) were added at 0 °C. The ice bath was removed and the reaction was stirred at rt for 16 h. The reaction was determined to be complete by TLC and water (100 mL) was added to the reaction and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. NaHC0₃ solution (250 mL), brine (300 mL), dried (Na₂S0₄) and evaporated under reduced pressure. The crude material was triturated with 30% Et₂0/pentane to afford racemic 2-allyl-l -(7-cthyl-7-hydiOxy-6,7-di hydro-5 /7-cyclopcnta[/?]pyndin-2-yl)-6-((4-(4- methylpiperazin-l-yl)phenyl)amino)-lH-pyrazolo[3,4-d]pyrimidin-3(2H)-one (5.2 g, 84%).

[0156] In a pressure tube, to a stirred solution of 2-allyl-l-(7-ethyl-7-hydroxy-6,7- dihydro-5/7-cyclopcnta[/?]pyndin-2-yl)-6-((4-(4-mcthylpipcrazin- 1 -yl)phcnyl)amino)-l H- pyrazolo[3,4-d]pyrimidin-3(2H)-one (2 g, 3.79 mmol) in THE (30 mL) was added NH4HCO3 (1.67 g, 26.50 mmol), Pd(dppf)Cl2 (1.10 g, 1.50 mmol). The solution was degassed with argon and the reaction mixture was heated at 90 °C for 4 h. The reaction was filtered and concentrated. The residue was dissolved in 20 mL 20% IPA in chloroform and washed with water (1 X 20 mL). The organic layer was dried (Na₂S0₄), filtered and concentrated under reduced pressure to afford Intermediate 1 (1.2 g, 64%) as a yellow solid. MS (ESI) 487.1 [M+H]⁺. Example 1A

(S)-l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

Example IB

(R)-l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

[0157] To a stirred solution of Intermediate 1 (200 mg, 0.41 mmol) in anhydrous DMF (5 mL) at 0 °C was added 60 % NaH (16.4 mg, 0.41 mmol). The reaction was stirred for 30 min at 0 °C. Then, 80 % 3-bromoprop-l-yne in toluene (0.04 mL, 0.41 mmol) was added drop-wise at 0 °C. The reaction was stirred at 0 °C for 16 h. After completion as indicated by TLC, the reaction was diluted with water (20 mL) and extracted with 20% IPA in chloroform (3 x 20 mL). The combined extracts were dried (NaiSCri), filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (alumina, EtOAc:Hexanes) to afford racemic l-(7-ethyl-7-hydroxy-6,7- dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-l-yl)phenyl)amino)-2- (prop-2-yn-l-yl)-lH-pyrazolo[3,4-d]pyrimidin-3(2H)-one (52 mg) as a pale yellow solid. MS (ESI) 525.6 [M+H]⁺. The enantiomers (250 mg racemic) were separated by chiral SFC chromatography (Chiralpak AD-H, 45% (0.5% DEA in methanol)) to afford Peak 1 (Example 1A, 54 mg) and Peak 2 (Example IB, 50 mg). Example 1A: a yellow solid; ' H NMR (400 MHz, DMSO -d₆) 510.30 (br s, 1H), 8.84 (s, 1H), 7.95-7.87 (m, 2H), 7.60 (br s, 2H), 6.95 (d, 7=7.6 Hz, 2H), 5.05 (s, 1), 5.00-4.93 (m, 1H), 4.79 (dd, 7=18.0 Hz and 2.0 Hz, 1H), 3.20-3.14 (m, 5H), 3.12-2.96 (m, 1H), 2.70-2.80 (m, 1H), 2.45-2.50 (m, 4H,), 2.23-2.17 (m, 4H), 2.04-2.03 (m, 1H), 1.88-1.86 (m, 1H), 1.71-1.68 (m, 1H), 0.86 (t, 7=7.4 Hz, 3H); MS (ESI) 525.2 [M+H]⁺. Example IB: a yellow solid;

NMR (400 MHz, DMSO -d₆) d 10.30 (br s, 1H), 8.84 (s, 1H), 7.95-7.86 (m, 2H), 7.60 (br s, 2H), 6.95 (d, 7=4.0 Hz, 2H), 5.05 (s, 1H), 4.90-5.00 (m, 1H), 4.79 (dd, 7=17.0 Hz and 2.0 Hz, 1H), 3.15-3.11 (m, 5H), 2.97-2.95 (m, 1H), 2.85-2.75 (m, 1H), 2.45-2.50 (m, 4H), 2.23-2.17 (m, 4H), 2.03-1.95 (m, 1H), 1.88-1.85 (m, 1H), 1.71-1.68 (m, 1H), 0.86 (t, 7=7.4 Hz, 3H); MS (ESI) 525.2 [M+H]⁺. The absolute stereochemistry of Example 1A and Example IB was arbitrarily assigned.

Intermediate 2

l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4- methylpiperazin-l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0158] 2-allyl-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-

6-((3-methyl-4-(4-methylpiperazin-l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4- d]pyrimidin-3-one was prepared following similar procedure for preparing 2-allyl-l-(7-ethyl-

7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-l- yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo [3,4-d]pyrimidin-3-one using 2-chloro-7-methyl- 6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol.

[0159] Intermediate 2 was prepared according to the procedure for Intermediate 1. MS (ESI) 501.2 [M+H]⁺.

Example 2A

(S)-l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

Example 2B

(R)-l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

[0160] Racemic l-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)- 6-((3-methyl-4-(4-methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H- pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure for Example 1A and Example IB. MS (ESI) 539.3 [M+H]⁺. The enantiomers (260 mg racemic) were separated by chiral SFC chromatography (Chiralpak AD-H, 45% (0.5% DEA in methanol)) to afford Peak 1 (Example 2A, 55 mg) and Peak 2 (Example 2B, 58 mg). Example 2A: a yellow solid;

NMR (400 MHz, DMSO -d₆) d 10.25 (br s, 1H), 8.86 (s, 1H), 7.93-7.86 (m, 2H), 7.67 (brs, 1H), 7.43 (dd, 7=8.8 Hz, 2.4 Hz, 2H), 7.01 (d, 7=8.8 Hz, 1H), 5.05 (s, 1H), 4.96 (d, 7=18.0 Hz, 1H) 4.79 (dd, 7=18.0 Hz and 2.6 Hz, 1H), 3.14 (s, 1H), 2.99-2.92 (m, 1H), 2.83-2.72 (m, 5H), 2.51-2.47 (m, 3H), 2.23-2.15 (m, 7H), 2.07-1.98 (m, 1H), 1.89-1.84 (m, 1H), 1.71-1.65 (m, 1H), 0.86 (t, 7=7.36 Hz, 3H); MS (ESI) 539.2 [M+H]⁺. Example 2B: a yellow solid;

NMR (400 MHz, DMSO -d₆) d 10.25 (br s, 1H), 8.86 (s, 1H), 7.93- 7.86 (m, 2H), 7.67 (brs, 1H), 7.43 (dd, 7=8.8 Hz, 2.4 Hz, 2H), 7.01 (d, 7=8.8 Hz, 1H), 5.05 (s, 1H), 4.96 (d, 7=18.0 Hz, 1H) 4.79 (dd, 7=18.0 Hz and 2.6 Hz, 1H), 3.14 (s, 1H), 2.99-2.92 (m, 1H), 2.83-2.72 (m, 5H), 2.51-2.47 (m, 3H), 2.23-2.15 (m, 7H), 2.07-1.98 (m, 1H), 1.89- 1.84 (m, 1H), 1.71-1.65 (m, 1H), 0.86 (t, 7=7.36 Hz, 3H); MS (ESI) 539.2 [M+H]⁺. The absolute stereochemistry of Example 2A and Example 2B was arbitrarily assigned.

Intermediate 3

l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin- l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0161] 2-allyl-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)- 6-((4-(4-methylpiperazin-l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3- one was prepared as described herein.

[0162] Intermediate 3 was prepared according to the procedure for Intermediate 1. MS (ESI) 473.2 [M+H]⁺.

Example 3A

(S)-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

Example 3B

(R)-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

[0163] Racemic l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2- yl)-6-((4-(4-methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H- pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure for Example 1A and IB. (ESI) 511.2 M+H]⁺. The enantiomers (265 mg racemic) were separated by chiral SFC chromatography (Chiralpak IA, 35% (0.5% DEA in ethanol)) to afford Peak 1 (Example 3A, 45 mg) and Peak 2 (Example 3B, 45 mg). Example 3A: a yellow solid; ' H NMR (400 MHz, DMSO-ifc) d 10.3 (br s, 1H), 8.84 (s, 1H), 7.95-7.84 (m, 2H), 7.59 (br s, 2H), 6.94 (d, 7=8.4 Hz, 2H), 5.17 (s, 1H), 4.83 (d, 7=2.0 Hz, 1H), 4.79 (d, 7=2.4 Hz, 1H), 3.16-3.08 (m, 5H), 3.02-2.94 (m, 1H), 2.84-2.76 (m, 1H), 2.51-2.47 (m, 4H), 2.22 (s, 3H), 2.14 (t, 7=6.8 Hz, 2H), 1.45 (s, 3H); MS (ESI) 511.2 [M+H]⁺. Example 3B: a yellow solid:

NMR (400 MHz, DMSO-ifc) d 10.3 (br s, 1H), 8.84 (s, 1H), 7.95-7.84 (m, 2H), 7.59 (br s, 2H), 6.94 (d, 7=8.4 Hz, 2H), 5.17 (s, 1H), 4.83 (d, 7=2.0 Hz, 1H), 4.79 (d, 7=2.4 Hz, 1H), 3.16-3.08 (m, 5H), 3.02-2.94 (m, 1H), 2.84-2.76 (m, 1H), 2.51-2.47 (m, 4H), 2.22 (s, 3H), 2.14 (t, 7 = 6.8 Hz, 2H), 1.45 (s, 3H); MS (ESI) 511.2 [M+H]⁺. The absolute stereochemistry of Example 3A and Example 3B was arbitrarily assigned.

Intermediate 4

l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4- methylpiperazin-l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0164] 2-allyl-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)- 6-((3-methyl-4-(4-methylpiperazin-l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4- d]pyrimidin-3-one was prepared as described herein.

[0165] Intermediate 4 was prepared according to the procedure for Intermediate 1. MS (ESI) 487.2 [M+H]⁺. Example 4A

(S)-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

Example 4B

(R)-l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((3-methyl-4-(4- methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d] pyrimidin- 3 -one

[0166] Racemic l-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2- yl)-6-((3-methyl-4-(4-methylpiperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)- 1,2-dihydro- 3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared according to the procedure for Example 1A and IB. MS (ESI) 525.6 [M+H]⁺. The enantiomers (250 mg racemic) were separated by chiral SFC chromatography (Chiralpak AD-H, 40% (0.5% DEA in ethanol)) to afford Peak 1 (Example 4A, 62 mg) and Peak 2 (Example 4B, 54 mg). Example 4A: a yellow solid; ' H NMR (400 MHz, DMSO -d₆) d 10.30 (br s, 1H), 8.84 (s, 1H), 7.92 (d, 7=7.6 Hz, 1H), 7.86 (d, 7=8.4 Hz, 1H), 7.68 (brs, 1H), 7.41 (d, 7=8.0 Hz, 1H), 7.01 (d, 7=8.8 Hz, 1H), 5.18 (s, 1H), 4.92 (d, 7=18 Hz, 1H), 4.80 (d, 7=18.8 Hz, 1H), 3.15 (s, 1H), 2.99-2.93 (m, 1H), 2.82-2.76 (m, 5H), 2.45-2.50 (m, 4H), 2.26-2.23 (m, 6H), 2.14-2.10 (m, 2H), 1.43(s, 3H); MS (ESI) 525.2 [M+H]⁺. Example 4B: a yellow solid;

NMR (400 MHz, DMSO -d₆) d 10.30 (br s,

1H), 8.84 (s, 1H), 7.92 (d, 7=7.6 Hz, 1H), 7.86 (d, 7=8.4 Hz, 1H), 7.68 (brs, 1H), 7.41 (d, 7=8.0 Hz, 1H), 7.01 (d, 7=8.8 Hz, 1H), 5.18 (s, 1H), 4.92 (d, 7=18 Hz, 1H), 4.80 (d, 7=18.8 Hz, 1H), 3.15 (s, 1H), 2.99-2.93 (m, 1H), 2.82-2.76 (m, 5H), 2.45-2.50 (m, 4H), 2.26-2.23 (m, 6H), 2.14-2.10 (m, 2H), 1.43 (s, 3H); MS (ESI) 525.3 [M+H]⁺. The absolute stereochemistry of Example 4A and Example 4B was arbitrarily assigned.

Intermediate 5

l-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-l- yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0167] 2-allyl-l-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4- methyl-piperazin-l-yl)phenyl)amino)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was prepared following similar procedure for preparing 2-allyl-l-(7-ethyl-7-hydroxy-6,7-dihydro- 5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-l-yl)phenyl)amino)-l,2-dihydro-3H- pyrazolo [3,4-d]pyrimidin-3-one using 2-chloro-8-methyl-5,6,7,8-tetrahydroquinolin-8-ol.

[0168] Intermediate 5 was prepared according to procedure for Intermediate 1. MS (ESI) 487.4 [M+H]⁺.

Example 5A

(S)-l-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-l- yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

Example 5B

(R)-l-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4-methylpiperazin-l- yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0169] Racemic l-(8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-6-((4-(4- methyl-piperazin-l-yl)phenyl)amino)-2-(prop-2-yn-l-yl)-l,2-dihydro-3H-pyrazolo[3,4- d]pyrimidin-3-one was prepared according to the procedure for Example 1A and IB. (ESI) 525.2 [M+H]⁺. The enantiomers (210 mg racemic) were separated by chiral SFC chromatography (Chiralpak IA, 50% (0.5% DEA in IPA)) to afford Peak 1 (Example 5A, 37 mg) and Peak 2 (Example 5B, 54 mg). Example 5A: a yellow solid; ' H NMR (400 MHz, DMSO-de) 510.30 (br s, 1H), 8.83 (s, 1H), 7.84-7.80 (m, 2H), 7.58 (br s, 2H), 6.95 (d, 7=8.4 Hz, 2H), 5.00 (d, 7=18.8 Hz, 1H), 4.92 (s, 1H), 4.84 (dd, 7=18.0 Hz and 2.4 Hz, 1H), 3.14- 3.12 (m, 5H), 2.86-2.79 (m, 2H), 2.45-2.50 (m, 4H), 2.23 (s, 3H), 1.96-1.91 (m, 2H), 1.83-

1.73 (m, 2H), 1.48 (s, 3H); MS (ESI) 525.2 [M+H]⁺. Example 5B: a yellow solid;

NMR

(400 MHz, DMSO -d₆) 5 10.25 (br s, 1H), 8.83 (s, 1H), 7.85-7.80 (m, 2H), 7.58 (br s, 2H), 6.96 (d, 7=7.2 Hz, 2H), 5.01 (d, J=18.0 Hz, 1H), 4.92 (s, 1H) 4.84 (d, J=19.2 Hz, 1H), 3.14-

3.12 (m, 5H), 2.86-2.74 (m, 2H), 2.47-2.50 (m, 4H), 2.23 (s, 3H), 1.96-1.91 (m, 2H), 1.83-

1.72 (m, 2H), 1.49 (s, 3H); MS (ESI) 525.2 [M+H]⁺. The absolute stereochemistry of Example 5A and Example 5B was arbitrarily assigned.

Procedure A

Weel binding assay

[0170] Wee 1 kinase was determined by using Flurorescence Resonance Energy Transfer (FRET) assay. In 384-well plates, Weel kinase (2 nM final concentration) was mixed with AlexaFluor labeled tracer 178 (50 nM final concentration, K_d = 24 nM), Eu-anti- GST antibody (2 nM final concentration) and then inhibitor (0.003 to 10 micromolar) in a final volume of 16 pi kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCh, 1 mM EGTA). The plate was shaken for 30 seconds, incubated for 60 min at RT, and recorded on fluorescence plate reader. The results are shown in Table 1.

Procedure B

H23 cellular proliferation assay

[0171] H23[ATCC (CRL-5800™)] cells were grown and maintained in RPMI- 1640 medium with 10% FBSand 1% penicillin-streptomycin. Cells were treated with compounds diluted in DMSO and a 9 point 5-fold serial dilutions. Plates were placed in 37 °C, 5% CO2 for to incubate for 4 days. Before they were developed by adding 100 pL of CellTiter-Glo reagent (Promega) to the assay plate, plates were shaken briefly for 2 mins and allowed to incubate at rt for 10 mins. The plates are read with a M5e plate reader according to CellTiter-Glo protocol. The GraphPad Prism software is used to get IC50 values. The results are shown in Table 1.

Table 1. Weel Enzymatic and cellular data

For Weel enzymatic IC50: A = a single IC50 <10 nM; B = a single IC50 >10 nM and < 100 nM; C = a single IC50 >100 nM. For H23 CTG IC50: A = a single IC50 £ 100 nM; B = a single IC50 >100 nM and < 1000 nM; C = a single IC50 >1000 nM.

[0172] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein:

R¹ is selected from the group consisting of hydrogen, halogen and a substituted or unsubstituted C₁-C₆ alkyl;

Ring A is selected from the group consisting of a substituted or unsubstituted phenyl and a substituted or unsubstituted 5-6 membered monocyclic heteroaryl;

Ring B is selected from the group consisting of a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl and a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl;

R² is selected from the group consisting

m is 0, 1, 2 or 3;

R³ is selected from the group consisting of halogen and a substituted or unsubstituted Ci-C₆ alkyl;

X is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, a substituted or unsubstituted 4-6 membered monocyclic heterocyclyl, a substituted or unsubstituted amine(Ci-C₆ alkyl), a substituted or unsubstituted -NH-(CH2)i-6-amine, a mono-substituted amine, a di-substituted amine, an amino, a substituted or unsubstituted Ci- Ce alkyl, a substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C3-C6 cycloalkoxy, a substituted or unsubstituted (C1-C6 alkyl)acyl, a substituted or unsubstituted C-amido, a substituted or unsubstituted N-amido, a substituted or unsubstituted C-carboxy, a substituted or unsubstituted O-carboxy, a substituted or unsubstituted O-carbamyl and a substituted or unsubstituted N-carbamyl;

Y is CH or N;

Y¹ is CR^4A or N;

Y² is CR^4B or N;

Ring C is selected from the group consisting of a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted monocyclic 5-10 membered heteroaryl, a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl and a substituted or unsubstituted 7-10 membered bicyclic heterocyclyl;

R^4A and R^4B are independently selected from the group consisting of hydrogen, halogen and an unsubstituted C1-4 alkyl; and

R⁵ is a substituted or unsubstituted 5-7 membered monocyclic heterocyclyl.

2. The compound of Claim 1, wherein R¹ is an unsubstituted C1-C6 alkyl.

3. The compound of Claim 1 or 2, wherein R¹ is an unsubstituted methyl.

4. The compound of Claim 1, wherein R¹ is a substituted C1-C6 alkyl.

5. The compound of Claim 1 or 4, wherein R¹ is an unsubstituted C1-C6 haloalkyl.

6. The compound of any one of Claims 1 or 4-5, wherein R¹ is -CHF2, -CF3, -CF2CH3 or -CH2CF3.

7. The compound of Claim 1, wherein R¹ is hydrogen.

8. The compound of Claim 1, wherein R¹ is halogen.

9. The compound of Claim 1 or 8, wherein R¹ is fluoro.

10. The compound of any one of Claims 1-9, wherein Ring A is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl.

11. The compound of any one of Claims 1-10, wherein Ring A is selected from the group consisting of a substituted or unsubstituted pyrrole, a substituted or unsubstituted furan, a substituted or unsubstituted thiophene, a substituted or unsubstituted imidazole, a substituted or unsubstituted pyrazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazine, a substituted or unsubstituted pyrimidine and a substituted or unsubstituted pyridazine.

12. The compound of any one of Claims 1-11, wherein

selected from

wherein each of the aforementioned groups are substituted or unsubstituted.

13. The compound of any one of Claims 1-12, wherein Ring A is unsubstituted.

14. The compound of any one of Claims 1-12, wherein Ring A is substituted.

15. The compound of any one of Claims 1-9, wherein Ring A is a substituted phenyl.

16. The compound of any one of Claims 1-9, wherein Ring A is an unsubstituted phenyl.

17. The compound of any one of Claims 1-16, wherein Ring B is a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl.

18. The compound of any one of Claims 1-17, wherein Ring B is a substituted or unsubstituted monocyclic 5 membered carbocyclyl.

19. The compound of any one of Claims 1-17, wherein Ring B is a substituted or unsubstituted monocyclic 6 membered carbocyclyl.

20. The compound of any one of Claims 1-17, wherein Ring B is a substituted or unsubstituted monocyclic 7 membered carbocyclyl.

21. The compound of any one of Claims 1-20, wherein

selected from

the group consisting of:

groups are substituted or unsubstituted.

22. The compound of any one of Claims 1-16, wherein Ring B is a substituted or unsubstituted monocyclic 5-7 membered heterocyclyl.

23. The compound of any one of Claims 1-16 or 22, wherein Ring B is a substituted or unsubstituted monocyclic 5 membered heterocyclyl.

24. The compound of any one of Claims 1-16 or 22, wherein Ring B is a substituted or unsubstituted monocyclic 6 membered heterocyclyl.

25. The compound of any one of Claims 1-16 or 22, wherein Ring B is a substituted or unsubstituted monocyclic 7 membered heterocyclyl.

26. The compound of any one of Claims 1-16 or 22-25, wherein

selected from the group consisting of:

wherein each of the aforementioned groups are substituted or unsubstituted.

27. The compound of any one of Claims 1-26, wherein Ring B is substituted.

28. The compound of any one of Claims 1-27, wherein Ring B is substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, amino, an unsubstituted N-linked amido, an unsubstituted C1-C6 haloalkyl and a substituted or unsubstituted C1-C6 alkyl.

29. The compound of any one of Claims 1-28, wherein Ring B is substituted with 1, 2 or 3 substituents independently selected from the group consisting of fluoro, hydroxy, amino, an unsubstituted -NHC(0)Ci-C₆ alkyl, an unsubstituted C1-C6 haloalkyl and an unsubstituted C1-C6 alkyl.

30. The compound of any one of Claims 1-29, wherein Ring B is substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, hydroxy, amino, -CF3, -CF2CH3, -CHF2, an unsubstituted methyl, an unsubstituted ethyl and - NH(0)CH .

31. The compound of any one of Claims 1-26, wherein Ring B is unsubstituted.

32. The compound of any one of Claims 1-31, wherein

33. The compound of any one of Claims 1-32, wherein Y is CH.

34. The compound of any one of Claims 1-32, wherein Y is N.

35. The compound of any one of Claims 1-34, wherein X is a substituted or unsubstituted 4-6 membered monocyclic heterocyclyl.

36. The compound of any one of Claims 1-35, wherein X is selected from the group consisting of a substituted or unsubstituted azetidine, a substituted or unsubstituted oxetane, a substituted or unsubstituted diazetidine, a substituted or unsubstituted azaoxetane, a substituted or unsubstituted pyrrolidine, a substituted or unsubstituted tetrahydrofuran, a substituted or unsubstituted imidazoline, a substituted or unsubstituted pyrazolidine, a substituted or unsubstituted piperidine, a substituted or unsubstituted tetrahydropyran, a substituted or unsubstituted piperazine, a substituted or unsubstituted morpholine and a substituted or unsubstituted dioxane.

37. The compound of any one of Claims 1-36, wherein X is substituted.

38. The compound of any one of Claims 1-37, wherein X is substituted with 1 or 2 substituents independently selected from the group consisting of halogen, a substituted or unsubstituted C1-C6 alkyl, a mono-substituted amine, a di-substituted amine, an amino, substituted or unsubstituted amine(Ci-C₆ alkyl) and a substituted or unsubstituted (C1-C6 alkyl) acyl.

39. The compound of any one of Claims 1-38, wherein X is substituted with 1 or 2 substituents independently selected from the group consisting of fluorine, an unsubstituted Ci-C₆ alkyl, an unsubstituted C1-C6 hydroxyalkyl, an unsubstituted amine(Ci-C₆ alkyl) and an unsubstituted (C1-C6 alkyl)acyl.

40. The compound of any one of Claims 1-34, wherein X is a substituted or unsubstituted amine(Ci-C₆ alkyl).

41. The compound of any one of Claims 1-34 or 40, wherein X is selected from the group consisting

wherein each of the aforementioned groups are substituted or unsubstituted.

42. The compound of any one of Claims 1-34 or 40-41, wherein X is unsubstituted.

43. The compound of any one of Claims 1-34 or 40-41, wherein X is substituted.

44. The compound of any one of Claims 1-34, wherein X is a substituted or unsubstituted -NH-(CH2)i-6-amine.

45. The compound of any one of Claims 1-34 or 44, wherein X selected from the group consisting

H

wherein each of the aforementioned groups are substituted or unsubstituted.

46. The compound of any one of Claims 1-34 or 44-45, wherein X is unsubstituted.

47. The compound of any one of Claims 1-34 or 44-45, wherein X is substituted.

48. The compound of any one of Claims 1-34, wherein X is a mono-substituted amine or a di-substituted amine.

49. The compound of any one of Claims 1-34 or 48, wherein X is a mono- substituted amine or a di-substituted amine; wherein the substituents of the mono-substituted amine and the di-substituted amine are independently selected from an unsubstituted C₁-C₆ alkyl and an unsubstituted C₃-C₆ cycloalkyl.

50. The compound of any one of Claims 1-34 or 48-49, wherein X is selected

from the group consisting of

51. The compound of any one of Claims 1-34, wherein X is an unsubstituted Ci- C₆ alkyl.

52. The compound of any one of Claims 1-34 or 51, wherein X is selected from the group consisting of an unsubstituted methyl, an unsubstituted ethyl and an unsubstituted iso-propyl.

53. The compound of any one of Claims 1-34, wherein X is a substituted C1-C6 alkyl.

54. The compound of any one of Claims 1-34 or 53, wherein X is an unsubstituted Ci-C₆ haloalkyl.

55. The compound of any one of Claims 1-34 or 53-54, wherein X is selected from the group consisting of -CHF₂, -CF₃, -CF₂CH₃ and -CH₂CF₃.

56. The compound of any one of Claims 1-34 or 53, wherein X is an unsubstituted C1-C6 hydroxyalkyl.

57. The compound of any one of Claims 1-34, 53 or 56, wherein X is selected from the group consisting of -CH₂OH, -CH2CH2OH, -CH(OH)CH and -C(OH)(CH )₂.

58. The compound of any one of Claims 1-34 or 53, wherein X is an unsubstituted Ci-C₆ cyanoalkyl.

59. The compound of any one of Claims 1-34, 53 or 58, wherein X is selected from the group consisting o

60. The compound of any one of Claims 1-34 or 53, wherein X is an unsubstituted Ci-C₆ alkoxyalkyl

61. The compound of any one of Claims 1-34, 53 or 60, wherein X is selected from the group consisting of

, ,

62. The compound of any one of Claims 1-34 or 53, wherein X is selected from the group consisting

63. The compound of any one of Claims 1-34, wherein X is an unsubstituted Ci-

Ce alkoxy.

64. The compound of any one of Claims 1-34 or 63, wherein X is an unsubstituted methoxy, an unsubstituted ethoxy or an unsubstituted iso-propoxy.

65. The compound of any one of Claims 1-34, wherein X is a substituted C1-C6 alkoxy.

66. The compound of any one of Claims 1-34 or 65, wherein X is a C1-C6 alkoxy substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, an amino, a mono-substituted amine and a di-substituted amine.

67. The compound of any one of Claims 1-34 or 65-66, wherein X is selected from the group consisting of

68. The compound of any one of Claims 1-34, wherein X is a substituted or unsubstituted C3-C6 cycloalkoxy.

69. The compound of any one of Claims 1-34, wherein X is a substituted or unsubstituted (C1-C6 alkyl)acyl.

70. The compound of any one of Claims 1-34 or 69, wherein X is -(CO)-CH3.

71. The compound of any one of Claims 1-34, wherein X is hydrogen, hydroxy, cyano or an amino.

72. The compound of any one of Claims 1-34, wherein X is halogen.

73. The compound of any one of Claims 1-34 or 72, wherein X is chloro or fluoro.

74. The compound of any one of Claims 1-34, wherein X is selected from the group consisting of a substituted or unsubstituted C-amido, a substituted or unsubstituted N- amido, a substituted or unsubstituted O-carbamyl, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-carboxy and a substituted or unsubstituted O-carboxy.

75. The compound of Claim 74, wherein X is substituted.

76. The compound of Claim 74 or 75, wherein X is mono-substituted with an unsubstituted C1-C6 hydroxyalkyl.

77. The compound of Claim 74, wherein X is unsubstituted.

78. The compound of any one of Claims 1-31, wherein

79. The compound of any one of Claims 1-78, wherein R³ is halogen.

80. The compound of any one of Claims 1-79, wherein R³ is fluoro.

81. The compound of any one of Claims 1-79, wherein R³ is chloro.

82. The compound of any one of Claims 1-78, wherein R³ is a substituted C1-C6 alkyl.

83. The compound of any one of Claims 1-78 or 82, wherein R³ is an unsubstituted C1-C6 haloalkyl.

84. The compound of any one of Claims 1-78 or 82-83, wherein R³ is selected from the group consisting of -CHF2, -CF3, -CF2CH3 and -CH2CF3.

85. The compound of any one of Claims 1-78 or 82, wherein R³ is an unsubstituted C1-C6 hydroxyalkyl.

86. The compound of any one of Claims 1-78, 82 or 85, wherein R³ is selected from the group consisting of -CH₂OH, -CH2CH2OH, -CH(OH)CH and -C(OH)(CH₃)₂.

87. The compound of any one of Claims 1-78, wherein R³ is an unsubstituted Ci- C₆ alkyl.

88. The compound of any one of Claims 1-78 or 87, wherein R³ is selected from the group consisting of an unsubstituted methyl, an unsubstituted ethyl and an unsubstituted iso-propyl.

89. The compound of any one of Claims 1-77, wherein m is 0.

90. The compound of any one of Claims 1-88, wherein m is 1.

91. The compound of any one of Claims 1-88, wherein m is 2.

92. The compound of any one of Claims 1-88, wherein m is 3.

93. The compound of any one of Claims 1-31,

94. The compound of any one of Claims 1-31 or 93, wherein Y¹ is CR^4A.

95. The compound of any one of Claims 1-31 or 93-94, wherein R^4A is hydrogen.

96. The compound of any one of Claims 1-31 or 93-94, wherein R^4A is halogen.

97. The compound of any one of Claims 1-31 or 93-94, wherein R^4A is an unsubstituted Ci-4 alkyl.

98. The compound of any one of Claims 1-31 or 93, wherein Y¹ is N.

99. The compound of any one of Claims 1-31 or 93-98, wherein Y² is CR^4B.

100. The compound of any one of Claims 11-31 or 93-99, wherein R^4B is hydrogen.

101. The compound of any one of Claims 1-31 or 93-99, wherein R^4B is halogen.

102. The compound of any one of Claims 1-31 or 93-99, wherein R^4B is an unsubstituted Ci-4 alkyl.

103. The compound of any one of Claims 1-31 or 93-98, wherein Y² is N.

104. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted C6-C10 aryl.

105. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted Ce aryl

106. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 5-10 membered heteroaryl.

107. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 5-6 membered heteroaryl.

108. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted monocyclic 5 membered carbocyclyl.

109. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted monocyclic 6 membered carbocyclyl.

110. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted monocyclic 7 membered carbocyclyl.

111. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 5 membered monocyclic heterocyclyl.

112. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 6 membered monocyclic heterocyclyl.

113. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 7 membered monocyclic heterocyclyl.

114. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 7 membered bicyclic heterocyclyl.

115. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 8 membered bicyclic heterocyclyl.

116. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 9 membered bicyclic heterocyclyl.

117. The compound of any one of Claims 1-31 or 93-103, wherein Ring C is a substituted or unsubstituted 10 membered bicyclic heterocyclyl.

118. The compound of any one of Claims 1-31 or 93-117, wherein Ring C is substituted.

119. The compound of any one of Claims 1-31 or 93-118, wherein Ring C is substituted with one or more substituents independently selected from the group consisting of an unsubstituted C1-C6 alkyl and an unsubstituted (C1-C6 alkyl) acyl.

120. The compound of any one of Claims 1-31 or 93-117, wherein Ring C is unsubstituted.

121. The compound of any one of Claims 1-31 or 93, wherein R² is selected from

the group consisting of

wherein each of the aforementioned groups is substituted or unsubstituted.

122. The compound of Claim 1, wherein the compound is selected from the group consisting of:

pharmaceutically acceptable salt of any of the foregoing.

123. The compound of Claim 122, wherein the compound is selected from the group consisting of:

pharmaceutically acceptable salt of any of the foregoing.

124. A pharmaceutical composition comprising an effective amount of the compound of any one of any one of Claims 1-123, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

125. Use of an effective amount of a compound of any one of Claims 1-123, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 124 in the manufacture of a medicament for ameliorating or treating a cancer, wherein the cancer is selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer , a stomach cancer, a gallbladder/bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis/ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma, and a non-Hodgkin’s lymphoma.

126. Use of an effective amount of a compound of any one of Claims 1-123, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 124 in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non small cell cancer, a breast cancer, a lung cancer , a stomach cancer, a gallbladder/bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis/ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma, and a non-Hodgkin’s lymphoma.

127. Use of an effective amount of a compound of any one of Claims 1-123, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 124 in the manufacture of a medicament for ameliorating or treating a malignant growth or tumor, wherein the malignant growth or tumor is due to a cancer selected from a brain cancer, a cervicocerebral cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non small cell cancer, a breast cancer, a lung cancer , a stomach cancer, a gallbladder/bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis/ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma, and a non-Hodgkin’s lymphoma.