Methods of use for quinazoline compounds

Abstract

Disclosed is a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more additional therapeutic agents or therapies, wherein Formula (I) is: (I) wherein R1, R2, R3, R4, R5, R6, R7 are as described in the specification.

Description

METHODS OF USE FOR QUINAZOLINE COMPOUNDSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 621,970 filed January 17, 2024, which application is incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] Division and proliferation of mammalian cells mediated by the cell cycle is an important and fundamental biological process, which controls production and generation of cells with critical biological functions. Cell cycle is a highly regulated process and responds to a complex set of cell signals within the cell and externally. The complex network of cell signaling, including components promoting and suppressing cancer, plays a key role controlling the cell cycle. Gain-of-function of tumor-promoting components or loss-of- function of tumor-suppressing products can lead to unregulated cell cycle and subsequently tumorigenesis.

[0003] Cyclins and cyclin-dependent kinases (CDKs) are crucial for driving and controlling cell cycle transitions and cell division (34176404). Cyclin is a family of proteins whose expression levels vary at different stages in the cell cycle. Cyclins bind and activate CDKs during different stages of cell cycle, of which the progression is tightly synchronized involving sequential activation of several cyclin-CDK complexes. Of more than 20 CDKs discovered so far, CDK1, 2, 4, 6 have been reported to play a direct role in cell cycle progression. CDK4-cyclin D and CDK6-cyclin D complexes are essential for entry in G1 phase of cell cycle. CDK2-cyclin E complex regulates progression from G1 into S phase, while CDK2-cyclin A is required during S phase. CDK1 -cyclin A complex promotes entry into M phase, and mitosis is further regulated by CDKl-cyclin B complex. Progressive phosphorylation of retinoblastoma (Rb) by CDK4-cyclin D, CDK6-cyclin D and CDK2- cyclin E releases the GI transcription factor, E2F, and promotes S-phase entry. Activation of CDK2-cyclin A during early S-phase promotes phosphorylation of endogenous substrates that permit DNA replication and inactivation of E2F, for S-phase completion.

[0004] Dysregulation of cell-cycle machinery is a hallmark of cancer, leading to overactivation of CDKs and uncontrolled cell division and proliferation. Genetic alterations of the genes encoding cyclin D, CDK4 / 6, and CDK4 / 6-inhibiting proteins (such as p21, p27) all contribute to tumorigenesis. Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Since tumor development is closely related to gene mutation and deregulation of CDK and its regulators, CDK inhibitors are useful for anticancer therapy.CDK inhibitors have been developed as cancer therapy since the early 90s, with multiple FDA-approved drugs (Palbociclib, ribociclib and abemaciclib). However, these early generation CDK inhibitors on the market have poor selectivity and high toxicity (such as myelosuppression), leading to adverse effects limiting clinical dosing level for further patient benefit. There remains an unmet medical need to develop methods of use for novel CDK inhibitors with better selectivity and less side effects for normal cells.SUMMARY OF THE INVENTION

[0005] The present disclosure generally relates methods of use for substituted quinolinone amide compounds or salts of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) and pharmaceutical compositions thereof. The substituted quinazoline compounds or salts of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) disclosed herein may be used for the treatment of abnormal cell growth, such as cancer, in a subject in need thereof.

[0006] In some aspects, methods of treating cancer may comprise administering a compound or pharmaceutically acceptable salt of any one of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) in an individual in need thereof.

[0007] In certain aspects, the disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more additional therapeutic agents or therapies, wherein Formula (I) is:wherein,R1is selected from optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;R2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;-each of R3, R4, R5, R6, is independently selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl;R7is selected from hydrogen and optionally substituted C1-6alkyl; wherein if R1is an optionally substituted pyrazole, R2is not piperidine.

[0008] In certain aspects, the disclosure provides methods of use of a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient in combination with one or more additional therapeutic agents or therapies.DETAILED DESCRIPTION OF THE INVENTION

[0009] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0010] Basic functions for cell regulation, cell division, and cell proliferation are controlled by cyclin-dependent kinases (CDKs) activated by regulatory subunits such as cyclins. CDK inhibitors are useful in the treatment of cancer due to CDKs role in cell regulation. It has been shown that increased activity or transient abnormal activation of CDKs leads to the development of tumors; development of tumors are often associated with changes in the CDKs or regulators of CDKs.

[0011] CDKs bind to cyclin, which a regulatory protein., and without cyclin, it has little kinase activity. The cyclin-CDK complex is an active kinase typically modulated by phosphorylation and other binding proteins. There are currently 21 CDKs and 5 CDK-like genes that are known in the human genome. While many of the CDKs have been linked to transcription, CDK2, CDK4, and CDK6 are associated with the cell cycle. CDK2 is associated with DNA replication in higher eukaryotes whereas CDK4 and CDK6 are associated with various growth-regulatory signals.

[0012] CDK2 overexpression is associated with abnormal regulation of the cell cycle. Cyclin E, the cyclin partner of CDK2, binds to CDK2 to form an active kinase complex. The CDK2- cyclin E complex is important in the regulation of the Gl / S transition, centrosome replication, and histone biosynthesis. Progressive phosphorylation can release the G1transcription factor E2F and promote entry into the S phase. Another cyclin partner of CDK2, cyclin A, can bind and activate CDK2 during the initial phase of the S phase, and promote endogenous substrate phsophorlation, which allows DNA replication and E2F inactivation to complete the S phase.

[0013] CDK4 and CDK6 are also associated with the cell cycle. CDK4 and CDK6 inhibitors can arrest the cell cycle form the G1 to S phase by blocking phosphorylation of Rb protein and inhibiting proliferation of Rb-positive tumor cells. Besides cell cycle activity, CDK4 and CDK6 inhibitors can also suppress tumor growth through other mechanisms including, but not limited to inducing senescence, promoting anti-tumor immune responses, regulation of cell metabolism, and enhancing cytostasis caused by signaling pathway inhibitors.Definitions

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0015] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0016] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0017] "Amino" refers to the -NH2 radical.

[0018] "Cyano" refers to the -CN radical.

[0019] "Nitro" refers to the -NO2 radical.

[0020] "Oxa" refers to the -O- radical.

[0021] "Oxo" refers to the =0 radical.

[0022] "Thioxo" refers to the =S radical.

[0023] "Imino" refers to the =N-H radical.

[0024] "Oximo" refers to the =N-0H radical.

[0025] "Hydrazino" refers to the =N-NH2 radical.

[0026] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., Ci- C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1- methylethyl (iso-propyl), 1 -butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1 -dimethylethyl (fert-butyl), 1 -pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0027] “Heteroalkyl” refers to an alkyl group, as defined above, having from one or more carbon atoms replaced with a heteroatom, such as wherein the heteroatom is individually selected from N, O and S at each replacement location. Additional heteroatoms can also be usefill, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heteroalkyl can include ethers, thioethers and alkyl-amines. Hetoroalkyl consisting of the stated number of carbon atoms and may include one or more heteroatoms selected from tlie group consisting of O, N, Si and S, wherein tlie nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Two heteroatoms may be consecutive, such as, for example, Heteroalkyl can include any statednumber of carbon atoms as defined herein and in the definition of alkyl.

[0028] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0029] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0030] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises twoto eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0031] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene).

[0032] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene).

[0033] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene).

[0034] “Heteroalkylene” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group, consisting of heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroalkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, a heteroalkylene comprises one heteroatom. In certain embodiments, a heteroalkylene comprises two heteroatoms. In certain embodiments, a heteralkylene comprises three heteroatoms. In certain embodiments, a heteralkylene comprises four heteroatoms. In certain embodiments, a heteralkylene comprises five heteroatoms. In certain embodiments, the heteroatoms can be N, O, S, Si, or P, or a combination thereof. In certain embodiments, the heteroatoms can be N, O, or S, or a combination thereof. In certain embodiments, the heteroatoms can be N, O, or a combination thereof.

[0035] The term “Cx.y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.

[0036] The terms “Cx.yalkenyl” and “Cx.yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0037] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane. A bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicy clo[ 1.1.1 Jpentanyl .

[0038] The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) Tt-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0039] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbomyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclofl.1.1 Jpentanyl, and the like.

[0040] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0041] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0042] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1 -chloromethyl -2-fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

[0043] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. A monocylic heterocycle includes any saturated, unsatured, and aromatic rings as valence permits. A monocyclice heterocycle includes but is not limited to, oxetane, azetidine, furan, tetrahydrofuran, pyrrole, pyrrolidine, pyran, piperidine, piperazine, imidazole, thiazole, morpholine, pyridine, and pyrimidine. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Examples of fused ring systems include, but are not limited to, isoindoline, isoquinoline, tetrahydroisoquinoline,3-azabicyclo[3.1.0]hexane and 6-oxa-3-azabicyclo[3.1.1]heptane. A bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as but not limited to 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6- diazaspiro[3.3]heptane, l-thia-6-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 2,6- diazaspiro[3.4]octane, 2-thia-6-azaspiro[3.4]octane, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide,4-oxa-7-azaspiro[2.5]octane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 2-oxa-6- azaspiro[3.5]nonane, 7-oxa-2-azaspiro[3.5]nonane, 2-azaspiro[4.5] decane, 2,8- diazaspiro[4.5]decane, 8-oxa-2-azaspiro[4.5]decane, and 2-oxa-7-azaspiro[4.5]decane.

[0044] The term "heteroaryl" refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) jr-electron system in accordance with the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridopyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and thiophenyl (i.e. thienyl).

[0045] The term "heterocycloalkyl" refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, azetidinyl, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 3-azabicyclo[3.1.0]hexane, 2- azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6- diazaspiro[3.3]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, l-thia-6-azaspiro[3.3]heptane, 6- azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-thia-6-azaspiro[3.4]octane, 2-thia-6- azaspiro[3.4]octane 2,2-dioxide, 4-oxa-7-azaspiro[2.5]octane, 2-azaspiro[4.4]nonane, 2,7- diazaspiro[4.4]nonane, 2-oxa-6-azaspiro[3.5]nonane, 7-oxa-2-azaspiro[3.5]nonane, 2-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 8-oxa-2-azaspiro[4.5]decane, 2-oxa-7- azaspiro[4.5]decane, and 1,1-dioxo-thiomorpholinyl.

[0046] The term “heterocycloalkenyl” refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12- membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms. The heterocycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), - 11 -ydrazine- 11 -ne (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0047] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, spirocyclic and non-spirocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0048] In some embodiments, each substituent may individually include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, - Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rh-N^, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), R* -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, - Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, - Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0049] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)”. Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”.

[0050] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0051] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0052] The phrase “pharmaceutically acceptable excipienf ’ or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0053] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine,-diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0054] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treatment via administration of a compound described herein does not require the involvement of a medical professional.Table of Abbreviations- 14 -Combination Therapies

[0055] The combination therapies contemplated in this disclosure include, for example, coadministering a disclosed compound and an additional therapeutic agent or therapy, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually hours, days, weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each- 15 -therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0056] The components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that are administered either simultaneously or sequentially.Embodiments of Combination Therapies

[0057] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. In certain embodiments, the compounds and salts are described in Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD).

[0058] Embodiment 1 of this disclosure relates to method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more additional therapeutic agents or therapies, wherein Formula (I) is: wherein,R1is selected from optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;R2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle; each of R3, R4, R5, R6, is independently selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl;R7is selected from hydrogen and optionally substituted C1-6alkyl; wherein if R1is an optionally substituted pyrazole, R2is not piperidine.

[0059] Embodiment 2 of this disclosure relates to the method according to Embodiment 1, wherein R1is selected from optionally substituted piperidine, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substiutedf pyrrolpyrimidine, optionally substiuted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine.

[0060] Embodiment 3 of this disclosure relates to the method according to Embodiment 1, wherein R1is selected from optionally substituted piperidine, optionally substituted 2- pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine.

[0061] Embodiment 4 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted piperidine.

[0062] Embodiment 5 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted azabicyclo[3.1.0]hexane.

[0063] Embodiment 6 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted indole.

[0064] Embodiment 7 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted isoindole.

[0065] Embodiment 8 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted azetidine.

[0066] Embodiment 9 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted indazole.- 17 -

[0067] Embodiment 10 of this disclosure relates to the method according to Embodiment 1, wherein R1is optionally substituted tetrahydroisoquinoline.

[0068] Embodiment 11 of this disclosure relates to the method according to any one of the preceding embodiments, wherein R2isY1is selected from -N- and -CR10-; each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -C(O)- wherein Z5is additionallyselected from a bond; each of a, b, c, and d are independently selected from 1, 2, 3, and 4; each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R10substituents come together to form an optionally substituted heterocycle or an optionally substituted carbocycle, or R10and R11substituents come together to form an optionally substituted heterocycle; and each R11is independently selected from hydrogen and optionally substituted C1-6alkyl.

[0069] Embodiment 12 of this disclosure relates to the method according to Embodiment 1 or 2, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of one or more of the following Formula:wherein,R8is selected from halogen, -CN, and optionally substituted C1-6alkyl;R9is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and 3- to 6- membered heterocycloalkyl; n is selected from 0 to 9; each of X1, X2, and X3is independently selected from N and CR13;R12is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle, or R12comes together with R13to form an optionally substituted ring; and each R13is independently selected from hydrogen, halogen, -CN, and optionally substituted C1-6alkyl.R14is selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl, or R14and R15come together to form an optionally substituted heterocycle; andR15is selected from -S(O)2R 1166-, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl.

[0070] Embodiment 12(a) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (IA).

[0071] Embodiment 12(b) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (IB).

[0072] Embodiment 12(c) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (IC).

[0073] Embodiment 13 of this disclosure relates to the method according to Embodiment 12, wherein R2is optionally substituted heterocycle.

[0074] Embodiment 14 of this disclosure relates to the method according to Embodiment 1, wherein R2is selected from optionally substituted C3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.- 19 -

[0075] Embodiment 15 of this disclosure relates to the method according to Embodiment 1 or 14, wherein R2is substituted with -CN, -SChR2*, -NR2*, oxo, C1-3 alkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkylene-Cs-e cycloalkyl, oxetane, or azetidine, wherein R2* is selected from C1-6alkyl.

[0076] Embodiment 16 of this disclosure relates to the method according to Embodiment 1, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of one or more of the following Formula:wherein,Y1is selected from -N- and -CR10-; each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -C(O)- wherein Z5is additionallyselected from a bond; each of a, b, c, and d are independently selected from 1, 2, 3, and 4;R8is selected from halogen, -CN, and optionally substituted C1-6alkyl;R9is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and 3- to 6- membered heterocycloalkyl; n is selected from 0 to 9;X1, X2, and X3are each CH; each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R10substituents come together to form an optionally substituted heterocycle or an optionally substituted carbocycle, or R10and R11substituents come together to form an optionally substituted heterocycle; each R11is independently selected from hydrogen and optionally substituted C1-6alkyl;R16is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl;R17is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl, or R13and R14come together to form an optionally substituted heterocycle; andR18is selected from halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl.

[0077] Embodiment 16(a) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (IAA).

[0078] Embodiment 16(b) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (IBB).

[0079] Embodiment 16(c) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (ICC).

[0080] Embodiment 16(d) of this disclosure relates to the method according to Embodiment 12, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is Formula (H)D).

[0081] Embodiment 17 of this disclosure relates to the method according to Embodiment 11 or 16, wherein Y1is -N-.

[0082] Embodiment 18 of this disclosure relates to the method according to Embodiment 11 or 16, wherein Y1is -CR10-.

[0083] Embodiment 19 of this disclosure relates to the method according to Embodiment 11 or 16, wherein each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -NR11--21 -, -N(C(O)R10)-, -NS(02)Rn, -0-, and -S(0)2-, wherein Z5is additionally selected from a bond.

[0084] Embodiment 20 of this disclosure relates to method of any one of Embodiments 11 or 16 to 19, wherein each of a, b, c, and d are independently selected from 1, 2, and 3.

[0085] Embodiment 21 of this disclosure relates to the method according to Embodiment 20, wherein each of a, c, and d are independently selected from 1 and 2.

[0086] Embodiment 22 of this disclosure relates to the method of according to any one of Embodiments Il or l6 to 21, wherein each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted C1-3 alkyl, and optionally substituted C3-6 cycloalkyl.

[0087] Embodiment 23 of this disclosure relates to the method according to Embodiment 22, wherein each R10is independently selected from hydrogen, halogen, -CN, -OH, methyl, - OMe, -CH2CH2OCH3, and cyclopropyl.

[0088] Embodiment 24 of this disclosure relates the method according to any one of Embodiments 11 or 16 to 23, wherein each R11is independently selected from hydrogen and optionally substituted C1-2 alkyl.

[0089] Embodiment 25 of this disclosure relates to the method according to Embodiment 24, wherein each R11is independently selected from hydrogen, methyl, and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0090] Embodiment 26 of this disclosure relates to the method according to Embodiment 1, wherein R1is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole.

[0091] Embodiment 27 of this disclosure relates to the method according to Embodiment 26, wherein R1is selected from optionally substituted azabicyclo[3.1.0]hexane, and optionally substituted isoindole.

[0092] Embodiment 28 of this disclosure relates to the method according to Embodiment 26 or 27, wherein R1is substituted with -SO2R1* or C1-3 alkyl, wherein Rlais selected from C1-6 alkyl.

[0093] Embodiment 29 of this disclosure relates to the method according to any one of Embodiments 1, 2, 26, 27 or 28, wherein R2is selected from optionally substituted heterocycle and optionally substituted cycloalkyl.

[0094] Embodiment 30 of this disclosure relates to the method according to Embodiment 29, wherein R2is optionally substituted heterocycloalkyl.

[0095] Embodiment 31 of this disclosure relates to the method according to Embodiment 30, wherein R2is selected from optionally substituted 3- to 6- membered heterocycloalkyl.

[0096] Embodiment 32 of this disclosure relates to the method according to Embodiment 31, wherein R2is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, and optionally substituted morpholine.

[0097] Embodiment 33 of this disclosure relates to the method according to any one of Embodiments 29 to 32, wherein R2is substituted with halogen, -SChR2*, -NR2*, -C(O)CH3, - CN, optionally substituted 3- to 6- membered hterocycloalkyl, optionally substituted C3-5 carbocycle, oxo, and optionally substituted C1-3 alkyl, wherein R2* is selected from C1-6 alkyl.

[0098] Embodiment 34 of this disclosure relates to the method according to Embodiment 32, wherein R2is substituted with fluoro, -SO2Me, oxo, and methyl.

[0099] Embodiment 35 of this disclosure relates to the method according to any one of Embodiments 1-10, 12, or 29, wherein R2is selected from- 23

[0100] Embodiment 36 of this disclosure relates to the method according to Embodiment 35, wherein R2is selected from

[0101] Embodiment 37 of this disclosure relates to the method according to any one ofEmbodiments 1-10 or 12, wherein R2is optionally substituted heterocycloalkyl.

[0102] Embodiment 38 of this disclosure relates to the method according to any one of the preceding embodiments, wherein R3is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

[0103] Embodiment 39 of this disclosure relates to the method according to Embodiment 38, wherein R3is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0104] Embodiment 40 of this disclosure relates to the method according to Embodiment 38, wherein R3is selected from hydrogen, fluoro, and -CN.

[0105] Embodiment 41 of this disclosure relates to the method according to the method according to Embodiment 40, wherein R3is selected from hydrogen and -CN.

[0106] Embodiment 42 of this disclosure relates to the method according to any one of the preceding embodiments, wherein R4is selected from hydrogen, halogen, -CN, optionally substituted Ci alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

[0107] Embodiment 43 of this disclosure relates to the method according to Embodiment 42, wherein R4is selected from hydrogen, -CN, -CHF2, -CF3, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0108] Embodiment 44 of this disclosure relates to the method according to Embodiment 43, wherein R4is selected from hydrogen, -CN and -CHF2

[0109] Embodiment 45 of this disclosure relates to the method according to any one of the preceding embodiments, wherein R5is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

[0110] Embodiment 46 of this disclosure relates to the method according to Embodiment 45, wherein R5is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0111] Embodiment 47 of this disclosure relates to the method according to Embodiment 46, wherein R5is hydrogen.

[0112] Embodiment 48 of this disclosure relates to the method according to any one of the preceding embodiments wherein R6is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

[0113] Embodiment 49 of this disclosure relates to the method according to Embodiment 48, wherein R6is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0114] Embodiment 50 of this disclosure relates to the method according to Embodiment 49, wherein R6is hydrogen.

[0115] Embodiment 51 of this disclosure relates to the method according to any one of the preceding embodiments, wherein R7is hydrogen.

[0116] Embodiment 52 of this disclosure relates to the method according to Embodiment 1, wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the compounds in Table I.

[0117] Embodiment 53 of this disclosure relates to the method according to Embodiment 12, wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the compounds in Table I.

[0118] Embodiment 54 of this disclosure relates to the method according to Embodiment 16, wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the compounds in Table I.

[0119] Embodiment 55 of this disclosure relates to the method according to any one of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that further comprises one or more pharmaceutically acceptable excipients.

[0120] Embodiment 56 of this disclosure relates to the method according to any one of the preceding embodiments, wherein the one or more agents are selected from the group consisting of a platinum compound, a taxane, apigenin, a Wee-1 inhibitor, a PRMT5-inhibitor, an MDM2 inhibitor, a Src inhibitor, a Raf inhibitor, a MEK inhibitor, an XP01 inhibitor, a vitamin D analog, a type-I TGF-b receptor inhibitor, a TRK inhibitor, a tankyrase inhibitor, a senolytic agent, a RET inhibitor, a proteosome inhibitor, a menin inhibitor, an LC 3-KAT inhibitor, a KIT inhibitor, a KIFC inhibitor, an IGF-1R inhibitor, an HIF-2 alpha inhibitor, an HER2 antibody drug conjugate, a heat shock protein, an HDAC inhibitor, a GLI1 inhibitor, a F0XM1 inhibitor, an EZH2 inhibitor, an estrogen receptor antagonist, an estrogen receptor alpha antagonist, an elF4A inhibitor, a dihydrofolate reductase inhibitor, a CD73 inhibitor, a BTK inhibitor a BMI inhibitor, a beta-catenin inhibitor, a CBP / p300 dual inhibitor, an ALDH1 A3 inhibitor, a dual c-Met / Trk inhibitor, an antrogen receptor inhibitor, a Bcl-2 inhibitor, glyoxalase 1 inhibitor, a KIFC1 inhibitor, a USP10 inhibitor, an antioxidant defense inhibitor, RANKL inhibitor, a FLT3 inhibitor, a notch inhibitor, a BRAF inhibitor, a HER2 inhibitor, an eIF4A inhibitor, SHP2 inhibitor, an ERK1 / 2 inhibitor, an EGFR inhibitor, an IKK beta inhibitor, a PAK inhibitor, a steroid, a steroidogenesis inhibitor, a KIT D816V inhibitor, BET inhibitor, a PI3K inhibitor, an mTOR inhibitor, an FGFR inhibitor, a pan- ERBB inhibitor, an ALK-inhibitor, an anti-PD-1 monoclonal antibody, an anti-PD-Ll monoclonal antibody, an autophagy inhibitor, a YAP -inhibitor, an androgen receptor inhibitor, a PARP inhibitor, a F0XM1 inhibitor, an aromatase inhibitor, a CDK2 inhibitor, a CDK4 inhibitor, and a CDK4 / 6 inhibitor.

[0121] Embodiment 57 of this disclosure relates to a method of treating a disease or condition according to any one of the preceding Embodiments, wherein the one or more agents are selected from the group consisting of mTOR inhibitors, PI3K inhibitors, PARP inhibitors, Her2 antibody drug conjugates, and Trop2 antibody drug conjugates.Embodiment 58 of this this disclosure relates to a method of treating a disease or condition according to any one of the preceding Embodiments, wherein the method further comprises hormone therapy.

[0122] Embodiment 59 of this disclosure relates to the method according to any one of Embodiments 1-55, wherein the one or more additional therapeutic agents are selected from the group consisting of caiboplatin, cisplatin, oxaliplatin, nedaplatin, phenanthriplatin, lobaplatin, enloplatin, paclitaxel, docetaxel, apigenin, adavosertib, pemrametosta, AZDI 775, inecalcitol, SNDX-50469, NVP-CGM097, idasanutlin, nutlin-3, siremadlin, brigimadlin, saracatinib, bosutinib, dasatinib, sorafenib, trametinib, binimetinib, cobimetinib, KPT-330, SB-505124, entrectinib, MSC2504877, alectinib. bortezomib, selumetinib, PD0325901, trimetazidine, midostaurin, avapritinib, nintedanibispinesib, SR31527, ganitumab, NVP- AEW541, PT2399, T-DM1, SHetA2, tucidinostat, suberanilohydroxamic acid, vorinostat,valproate, GANT61, NB55, NB73, NB115AQB, lasofoxifene, CR-1-31-B, celastrol, gambogic acid, pralatrexate, ibrutinib, tirabrutinib, PTC-209, ICG-001, NEO2734, N,N- diethylaminobenzaldehyde, altiratinib, seviteronel, RAD 140, MLN0128, temsirolimus, sapanisertib, navitoclax, venetoclax, BBGC, ispinesib, spautin-1, auranofin, neratinib, pyrotinib, tucatinib, OPG-Fc, quizartinib, CB-103, encorafenib, vemurafenib, dabrafenib, trastuzumab, CR-1-31-B, TNO155, SCH772984, LY3214996, cetuximab, PF-0647775, erlotinib, Bay 11-7082, PF03758309, progesterone, mitotane, midostaurin, avapritinib, JQ1, ZEN-3694, ARV-825, alpelisib, pictilisib, vistusertib, everolimus, infigratinib, LY2874455, rogaratinib, BLU9931, H3B-6527, FIIN-2, FUN-3, lenvatinib, ponatinib, regorafenib. Pemigatinib, buparlisib, paxalisib, futibatinib, infigratinib, afatinib, ceritinib, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, hydroxychloroquine, chloroquine, verteporfin, pyrvinium pamoate, enzalutamide, N-desmethyl enzalutamide, darolutamide, apalutamide, ralaniten, EPI-7170, abiraterone, bafilomycin Al, albendazole, letrozole, fulvestrant, olaparib, talazoparib, NB55, NB73, NB115, gedatolisib, eribulin, temozolomide, cytarabine, doxorubicin, gemcitabine, pemetrexed, dexamethasone, L- asparaginase, vincristine, 5-FU, sunitinib, and irinotecan.

[0123] Embodiment 60 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of vistusertib, MLN0128, alpelisib, buparlisib, paxalisib, gedatolisib, pictilisib, talazoparib, laparib, T-DM1, sacituzumab govtecan, and datopotamab deruxtecan.

[0124] Embodiment 61 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of caiboplatin, cisplatin, oxaliplatin, nedaplatin, phenanthriplatin, lobaplatin, and enloplatin.

[0125] Embodiment 62 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of paclitaxel and docetaxel.

[0126] Embodiment 63 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents is apigenin.

[0127] Embodiment 64 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeuticagents are selected from the group consisting of adavosertib, pemrametosta, nutlin-3, saracatinib, and dasatinib.

[0128] Embodiment 65 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of sorafenib, trametinib, cobimetinib, alpelisib, pictilisib, vistusertib, and irinotecan.

[0129] Embodiment 66 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of FHN-2, FHN-3, lenvatinib, ponatinib, regorafenib, pemigatinib, futibatinib, and infigratinib.

[0130] Embodiment 67 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of afatinib and ceritinib.

[0131] Embodiment 68 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

[0132] Embodiment 69 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of hydroxychloroquine, verteporfin, and olaparib.

[0133] Embodiment 70 of this disclosure relates to a method of treating a disease or condition according to Embodiment 59, wherein the one or more additional therapeutic agents are selected from the group consisting of enzalutamide, N-desmethyl enzalutamide, darolutamide, apalutamide, and abiraterone.

[0134] Embodiment 71 of this disclosure relates to the method according to any one of Embodiments 1-55, wherein the therapy is radiotherapy or ultrasound therapy.

[0135] Embodiment 71(a) relates to the method according to Embodiment 71, wherein the therapy is radiotherapy.

[0136] Embodiment 71(b) relates to the method according to Embodiment 71, wherein the therapy is ultrasound therapy.

[0137] Embodiment 72 of this disclosure relates to the method according to any one of the preceding embodiments, wherein the disease or condition is cancer.

[0138] Embodiment 73 of this disclosure relates to the method according to Embodiment 72, wherein the cancer is a solid tumor.

[0139] Embodiment 74 of this disclosure relates to the method according to Embodiment 72, wherein the cancer is ovarian cancer, pancreatic cancer, bladder cancer, brain cancer, sarcoma, melanoma, lung cancer, urothelial carcinoma mantle cell lymphoma, large B-cell lymphoma, leukemia, colorectal cancer, adenocarcinoma, adrenocortical carcinoma, breast cancer, medulloblastoma, cholangiocarcinoma, glioma, esophageal squamous cell carcinoma, meningioma, Ewing sarcoma, well-differentiated liposarcoma, dedifferentiated liposarcoma, clear cell renal cell carcinoma, lung squamous cell carcinoma, endometrial cancer, gastric cancer, pediatric astrocytoma, rare pediatric undifferentiated sarcoma, mastocytosis, glioblastoma, glioblastoma multiforme, esophageal carcinoma, thyroid cancer, neuroblastoma, colon cancer, rectal cancer, esophageal carcinoma, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, well-differentiated liposarcoma, dedifferentiated liposarcoma, advanced dedifferentiated liposarcoma, leiomyosarcoma, neuroendocrine tumor, peripheral nerve sheath tumors, pediatric cancer, mesothelioma, myeloma, chordomas, bladder cancer, nasopharyngeal carcinoma, cervical cancer, testicular germ cell tumors, brain metastasis, head and neck squamous cell carcinoma, oral squamous cell carcinoma, osteosarcoma, or prostate cancer.

[0140] Embodiment 75 of this disclosure relates to a method of treating a disease or condition according to Embodiment 74, wherein the cancer is metastatic triple-negative breast cancer, non-small cell lung cancer, small cell lung cancer, metastatic urothelial carcinoma, HR+ HER2- metastatic breast cancer, colorectal cancer, esophageal carcinoma, endometrial cancer, pancreatic ductal adenocarcinoma, castrate-resistant prostate cancer, epithelial ovarian cancer, gastric adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, cervical cancer, or renal cell carcinoma.

[0141] Embodiment 76 of this disclosure relates to a method of treating a disease or condition according to Embodiment 74, wherein the cancer is osteosarcoma, glioma, cholangiocarcinoma, glioblastoma, head and neck squamous cell carcinoma, medulloblastoma, advanced dedifferentiated liposarcoma, leiomyosarcoma, chordomas, breast cancer, or pediatric cancer.

[0142] Embodiment 77 of this disclosure relates to a method of treating a disease or condition according to Embodiment 74, wherein the cancer is medulloblastoma, head and neck squamous cell cancer, chorodomas, mesothelioma, colorectal cancer, chordomas,-medulloblastoma, pancreatic ductal adenocarcinoma, thyroid cancer, or oral squamous cell carcinoma.

[0143] Embodiment 78 of this disclosure relates to a method of treating a disease or condition according to Embodiment 74, wherein the cancer is colorectal cancer, prostate cancer, castration-resistant prostate cancer, or neuroendocrine prostate cancer.

[0144] Embodiment 79 of this disclosure relates to the method according to any one of the preceding embodiments wherein the compound inhibits CDK 2, CDK 4, CD6, or any combination thereof.

[0145] Embodiment 80 of this disclosure relates to the method according to Embodiment 79, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK 2 / 4 / 6.

[0146] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a platinum compound. Non-limiting examples of platinum compounds include caiboplatin, cisplatin oxaliplatin, nedaplatin, phenanthriplatin, loboplatin, and enloplatin. In another embodiment, the additional therapeutic agent is a platinum compound, and the disease or condition that is treated is mesothelioma (such as, for example, malignant pleural mesothelioma), non-small cell lung cancer, triple-negative breast cancer, testicular germ cell tumors, cervical cancer or ovarian cancer.

[0147] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a taxane. Non-limiting examples of taxanes include paclitaxel and docetaxel. In another embodiment, the additianl agent is a taxane, and the disease or condition that is treated is pancreatic cancer, squamous cell lung cancer, breast cancer, cervical cancer, prostate cancer (such as, for example, castration-resistant prostate cancer), or ovarian cancer.

[0148] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is Apigenin. In another embodiment, the additional therapeutic agent is a taxane, and the disease or condition that is treated is bladder cancer.

[0149] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a Wee-1 inhibitor. Non-limiting examples of Wee- 1 inhibitors include adavosertib and AZD1775. In another embodiment the additional therapeutic agent is a Wee- 1 inhibitors, and the disease or condition that is treated is sarcoma or breast cancer (such as, for example, HR+ Breast Cancer).

[0150] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a PRMT5 inhibitor. Non-limiting examples of PRMT5 inhibitors include Pemrametosta. In another embodiment the additional therapeutic agent is a PRMT5 inhibitor,- 32 -and the disease or condition that is treated is melanoma, breast cancer, pancreatic cancer, or esophageal carcinoma.

[0151] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an MDM2 inhibitor (such as, for example, a p53-MDM2 inhibitor). Nonlimiting examples of MDM2 inhibitors include nutlin-3, NVP-CGM097, idasanutlin, siremadlin, and brigimadlin. In another embodiment, the additional therapeutic agent is an MDM2 inhibitor, and the disease or condition that is treated is melanoma, ER+ breast cancer, well-differentiated liposarcoma, or dedifferentiated liposarcoma.

[0152] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a Src inhibitor. Non-limiting examples of Src inhibitors include saracatinib and bosutinib. In another embodiment, the additional therapeutic agent is a Src inhibitor, and the disease or condition that is treated is colorectal cancer, or breast cancer.

[0153] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a Raf inhibitor. Non-limiting examples of Raf inhibitors include Sorafenib. In another embodiment, the additional therapeutic agent is a Raf inhibitor, and the disease or condition that is treated is breast cancer, such as, for example, tripe-negative breast cancer.

[0154] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a MEK inhibitor optionally in combination with a BRAF inhibitor. Nonlimiting examples of MEK inhibitors include selumetinib, PD0325901, trametinib, binimetinib, and cobimetinib. In another embodiment, the additional therapeutic agent is a MEK inhibitor, and the disease or condition that is treated is a neuroendocrine tumor, neuroblastoma, melanoma (such as, for example NRAS mutant melanoma), head and neck cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, non-sall cell lung cancer (such as KRAS-mutant non-small cell lung cancer or RAS-mutant non-small cell lung cancer), thyroid cancer, colon cancer (such as, for example, KRAS mutant colon cancer), or prostate cancer.

[0155] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a PI3K inhibitor. Non-limiting examples of PI3K inhibitors include alpelisib, buparlisib, paxalisib, gedatolisib, and pictilisib. In another embodiment, the additional therapeutic agent is a PI3K inhibitor, and the disease or condition that is treated is medulloblastoma, NUT midline carcinoma, neuroendocrine tumors, chordomas, pancreatic neuroendocrine neoplasms or breast cancer (such as, for example, triple-negative breast cancer, metastatic triple-negative breast cancer, hormone-receptor positive breast cancer,HER2 negative breast cancer, or estrogen receptor positive breast cancer), head and neck squamous cell carcinoma, mesothelioma (such as, for example, malignant pleural mesothelioma), colorectal cancer, chordomas, medulloblastoma, pancreatic ductal adenocarcinoma, thyroid cancer, oral squamous cell carcinoma, or non-keratyinizaing nasopharyngeal carcinoma.

[0156] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include vistusertib, MLN0128, temsirolimus, sapanisertib, rapamycin, and everlolimus. In another embodiment, the additional therapeutic agent is an mTOR inhibitor, and the disease or condition that is treated is osteosarcoma, glioma (such as, for example, diffuse intrinsic pontine glioma), cholangiocarcinoma, glioblastoma, head and neck squamous cell carcinoma, medulloblastoma, advanced dedifferentiated liposarcoma (DDL), leiomyosarcoma (LMS), chordomas, breast cancer (such as, for example, triple-negative cancer, estrogen receptor positive (ER+) breast cancer, or hormone-receptor positive breast cancer), or pediatric cancer (children with recurrent or refractory malignancies).

[0157] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an FGFR inhibitor. Non-limiting examples of FGFR inhibitors include infigratinib, LY2874455, rogaratinib, BLU9931, H3B-6527, FIIN-2, FIIN-3, lenvatinib, ponatinib, regorafenib, dovitinib, lucitanib, cediranib, intedanib, and brivanib. In another embodiment the additional therapeutic agent is an FGFR inhibitor, and the disease or condition that is treated is lung squamous cell carcinoma, advanced dedifferentiated liposarcoma, leiomyosarcoma, hepatocellular carcinoma, hepatoblastoma, or breast cancer, such as, for example, triple-negative cancer and hormone-receptor positive breast cancer.

[0158] In other embodiments of the methods of treatment of this disclosure, additional therapeutic agent is a pan-ERBB inhibitor. Non-limiting examples of pan-ERBB inhibitors include afatinib. In another embodiment, the additional therapeutic agent is a pan-ERBB inhibitor, and the disease or condition that is treated is esophageal carcinoma.

[0159] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an ALK-inhibitor. Non-limiting examples of ALK-inhibitor inhibitors include ceritinib. In another embodiment, the additional therapeutic agent is an ALK- inhibitor, and the disease or condition that is treated is non-small cell lung cancer or neuroblastoma.

[0160] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an anti-PD-1 or an anti-PD-Ll monoclonal antibody either of which is- 34 -optionally in further combination with a CTLA4 antibody. Non-limiting examples of anti- PD-1 monoclonal antibodies include pembrolizumab, nivolumab, cemiplimab. Non-limiting examples of anti-PD-Ll monoclonal antibodies include atezolizumab, avelumab, and durvalumab. In another embodiment, the additional therapeutic agent is an anti-PD-1 or anti- PD-Ll monoclonal antibody, and the disease or condition that is treated is breast cancer (such as, for example, hormone receptor positive breast cancer, hormone receptor positive metastatic breast cancer, or HER2 negative breast cancer), bladder cancer, melanoma, brain metastasis, head and neck squamous cell carcinoma, or colon cancer.

[0161] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an autophagy inhibitor. Non-limiting examples of autophagy inhibitors include chloroquine or hydroxychloroquine. In another embodiment, the additional therapeutic agent is an autophagy inhibitor, and the disease or condition that is treated is acute myeloid leukemia, pancreatic ductal adenocarcinoma or breast cancer, such as, for example, hormone-receptor positive breast cancer.

[0162] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a YAP-inhibitor. Non-limiting examples of YAP-inhibitors include verteporfm, pyrivinium pamoate, and CA3. In another embodiment, the additional therapeutic agent is a YAP-inhibitor, and the disease or condition that is treated is pancreatic cancer or esophageal carcinoma.

[0163] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an androgen receptor inhibitor. Non-limiting examples of androgen receptor inhibitors include enzalutamide, N-desmethyl enzalutamide, darolutamide, apalutamide, ralaniten, EPI-7170, and abiraterone. In another embodiment, the additional therapeutic agent is an androgen receptor inhibitor and the disease or condition that is treated is prostate cancer, breast cancer (such as, for example, CDK4 / 6 resistant breast cancer or androgen receptor positive breast cancer), lung cancer (such as, for example, non-small cell lung cancer), liver cancer (such as, for example, hepatocellular carcinoma), kidney cancer, bladder cancer or ovarian cancer.

[0164] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a PARP inhibitor. Non-limiting examples of PARP inhibitors include talazoparib and olaparib. In another embodiment, the additional therapeutic agent is a PARP inhibitor and the disease or condition that is treated is colon cancer (colorectal cancer), prostate cancer, such as, for example, castration-resistant prostate cancer, and neuroendocrine prostate cancer.- 35 -

[0165] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include irinotecan, eribulin, temozolomide, cytarabine, doxorubicin, gemcitabine, pemetrexed, dexamethasone, L-asparaginase, vincristine, and 5-FU. In another embodiment, the additional therapeutic agent is a chemotherapeutic agent and the disease or condition that is treated is rectal cancer, colon cancer (such as, for example, colorectal cancer with a PI3K mutation), medulloblastoma, lung adenocarcinoma, prostate cancer (such as, for example, castration resistant prostate cancer with a PI3K mutation, HPV-negative cervical cancer, colon cancer (colorectal cancer), acute myeloid leukemia, brain cancer, osteosarcoma, pancreatic cancer (such as, for example, pancreatic ductal adenomcarcinoma), gastric cancer, head and neck squamous cell carcinoma, breast cancer (such as, for example, advanced breast cancer or metastatic breast cancer), rectal cancer, or colon cancer (such as, for example, colorectal cancer with ah PI3K mutation).

[0166] In other embodiments of the methods of treatment of this disclosure, the additional therapy is radiotherapy. In another embodiment, the additional therapy is radiotherapy and the disease or condition that is treated is glioma (such as, for example, diffuse intrinsic pontine gliomas or diffuse midline glioma), esophageal squamous cell carcinoma, meningioma, head and neck squamous cell carcinoma, metastatic breast cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, glioblastoma multiforme, or medulloblastoma.

[0167] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a FOXM1 inhibitor. Non-limiting examples of FOXM1 inhibitors include NB55, NB73 and NB115. In another embodiment, the additional therapeutic agent is a FOXM1 inhibitor and the disease or condition that is treated is ER+ breast cancer or triplenegative breast cancer.

[0168] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a BET inhibitor optionally in combination with a taxane. Non-limiting examples of BET inhibitors include JQ1, ZEN-3694, and ARV-825. In another embodiment, the additional therapeutic agent is a BET inhibitor and the disease or condition that is treated is triple negative breast cancer, NUT midline carcinoma, large B-cell lymphoma, gastric cancer, estrogen receptor positive breast cancer or medulloblastoma.

[0169] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a KIT D816V inhibitor. Non-limiting examples of KIT D816V inhibitors include midostaurin and avapritinib. In another embodiment, the additional therapeutic agent- 36is a KIT D816V inhibitor and the disease or condition that is treated is mastocytosis such as, for example, advanced systemic mastocytosis.

[0170] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a steroidogenesis inhibitor. Non-limiting examples of steroidogenesis inhibitors include mitotane. In another embodiment, the additional therapeutic agent is a steroidogenesis inhibitor and the disease or condition that is treated is adrenocortical carcinoma.

[0171] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a steroid. Non-limiting examples of steroidogenesis inhibitors include progesterone. In another embodiment, the additional therapeutic agent is a steroid and the disease or condition that is treated is adrenocortical carcinoma.

[0172] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a PAK inhibitor. Non-limiting examples of PAK inhibitors include PF03758309. In another embodiment, the additional therapeutic agent is a PAK inhibitor and the disease or condition that is treated is non-small cell lung cancer.

[0173] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an IKK beta inhibitor. Non-limiting examples of IKK beta inhibitors include Bay 11-7082. In another embodiment, the additional therapeutic agent is an IKK beta inhibitor and the disease or condition that is treated is hepatoblastoma, hepatocellular carcinoma, KRAS mutated lung cancer, or KRAS mutated colon cancer.

[0174] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an EGFR inhibitor. Non-limiting examples of EGFR inhibitors include cetuximab, , PF-0647775, afatinib, and erlotinib. In another embodiment, the additional therapeutic agent is an EGFR inhibitor and the disease or condition that is treated is non- small cell lung cancer, triple-negative breast cancer, glioblastoma, nasopharyngeal carcinoma, chordoma, KRAS mutated lung cancer or KRAS mutated colon cancer.

[0175] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an ERK1 / 2 inhibitor. Non-limiting examples of ERK1 / 2 inhibitors include SCH772984 and LY3214996. In another embodiment, the additional therapeutic agent is an ERK1 / 2 inhibitor and the disease or condition that is treated is a neuroendocrine tumor or a peripheral nerve sheath tumor (such as, for example, NF 1 -associated plexiform neurofibroma).

[0176] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a SHP2 ples of SHP2 inhibitors includeTNO155. In another embodiment, the additional therapeutic agent is a SHP2 inhibitor and the disease or condition that is treated is lung cancer or castration-resistant prostate cancer.

[0177] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an eIF4A inhibitor. Non-limiting examples of eIF4A inhibitors include CR-1-31-B. In another embodiment, the additional therapeutic agent is an eIF4A inhibitor and the disease or condition that is treated is estrogen receptor positive breast cancer and KRAS-mutant non-small cell lung cancer.

[0178] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a BRAF inhibitor optionally in combination with a MEK inhibitor. Nonlimiting examples of BRAF inhibitors include encorafenib, vemurafenib, and dabrafenib. In another embodiment, the additional therapeutic agent is a BRAF inhibitor and the disease or condition that is treated is thyroid cancer (such as, for example, papillary thyroid cancer or advanced thyroid cancer), BRAF-mutant melanoma, NRAS mutant melanoma, native melanoma, leukemia, neuroblastoma, pediatric astrocytoma, BRAF-mutant colon cancer, or BRAF-mutant non-small cell lung cancer.In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a notch inhibitor. Non-limiting examples of Notch inhibitors include CB- 103. In another embodiment, the additional therapeutic agent is a Notch inhibitor and the disease or condition that is treated is estrogen receptor positive breast cancer.

[0179] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a FLT-3 inhibitor. Non-limiting examples of FLT-3 inhibitors include quizartinib. In another embodiment, the additional therapeutic agent is a FLT-3 inhibitor and the disease or condition that is treated is acute myeloid leukemia.

[0180] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a RANKL inhibitor. Non-limiting examples of RANKL inhibitors include OPG-Fc. In another embodiment, the additional therapeutic agent is a RANKL inhibitor and the disease or condition that is treated is luminal breast cancer.

[0181] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an HER2 inhibitor optionally in combination with estrogen therapy, chemotherapy, or homone receptor therapy. Non-limiting examples of HER2 inhibitors include neratinib, pyrotinib, T-DM1, trastuzumab and tucatinib. In another embodiment, the additional therapeutic agent is an HER2 inhibitor and the disease or condition that is treated is EibB2+ gastric cancer, hormone receptor positive breast cancer EibB2+ breast cancer, or HER2+ breast cancer.

[0182] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an antioxidant defense inhibitor. Non-limiting examples of antioxidant defense inhibitors include auranofm. In another embodiment, the additional therapeutic agent is an antioxidant defense inhibitor and the disease or condition that is treated is mesothelioma.

[0183] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a USP10 inhibitor. Non-limiting examples of USP10 inhibitors include spautin-1. In another embodiment, the additional therapeutic agent is a USP10 inhibitor and the disease or condition that is treated is myeloma.

[0184] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a KIFC1 inhibitor. Non-limiting examples of KIFC1 inhibitors include ispinesib and SR31527. In another embodiment, the additional therapeutic agent is aKIFCl inhibitor and the disease or condition that is treated is bladder cancer.

[0185] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a glyoxalase 1 inhibitor. Non-limiting examples of glyoxalase 1 inhibitors include BBGC. In another embodiment, the additional therapeutic agent is a glyoxalase 1 inhibitor and the disease or condition that is treated is chronic lymphocytic leukemia.

[0186] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a Bcl-2 inhibitor optionally in combination with a hypomethylation agent, such as, for example, azacitidine. Non-limiting examples of Bcl-2 inhibitors include venetoclax and navitoclax. In another embodiment, the additional therapeutic agent is a Bcl-2 inhibitor and the disease or condition that is treated is breast cancer (such as, for example, triple-negative breast cancer or ER+ breast cancer), or acute myeloid leukemia.

[0187] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a dual c-Met / Trk inhibitor. Non-limiting examples of dual c-Met / Trk inhibitors include altiratinib. In another embodiment, the additional therapeutic agent is a dual c-Met / Trk inhibitor and the disease or condition that is treated is glioblastoma.

[0188] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an ALDH1 A3 inhibitor. Non-limiting examples of ALDH1A3 inhibitors include N,N-diethylaminobenzaldehyde. In another embodiment, the additional therapeutic agent is a dual c-Met / Trk inhibitor and the disease or condition that is treated is glioblastoma.

[0189] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an antrogen receptor inhibitor. Non-limiting examples of antrogenreceptor inhibitors include seviteronel and RAD140. In another embodiment, the additional therapeutic agent is an antrogen receptor inhibitor and the disease or condition that is treated is breast cancer (such as, for example, ER+ breast cancer or triple negative breast cancer.

[0190] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an aromatase inhibitor. Non-limiting examples of aromatase inhibitors include letrozole and fiilvestrant. In another embodiment, the additional therapeutic agent is an aromatase inhibitor and the disease or condition that is treated is endometrial cancer, cystic brain metastases, or breast cancer (such as, for example, HER2 negative breast cancer).

[0191] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a BET-CBP / p300 dual inhibitor. Non-limiting examples of BET- CBP / p300 dual inhibitors include NEO2734. In another embodiment, the additional therapeutic agent is a BET-CBP / p300 dual inhibitor and the disease or condition that is treated is breast cancer or prostate cancer. This combination may involve overcoming resistance of CDK4 / 6 inhibitors.

[0192] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a beta-catenin inhibitor. Non-limiting examples of beta-catenin inhibitors include ICG-001. In another embodiment, the additional therapeutic agent is a beta-catenin inhibitor and the disease or condition that is treated is endocrine-resistant breast cancer.

[0193] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a BMI inhibitor. Non-limiting examples of BMI inhibitors include PTC- 209. In another embodiment, the additional therapeutic agent is a BMI inhibitor and the disease or condition that is treated is breast cancer, colon cancer or prostate cancer.

[0194] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib and tirabrutinib. In another embodiment, the additional therapeutic agent is a BTK inhibitor and the disease or condition that is treated is mantle cell lymphoma or diffuse large B-cell lymphoma.

[0195] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a CD73 inhibitor. Non-limiting examples of CD73 inhibitors include AB680. In another embodiment, the additional therapeutic agent is a CD73 inhibitor and the disease or condition that is treated is colorectal cancer.

[0196] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a dihydrofolate reductase inhibitor. Non-limiting examples of dihydrofolate reductase inhibitors include pralatrexate. In another embodiment, the additional-40 -therapeutic agent is a dihydrofolate reductase inhibitor and the disease or condition that is treated is bladder cancer.

[0197] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an elF4A inhibitor. Non-limiting examples of elF4A inhibitors include CR-1-31-B. In another embodiment, the additional therapeutic agent is an elF4A inhibitor and the disease or condition that is treated is ER+ breast cancer or KRAS-mutant non-small cell lung cancer.

[0198] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an estrogen receptor antagonist. Non-limiting examples of estrogen receptor antagonists include lasofoxifene. In another embodiment, the additional therapeutic agent is an estrogen receptor antagonist and the disease or condition that is treated is endometrial cancer, such as, for example, ER+ recurrent endometrial cancer.

[0199] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an estrogen receptor alpha antagonist. Non-limiting examples of estrogen receptor alpha antagonists include celastrol and gambogic acid. In another embodiment, the additional therapeutic agent is an estrogen receptor alfa antagonist and the disease or condition that is treated is breast cancer, such as, for example, breast cancer with an estrogen receptor alpha Y537S mutation.

[0200] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an EZH2 inhibitor. Non-limiting examples of EZH2 inhibitors include AQB. In another embodiment, the additional therapeutic agent is an EZH2 inhibitor and the disease or condition that is treated is glioblastoma.

[0201] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an F0XM1 inhibitor. Non-limiting examples of F0XM1 inhibitors include NB55, NB73 and NB115. In another embodiment, the additional therapeutic agent is an F0XM1 inhibitor and the disease or condition that is treated is ER+ triple negative breast cancer.

[0202] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a GLI1 inhibitor. Non-limiting examples of GLI1 inhibitors include GANT61. In another embodiment, the additional therapeutic agent is a GLI1 inhibitor and the disease or condition that is treated is acute myeloid leukemia.

[0203] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an HD AC inhibitor. Non-limiting examples of HD AC inhibitors include tucidinostat, suberanilohydroxamic acid, vorinostat, and valproate. In another embodiment,the additional therapeutic agent is an HDAC inhibitor and the disease or condition that is treated is HR+ breast cancer, nasopharyngeal carcinoma, or mantle cell lymphoma.

[0204] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a heat shock protein which is also referred to as a chaperone inhibitor. Non-limiting examples of heat shock proteins include ShetA2. In another embodiment, the additional therapeutic agent is a heat shock protein and the disease or condition that is treated is cervical cancer.

[0205] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an HER2 antibody drug conjugate (ADC). Non-limiting examples of HER2 ADCs include T-DM1. In another embodiment, the additional therapeutic agent is an HER2 ADC and the disease or condition that is treated is HER2+ breast cancer.

[0206] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an HIF-2 alpha inhibitor. Non-limiting examples of HIF-2 alpha inhibitors include PT2399. In another embodiment, the additional therapeutic agent is a HIF- 2 alpha inhibitor and the disease or condition that is treated is clear cell renal cell carcinoma.

[0207] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an IGF-1R inhibitor. Non-limiting examples of IGF-1R inhibitors include ganitumab and NVP-AEW541. In another embodiment, the additional therapeutic agent is an IGF-1R inhibitor and the disease or condition that is treated is Ewing sarcoma, well- differentiated liposarcoma, or dedifferentiated liposarcoma.

[0208] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a KIFC inhibitor. Non-limiting examples of KIFC inhibitors include ispinesib and SR31527. In another embodiment, the additional therapeutic agent is a KIFC inhibitor and the disease or condition that is treated is bladder cancer.

[0209] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a KIT inhibitor. Non-limiting examples of KIT inhibitors include midostaurin, avapritinib, and nintedanib. In another embodiment, the additional therapeutic agent is a KIT inhibitor and the disease or condition that is treated is mastocytosis, such as, for example, advanced systemic mastocytosis.

[0210] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a menin inhibitor. Non-limiting examples of menin inhibitors include SNDX-50469. In another embodiment, the additional therapeutic agent is a menin inhibitor and the disease or condition that is treated is acute myeloid leukemia.

[0211] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an LC 3 -KAT inhibitor. Non-limiting examples of LC 3-KAT inhibitors include trimetazidine. In another embodiment, the additional therapeutic agent is an LC 3- KAT inhibitor and the disease or condition that is treated is triple negative breast cancer.

[0212] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a proteosome inhibitor. Non-limiting examples of proteosome inhibitors include bortezomib. In another embodiment, the additional therapeutic agent is a proteosome inhibitor and the disease or condition that is treated is multiple myeloma or mantle cell lymphoma.

[0213] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a RET inhibitor. Non-limiting examples of RET inhibitors include alectinib. In another embodiment, the additional therapeutic agent is a RET inhibitor and the disease or condition that is treated is RET fusion positive non-small cell lung cancer or metastatic medullary thyroid cancer.

[0214] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a synolytic . Non-limiting examples of RET inhibitors include alectinib. In another embodiment, the additional therapeutic agent is a RET inhibitor and the disease or condition that is treated is RET fusion positive non-small cell lung cancer or metastatic medullary thyroid cancer.

[0215] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a senolytic agent. Non-limiting examples of senolytic agents include navitoclax. In another embodiment, the additional therapeutic agent is a synolytic agent and the disease or condition that is treated is triple negative breast cancer or head and neck squamous cell carcinoma.

[0216] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a tankyrase inhibitor. Non-limiting examples of tankyrase inhibitors include MSC2504877. In another embodiment, the additional therapeutic agent is a tankyrase inhibitor and the disease or condition that is treated is colon cancer, such as, for example, APC mutant colon cancer.

[0217] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a TRK inhibitor. Non-limiting examples of TRK inhibitors include entrectinib. In another embodiment, the additional therapeutic agent is a TRK inhibitor and the disease or condition that is treated is glioma, such as, for example, ROSl / NTRK-fusion- positive pediatric high-grade gliomas (pHGG)

[0218] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a type-I TGF-b receptor inhibitor. Non-limiting examples of type-I TGF- b receptor inhibitors include SB-505124. In another embodiment, the additional therapeutic agent is a type-I TGF-b receptor inhibitor and the disease or condition that is treated pancreatic ductal adenocarcinoma.

[0219] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a vitamin D analog. Non-limiting examples of vitamin D analogs include inecalcitol. In another embodiment, the additional therapeutic agent is a vitamin D analog and the disease or condition that is treated is hormone receptor positive breast cancer.

[0220] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is an XP01 inhibitor. Non-limiting examples of XPO1 inhibitors include KPT-330. In another embodiment, the additional therapeutic agent is a XPO1 inhibitor and the disease or condition that is treated is rare pediatric undifferentiated sarcoma.

[0221] In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a Trop2 antibody drug conjugate (Trop2 ADC). Non-limiting examples of XPO1 inhibitors include sacituzumab govtecan and datopotamab deruxtecan. In another embodiment, the additional therapeutic agent is a Trop2 antibody drug conjugate and the disease or condition that is treated is metastatic triple-negative breast cancer, non-small cell lung cancer, small cell lung cancer, metastatic urothelial carcinoma, HR+ HER2- metastatic breast cancer, colorectal cancer, esophageal carcinoma, endometrial cancer, pancreatic ductal adenocarcinoma, castrate-resistant prostate cancer, epithelial ovarian cancer, gastric adenocarcinoma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, cervical cancer, or renal cell carcinoma.In other embodiments of the methods of treatment of this disclosure, the additional therapeutic agent is a Trop2 antibody drug conjugate, , a cytokine, an oncolytic virus, a bi-specific immune checkpoint inhibitor, a T-cell engager, a cancer vaccine, a cell therapy, a CD73 inhibitor, HER3 antibody drug conjugates such as patritumab deruxtecan, or a TLR agonist.

[0222] In other embodiments of the methods of treatment of this disclosure, the additional therapy is a cancer gene therapy, for example, gene therapies aimed to normalize tumor suppressors such Rb or P53. CDK inhibitors can be combined with gene therapies aimed to normalize tumor suppressors such Rb, P53 etc. More specifically, CDK2 / 4 / 6 inhibitors cause cell cycle arrest by preventing the phosphorylation of the tumor suppressor protein Rb. Loss of Rb function is one of the mechanisms of intrinsic and acquired resistance to CDK4 / 6 inhibitors. Rb gene therapies could be used to reintroduce Rb into Rb-deficient cancers sothat they become sensitive to CDK inhibitors. More patients could benefit from this combination strategy as Rb loss of function is highly prevalent in human cancers.

[0223] Additional embodiments of the compounds described in the methods of this disclosure include the following:

[0224] R1can be any suitable functional group known by one of skill in the art. In some embodiments, R1is selected from optionally substituted piperidine, optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R1is selected from optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R1is selected from optionally substituted piperidine, optionally substituted pyridine, optionally substituted azetidine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole. In some embodiments, R1is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole. In some mebodiments, R1is selected from optionally substituted azabicyclo[3.1.0]hexane, and optionally substituted isoindole. In some embodiments, R1is substituted with -SO2R1* or C1-3 alkyl, wherein Rlais selected from C1-6 alkyl.

[0225] In some embodiments, R1is selected from optionally substituted piperidine, optionally substituted phenyl, optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R1is selected from optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine.

[0226] In some embodiments, R1is In some embodiments, A is a ringselected from optionally substituted C3-6 carbocycle and optionally substituted 3- to 12- membered heterocycle. In some embodiments, A is selected from optionally substituted C5-6 carbocycle and optionally substituted 5- to 10-membered heterocycle. In some embodiments,A is selected from phenyl, pyrazole, and tetrahydroisoquinoline. In some embodiments, m is selected from 0 to 4. In some embodiments, m is selected from 0 to 2. In some embodiments, Rzis selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle. In some embodiments, Rzis selected from optionally substituted C1-3 alkyl, and optionally substituted 5- to 8- membered heterocycle. In some embodiments, Rzis selected from C1-3 alkyl, and substituted 5-to 8-membered heterocycle.

[0227] In some embodiments, R1is selected from optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R1is selected from optionally substituted piperidine, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R1is selected from optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R1is optionally substituted piperidine. In some embodiments, R1is optionally substituted azabicyclo[3.1.0]hexane. In some embodiments, R1is optionally substituted indole. In some embodiments, R1is optionally substituted isoindole. In some embodiments, R1is optionally substituted azetidine. In some embodiments, R1is optionally substituted indazole. In some embodiments, R1is optionally substituted tetrahydroisoquinoline.

[0228] R2can be any suitable functional group known by one of skill in the art. In some embodiments, R2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. In some embodiments, R2is selected from optionally substituted C3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.In some embodiments, R2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. In some embodiments, R2is selected from optionally substituted cycloalkyl. In some embodiments, R2is selected from cycloalkyl. In some embodiments, R2is selected from optionally substituted C3-6 cycloalkyl. In some embodiments, R2is selected from optionally substituted C5-6 cycloalkyl. In some embodiments, R2is selected from optionally substituted heterocycloalkyl. In some embodiments, R2is selected from heterocycloalkyl. In some embodiments, R2is selected from optionally substituted 3- to 10- membered heterocycloalkyl. In some embodiments, R2is selected from optionally substituted 3- to 8- membered heterocycloalkyl. In some embodiments, R2is selected from optionally substituted 3- to 7- membered heterocycloalkyl. In some embodiments, R2is selected from optionally substituted 3- to 6- membered heterocycloalkyl. In some embodiments, R2is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted morpholine, optionally substituted 2-azaspiro[3.3]heptane, optionally substituted 5-azaspiro[2.4]heptane, optionally substituted 2-oxa-6-azaspiro[3.3]heptane, optionally substituted 2,6- diazaspiro[3.3]heptane, optionally substituted l-thia-6-azaspiro[3.3]heptane, optionally substituted 6-azaspiro[3.4]octane, optionally substituted 2, 6-diazaspiro[3.4] octane, optionally substituted 2-thia-6-azaspiro[3.4]octane, optionally substituted 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, optionally substituted 4-oxa-7-azaspiro[2.5]octane, optionally substituted 2- azaspiro[4.4]nonane, optionally substituted 2,7-diazaspiro[4.4]nonane, optionally substituted 2-oxa-6-azaspiro[3.5]nonane, optionally substituted 7-oxa-2-azaspiro[3.5]nonane, optionally substituted 2-azaspiro[4.5]decane, optionally substituted 2,8-diazaspiro[4.5]decane, optionally substituted 8-oxa-2-azaspiro[4.5]decane, and optionally substituted 2-oxa-7- azaspiro[4.5]decane. In some embodiments, R2is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0229] In some embodiments, R2is substituted with halogen, -SO2R2*, -NR2*, oxo, -COR2*, C1-6alkyl, Ci-salkylene-Ci-salkoxy, -OR2*, -CN, -CH2-CN, and an optionally substituted 3- to 6- membered heterocycloalkyl, wherein R2* is selected from hydrogen and C1-6alkyl. In some embodiments, R2is substituted with -CN, -SO2R2*, -NR2*, oxo, C1-3 alkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkylene-C3-6cycloalkyl, oxetane, piperidine, piperazine, or azetidine, wherein R2* is selected from C1-6alkyl. In some embodiments, R2is substituted with halogen, -SO2R2*, oxo, and C1-6alkyl, wherein R2* is selected from C1-6alkyl. In some embodiments, R2is substituted with halogen, -SO2R2*, and -NR2*, oxo, and C1-3 alkyl, wherein R2* is selected from C1-6alkyl. In some embodiments, R2is substituted with fluoro, -SO2Me, oxo, acetyl, methyl, ethyl, propyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(Clfc^OMe, - (CH2)2OEt, -OH, -OMe, -OEt, -CN, -C-CN, oxetane, and azetidine. In some embodiments, R2is substituted with fluoro, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2- cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In someembodiments, R2is substituted with fluoro, -SOzMe, oxo, and methyl. In some embodiments, R2is substituted with -CN, -SChR2*, -NR2*, oxo, C1-3 alkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkylene-Cs-e cycloalkyl, oxetane, methyl piperidine, or azetidine, wherein R2* is selected from C1-6alkyl.

[0230] R3can be any suitable functional group known by one of skill in the art. In some embodiments, selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R3is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl. In some embodiments, R3is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R3is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R3is selected from hydrogen, fluoro, and -CN. In some embodiments, R3is selected from hydrogen and -CN.

[0231] R4can be any suitable functional group known by one of skill in the art. In some embodiments, R4is selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R4is selected from hydrogen, -CN, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R4is selected from hydrogen, -CN, - CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R4is selected from hydrogen, -CN, and -CHF2.

[0232] R5can be any suitable functional group known by one of skill in the art. In some embodiments, R5is selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R5is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl. In some embodiments, R5is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R5is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substitutedazetidine. In some embodiments, R5is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R5is hydrogen.

[0233] R6can be any suitable functional group known by one of skill in the art. In some embodiments, R6is selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R6is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R6is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl. In some embodiments, R6is selected from hydrogen, fluoro, - CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R6is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R6is hydrogen.

[0234] R7can be any suitable functional group known by one of skill in the art. In some embodiments, R7is selected from hydrogen, and optionally substituted C1-6alkyl. In some embodiments, R7is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R7is hydrogen.

[0235] R8can be any suitable functional group known by one of skill in the art. In some embodiments, R8is selected from halogen, -CN, and optionally substituted C1-6alkyl. In some embodiments, R8is selected from halogen and optionally substituted C1-6alkyl. In some embodiments, R8is fluoro, chloro, bromo, methyl, ethyl, or propyl.

[0236] R9can be any suitable functional group known by one of skill in the art. In some embodiments, R9is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and 3- to 6- membered heterocycloalkyl. In some embodiments, R9is selected from optionally substituted C1-6alkyl. In some embodiments, R9is selected from methyl, ethyl, and propyl.

[0237] Variable n can be any suitable number known by one of skill in the art. In some embodiments, n is 0 to 9. In some embodiments, n is 0 to 5. In some embodiments, n is 0 to 3. In some embodiments, n is 0 or 1. In some embodiments n is 0. In some embodiments, n is 1.

[0238] R8can be any suitable functional group known by one of skill in the art. In some embodiments, R8is selected from halogen, -CN, and optionally substituted C1-6alkyl. In some embodiments, R8is selected from halogen and optionally substituted C1-6alkyl. In some embodiments, R8is fluoro, chloro, bromo, methyl, ethyl, or propyl.

[0239] R9can be any suitable functional group known by one of skill in the art. In some embodiments, R9is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and 3- to 6- membered heterocycloalkyl. In some embodiments, R9is selected from optionally substituted C1-6alkyl. In some embodiments, R9is selected from methyl, ethyl, and propyl.Y1can be any suitable atom known by one of skill in the art. In some embodiments, Y1is selected rom -N- and -CR10-. In some embodiments, Y1is -N-. In some embodiments, Y1is - CR10-.

[0240] Z1, Z2, Z3, Z4and Z5are each independently any suitable atom known by one of skill in the art. In some embodiments, each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -C(O)-, -NR11-, -N(C(O)R10)-, -NS(O2)Rn, -O-, -S-, -S(O)-, and -S(O)2-, wherein Z5is additionally selected from a bond. In some embedments, each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -NR11-, -N(C(O)R10)-, -NS(O2)Rn, -O-, and -S(O)2-, wherein Z5is additionally selected from a bond.

[0241] Variables a, b, c, and d can be any suitable number known by one of skill in the art. In some embodiments, each of a, b, c, and d are independently selected from 1, 2, 3 and 4. In some embodiments, each of a, b, c, and d are independently selected from 1, 2, and 3. In some embodiments, each of a, c, and d are independently selected from 1 and 2.

[0242] R10can be any suitable functional group known by one of skill in the art. In some embodiments, each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R10substituents come together to form an optionally substituted heterocycle or an optionally substituted caibocycle, or R10and R11substituents come together to form an optionally substituted heterocycle. In some embodiments, each R10is independently selected from hydrogen, halogen, -OH, optionally substituted C1-3 alkyl, and optionally substituted C3-6 cycloalkyl. In some embodiments, each R10is independently selected from hydrogen, fluoro, chloro, bromo, -OH, methyl, ethyl, propyl, cyclopropyl and cyclobutyl. In some embodiments, each R10is independently selected from hydrogen, fluoro, -OH, methyl, and cyclopropyl.

[0243] R11can be any suitable functional group known by one of skill in the art. In some embodiments, each R11is independently selected from hydrogen and optionally substituted C1-6alkyl. In some embodiments, each R11is independently selected from hydrogen and optionally substituted C1-2 alkyl. In some embodiments, each R11is independently selected from hydrogen, methyl, and ethyl, wherein the methyl and ethyl are optionally substitutedwith -OMe, -OEt, and -OPr. In some embodiments, each R11is independently selected from hydrogen, methyl, and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0244] Each of X1, X2, and X3can be any suitable atom known by one of skill in the art. In some embodiments, each of X1, X2, and X3is independently selected from N and CR13. In some embodiments, each of X1, X2, and X3is independently N. In some embodiments, each of X1, X2, and X3is independently selected form CR13. In some embodiments, X1, X2, and X3are each CH.

[0245] R12can be any suitable functional group known by one of skill in the art. In some embodiments, R12is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle, or R12comes together with R13to form an optionally substituted ring. In some embodiments, R12is an optionally substituted heterocycle. In some embodiments, R12is an optionally substituted 3- to 8-membered heterocycle. In some embodiments, R12is an optionally substituted 5- to 8-membered heterocycle. In some embodiments, R12is an optionally substituted 6- to 7-membered heterocycle.

[0246] Each R13can be any suitable functional group known by one of skill in the art. In some embodiments, each R13is independently selected from hydrogen, halogen, -CN, and optionally substituted C1-6alkyl, or R12comes together with R13to form an optionally substituted ring. In some embodiments, each R13is independently selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, and propyl. In some embodiments, each R13is independently selected from hydrogen, fluoro, -CN, methyl, and ethyl. In some embodiments, each R13is independently hydrogen.

[0247] Z1, Z2, Z3, Z4and Z5are each independently any suitable atom known by one of skill in the art. In some embodiments, each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -C(O)-, -NR11-, -N(C(O)R10)-, -NS(O2)Rn, -O-, -S-, -S(O)-, and -S(O)2-, wherein Z5is additionally selected from a bond. In some embedments, each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -NR11-, -N(C(O)R10)-, -NS(O2)Rn, -O-, and -S(O)2-, wherein Z5is additionally selected from a bond.

[0248] R14can be any suitable functional group known by one of skill in the art. In some embodiments, R14is selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl, or R14and R15come together to form an optionally substituted heterocycle. In some embodiments, R14is selected from halogen, -CN, and optionally substituted C1-6alkyl. In some embodiments, R14is selected from fluoro, chlor, bromo, methyl, ethyl, and propyl.

[0249] R15can be any suitable functional group known by one of skill in the art. In some embodiments, R15is selected from -S(O)2R16-, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl, or R15and R14come together to form an optionally substituted heterocycle. In some embodiments, R15is selected from -S(O)2R16- and optionally substituted C1-6alkyl. In some embodiments, R15is optionally substituted C3-6 carbocycle. In some embodiments, R15is optionally substituted 3- to 6- membered heterocycloalkyl.

[0250] R16can be any suitable functional group known by one of skill in the art. In some embodiments, R16is selected from optionally substituted C1-6alkyl, optionally substituted C3- 6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl. In some embodiments, R16is selected form optionally substituted C1-6alkyl. In some embodiments, R16is methyl, ethyl, or propyl. In some embodiments, R16is methyl.

[0251] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0252] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0253] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuteriumiodine-125 (125I) or carbon-14 (14C). Isotopic substitution withcontemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0254] In certain embodiments, the compounds disclosed herein have some or all of the atoms replaced with2H atoms. The methods of synthesis for deuterium-containingcompounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0255] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1- 2), 9-32.

[0256] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0257] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0258] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0259] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.-

[0260] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0261] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphoric acids) are preferred prodrugs of the present disclosure.

[0262] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0263] Prodrugs are often useftd because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0264] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol, 269:0210-218 (1995); McLoed et al, Gastroenterol, 106:405-413 (1994); Hochhaus et al, Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.Pharmaceutics, 47, 103 (1988); Sinkula etal., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0265] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M.Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0266] Additional embodiments of the pharmaceutical formulations contemplated in the methods of this disclosure are described below:Pharmaceutical Formulations

[0267] . Formulation may be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate may be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions may also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.

[0268] Methods for formulation of a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates may be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may comprise at least one activeingredient (e.g., a compound, salt or conjugate and other agents). The active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0269] The compositions and formulations may be sterilized. Sterilization may be accomplished by filtration through sterile filtration.

[0270] The compositions comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may be formulated for administration as an injection. Non-limiting examples of formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension. The suspension may also contain suitable stabilizers. Injections may be formulated for bolus injection or continuous infusion. Alternatively, the compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.For parenteral administration, a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles may be inherently non-toxic, and non- therapeutic. Vehicles may be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used. Liposomes may be used as carriers. The vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0271] In one embodiment the invention relates to methods and compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) formulated for oral delivery to a subject in need. In one embodiment a composition is formulated so as to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the mouth or esophagus. In another embodiment the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the stomach and / or intestines.-

[0272] In one embodiment compositions of Formula Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) are provided in modified release dosage forms. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The compositions may also comprise nonrelease controlling excipients.

[0273] In another embodiment compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD)) are provided in enteric coated dosage forms. These enteric coated dosage forms can also comprise non-release controlling excipients. In one embodiment the compositions are in the form of enteric-coated granules, as controlled-release capsules for oral administration. The compositions can further comprise cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate. In another embodiment the compositions are in the form of enteric-coated pellets, as controlled-release capsules for oral administration. The compositions can further comprise glycerol monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[0274] In another embodiment the compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) are enteric-coated controlled-release tablets for oral administration. The compositions can further comprise carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow ferric oxide.

[0275] Sustained-release preparations comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may also be prepared. Examples of sustained-release preparations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound, salt or conjugate, and these matrices may be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices may include polyesters, hydrogels (e.g., poly(2-hydroxyethyl- methacrylate), or poly (vinyl alcohol)), polylactides, copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0276] Pharmaceutical formulations comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and / or a stabilizer. This formulation may be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers may be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and / or non-ionic surfactants or polyethylene glycol.

[0277] In another embodiment the compositions of (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) can further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0278] In another embodiment compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) are provided in effervescent dosage forms. These effervescent dosage forms can also comprise non-release controlling excipients.

[0279] In another embodiment compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) can be provided in a dosage form that has at least one component that can facilitate the immediate release of an active agent, and at least one component that can facilitate the controlled release of an active agent. In a further embodiment the dosage form can be capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours. The compositions can comprise one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi-permeable membrane and as swellable substances.

[0280] In another embodiment compositions Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) are provided in a dosage form for oral administration to a subject, which comprise one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material-partially neutralized with alkali and having cation exchange capacity and a gastric juiceresistant outer layer.

[0281] In some embodiments, the compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) provided herein can be in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human or non-human animal subjects and packaged individually. Each unitdose can contain a predetermined quantity of an active ingredients) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which can be administered in segregated unit-dosage form. Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment the multiple dosage forms comprise different pharmaceutically active agents.

[0282] In some embodiments, the compositions of (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), or (IDD) may also be formulated as a modified release dosage form, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to known methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126, which are herein incorporated by reference in their entirety).EXAMPLES

[0283] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0284] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic 59 -route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.General Synthetic Schemes 1-4Scheme 1Synthesis of IntermediatesDetailed ProcedureStep 1 : 8-bromo-7V-(l-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0285] To a stirred mixture of 8-bromo-2-chloroquinazoline (20 g, 82.1 mmol) and 1- (methylsulfonyl)piperidin-4-amine (14.64 g, 82.1 mmol) in dimethyl sulfoxide (400 mL) was added N,N-diisopropy 1 ethyl amine (31.8 g, 246.3 mmol). The resulting mixture was stirred for 3 hours at room temperature, diluted with water (1000 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the crude product. The residue was purified by silica gel column chromatography (1 : 1 petroleum ether / ethyl acetate) to afford 8-bromo-Ar-(l-(methylsulfonyl)piperidin-4- yl)quinazolin-2-amine (5.04 g, 13.09 mmol, 15.9% yield).

[0286] LCMS (ESI) m / z = 385 [M+H]+.

[0287] (m, 2H), 7.17-7.13 (m, 1H), 4.03-4.01 (m, 1H), 3.59-3.56 (m, 2H), 2.95-2.90 (m, 5H), 2.13- 1.96 (m, 2H), 1.69-1.60 (m, 2H).Intermediate 2: 8-(8.8-difluoro-2.6-diazaspiror 3.41octan-6-vl)-6-methvl-N-( 1 -(( 1 -methvl- lH-pyrazol-4-yDsulfonyltoiperidin-4-yltoyridor3.4-d1pyrimidin-2-amineDetailed ProcedureStep 1: Tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0288] DIEA (9.78 g, 75.6 mmol) was added to a stirred mixture of tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (5.0 g, 25.2 mmol) and 5-fluoro-2-nitropyridine (5.37 g, 37.8 mmol) in DMSO (30 mL). The resulting mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with water (500 mL) and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the crude product. The residue was purified by trituration with 100 mL of 1 :5 EA / PE to afford the desired product tert-butyl 6-(6- nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield).

[0289] LCMS (ESI) m / z= 321.1 [M+H]+.Step 2: Tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0290] Pd / C (10% on carbon, 200 mg) was added to a mixture of tert-butyl 6-(6-nitropyridin- 3-yl)-2,6-diazaspiro[3.3]heptane-2-caiboxylate (1 g, 3.12 mmol) in EtOH (25 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude tert-butyl 6-(6-aminopyridin-3-yl)-2,6- diazaspiro[3.3]heptane-2 -carboxylate (800 mg, 83.8% yield).LCMS (ESI-MS) m / z = 291.2 [M+H]+.Step 3: TTeerrtt--bbuuttyyll 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate

[0291] A mixture of tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (4.7 g, 16.2 mmol) and lH-benzo[d][l,2,3]triazole-l-carbaldehyde (2.62 g, 17.8 mmol) in THF (50 mL) was heated to 80 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to afford the crude product. The residue was purified by silica gel column chromatography (EA / PE, 7:3) to afford the desired product tert-butyl 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane- 2-carboxylate (5.2 g, 95.8% yield).

[0292] LCMS (ESI-MS) m / z = 319.2 [M+H]+.Step 4: Tert-butyl 6-(6-((8-bromoquinazolin-2-yl)amino)pyridin-3-yl)-2,6- diazaspiro [3.3] heptane-2-carboxylate

[0293] NaH (60% in mineral oil, 0.23 g, 9.42 mmol) was added to a stirred mixture of tertbutyl 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-caiboxylate (1 g, 3.14 mmol) in DMF (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h and 8-bromo-2-(methylsulfonyl)quinazoline (0.99 g, 3.45 mmol) was added. The resulting mixture was warmed to room temperature and stirred for another 1 h. The reaction mixture was quenched by addition of water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford the crude product. The residue was purified by trituration with DCM (40 mL) to afford the desired product tertbutyl 6-(6-((8-bromoquinazolin-2-yl)amino)pyridin-3 -yl)-2,6-diazaspiro[3.3 ]heptane-2- carboxylate (800 mg, 46.1% yield).

[0294] LCMS (ESI-MS) m / z = 497.2 [M+H]+.Step 5: N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-8-bromoquinazolin-2-amine

[0295] TFA (3 mL) was added to a stirred mixture of tert-butyl 6-(6-((8-bromoquinazolin-2- yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (800 mg, 1.60 mmol) in DCM (9 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure to afford crude N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-8- bromoquinazolin-2-amine (1 g). The crude product was used for the next step without further purification.LCMS (ESI-MS) m / z = 397.1 [M+H]+.Step 66:: 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(l-((l-methyl-lH- pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0296] To a solution of N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-8- bromoquinazolin-2-amine (1.1 g, 2.76 mmol) in methanol (10 mL) was added triethylamine (0.56 g, 5.53 mmol). The resulting mixture was stirred for 5 minutes and acetaldehyde (0.61 g, 13.8 mmol), AcOH (0.02 g, 0.27 mmol) and NaBHaCN (1.74 g, 27.7 mmol) were added. The resulting mixture was stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 1 : 10) to afford the desired product 8-bromo-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2- yl)quinazolin-2-amine (200 mg, 15.3% yield).

[0297] LCMS (ESI) m / z= 425.1 [M+H]+.Detailed ProcedureStep 1: tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0298] To a stirred mixture of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (5 g, 25.21 mmol) and 5-fluoro-2-nitropyridine (5.37 g, 37.82 mmol) in dimethyl sulfoxide (30 mL) was N,N-diisopropylethylamine (9.78 g, 75.65 mmol). The resulting mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford the crude product. The residue was purified by trituration with petroleum ether / ethyl acetate (5: 1,100 mL) to afford tertbutyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield).

[0299] LCMS (ESI) m / z= 321 [M+H]+.Step 2: 2-(6-nitropyridin-3-yl)-2,6-diazaspiro [3.3] heptane

[0300] To a stirred mixture of tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (6.78 g, 21.16 mmol) in dichloromethane (80 mL) was added trifluoroacetic acid (16 mL). The resulting mixture was stirred for 1 hour at room temperature and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL) and concentrated under vacuum again to afford crude 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetic acid salt (6 g). The crude product was used for the next step without further purification.

[0301] LCMS (ESI) m / z = 221 [M+H]+.Step 3: 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro [3.3] heptane

[0302] A solution of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetic acid salt (6 g, 18.9 mmol) in methanol (100 mL) was treated with triethylamine (5.73 g, 56.7 mmol) for 10 minutes followed by the addition of acetaldehyde (4.16 g, 94.5 mmol), acetic acid (0.23 mL, 4.08 mmol) and sodium cyanoborohydride (2.51 g, 39.8 mmol). The resulting mixture was stirred for 3 hours at room temperature and concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford the crude product. The residue was purified by trituration with dichloromethane (100 mL) to afford 2- ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 58.9 % yield).

[0303] LCMS (ESI) m / z= 249 [M+H]+.Step 4: 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl) pyridin-2-amine

[0304] A solution of 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 16.11 mmol), ammonium chloride (4.31 g, 80.55 mmol), iron powder (9.00 g, 161.100 mmol) and water (20 mL) in ethanol (60 mL) was stirred for 1 hour at 80 °C. The resulting mixture was filtered and the filter cake was washed with ethanol (100 mL). The filtrate was concentrated under vacuum to afford the crude product. The residue was purified by reversed-phase flash chromatography (Cl 8 silica gel, acetonitrile / water (with lOmmol / L NH4HCO3) gradient) to afford 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine (2 g, 56.6% yield).

[0305] LCMS (ESI) m / z= 219 [M+H]+.Step 5: 7V-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl) pyridin-2-yl) formamide

[0306] A solution of acetic anhydride (2 mL) in formic acid (4 mL) was stirred for 1 hour at room temperature followed by the addition of 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2- yl)pyridin-2-amine (400 mg, 1.83 mmol) in portions at room temperature. The resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was neutralized to PH = 7 with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative reverse phase HPLC (acetonitrile / water (with 10 mM NH4HCO3 and 0.1%NH3.H2O ) gradient) to afford the title compound (70 mg, 15.3% yield).

[0307] LCMS (ESI) m / z= 247 [M+H]+.Intermediate 4: 8-bromo-7-fluoro-N-( 1 -(methvlsulfonvDpiperidin-4-vDauinazolin-2-amineReaction SchemeDetailed ProcedureStep 1: 8-bromo-7-fluoroquinazolin-2-amine

[0308] A mixture of 3-bromo-2,4-difluorobenzaldehyde (5 g, 22.6 mmol) and guanidine (4.01 g, 67.8 mmol) in NMP (50 mL) was heated to 130 °C and stirred for 5 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extractedwith EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude product. The residue was purified by silica gel column chromatography (EA / PE, 2: 1) to afford the desired product 8-bromo-7-fluoroquinazolin-2-amine (800 mg, 14.6% yield).

[0309] LCMS (ESI-MS) m / z = 242.0 [M+H]+.Step 2: 8-bromo-2-chloro-7-fluoroquinazoline

[0310] A mixture of tert-butyl nitrite (511 mg, 4.95 mmol) and copper(I) chloride (490 mg, 4.95 mmol) in acetonitrile (10 mL) was stirred for 1 h at 60 °C. 8-Bromo-7-fluoroquinazolin- 2-amine (800 mg, 3.30 mmol) was added in portions over 1 minute at room temperature. The resulting mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by Prep- TLC (PE / EA, 1:1) to afford 8-bromo-2-chloro-7-fluoroquinazoline (300 mg, 34.7% yield).

[0311] LCMS (ESI-MS) m / z = 261.0 [M+H]+.Step 3: 8-bromo-7-fluoro-N-(l-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0312] l,8-diazabicyclo[5.4.0]undec-7-ene (349 mg, 2.29 mmol) was added to a mixture of 8-bromo-2-chloro-7-fluoroquinazoline (300 mg, 1.15 mmol) and 1- (methylsulfonyl)piperidin-4-amine (206 mg, 1.15 mmol) in MeCN (3 mL). The resulting mixture was stirred overnight at 65 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate) to afford the desired product 8-bromo-7-fluoro-N-(l- (methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (120 mg, 25.8% yield).

[0313] LCMS (ESI-MS) m / z = 403.1 [M+H]+.Intermediate 5: 8-bromo-2-chloro-6-(difluoromethvlkiuinazolineReaction Scheme

[0314] DAST (47.6 g, 296 mmol) was added to a stirred mixture of 3-bromo-4- fluorobenzaldehyde (30 g, 148 mmol) in DCM (300 mL) dropwise at 0 °C. The resulting mixture was stirred overnight at 40 °C and quenched by the addition of saturated aqueous NaHCCh (500 ml) at 0 °C. The mixture was extracted with DCM (3 x 500 mL) and the combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford crude 2-bromo-4-(difluoromethyl)-l- fluorobenzene (32.2 g, 96.8% yield).LCMS (ESI-MS) m / z = 225.0 [M+H]+.Step 2: 3-bromo-5-(difluoromethyl)-2-fluorobenzaldehyde

[0315] To a cooled to -78 °C mixture of 2-bromo-4-(difluoromethyl)-l -fluorobenzene (10 g, 44.4 mmol) in 100 mL of THF was added LDA (2 M in THF, 24.4 mL, 48.8 mmol) dropwise under a nitrogen atmosphere. The mixture was stirred at -78 °C for 0.5 h. DMF (3.89 g, 53.3 mmol) was added dropwise and the resulting mixture was stirred at -78 °C for another 1 h. The reaction mixture was slowly poured into 200 mL of saturated aqueous NH4CI at 0 °C and stirred for 1 h. The solution was diluted with H2O (200 mL) and extracted with EA (400 mL x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reducedpressure to afford crude 3-bromo-5-(difhioromethyl)-2-fluorobenzaldehyde (15 g). The crude product was used for the next step without further purification.Step 3: 8-bromo-6-(difluoromethyl)quinazolin-2-amine

[0316] Guanidine (3.85 g, 65.21 mmol) was added to a mixture of 3 -brom o- 5- (difluoromethyl)-2-fluorobenzaldehyde (15 g, 59.28 mmol) in NMP (13 mL). The mixture was stirred at 150 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL). The organic layers were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 45:55) to afford 8-bromo-6-(difluoromethyl)quinazolin-2-amine (0.9 g, 5.54% yield).

[0317] LCMS (ESI-MS) m / z = 274.0 [M+H]+.Step 4: 8-bromo-2-chloro-6-(difluoromethyl)quinazoline

[0318] Tert-Butyl nitrite (3.9 mL) was added to a mixture of 8-bromo-6- (difluoromethyl)quinazolin-2-amine (3 g, 10.94 mmol), TBA-CI (5.4 mL) in TMSCI and t- BuOH (15 mL). The mixture was stirred overnight at 60 °C. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 6:94) to afford 8-bromo-2-chloro-6- (difluoromethyl)quinazoline (1.03 g, 31.9% yield).

[0319] Intermediate 6: 8-Bromo-6-(difluoromethvl)-N-(2-methvlisoindolin-5-vlkiuinazolin-2-aminReaction SchemeDetailed ProcedureStep 1: 2-amino-3-bromo-5-(trifluoromethyl)benzaldehyde

[0320] A solution of n-BuLi (2.5 M in hexane, 52.6 mL, 131.5 mmol) was added to a stirred mixture of 2,6-dibromo-4-(trifluoromethyl)aniline (20 g, 62.7 mmol) in THF (250 mL) at -78 °C under a nitrogen atmosphere. A solution of DMF (6.42 g, 87.8 mmol) in THF (10 mL) was slowly added and the resulting mixture was stirred at -78 °C for 3 h, quenched by addition of water (500 mL) and extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (2 x 1000 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 2-amino-3-bromo-5- (trifluoromethyl)benzaldehyde (10.2 g, 60.7% yield).

[0321] LCMS (ESI-MS) m / z = 268.1 [M+H]+.Step 2: 8-bromo-6-(trifluoromethyl)quinazolin-2(lZ7)-one

[0322] A mixture of 2-amino-3-bromo-5-(trifluoromethyl)benzaldehyde (10.2g, 38.2 mmol) and urea (34.4 g, 57.3 mmol) was heated to 180 °C and stirred for 5 h. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with water (2 x 200 mL) and EA (2 x 200 mL). The collected solid was dried under high vacuum to afford crude 8-bromo-6-(trifluoromethyl)quinazolin-2(12 / )-one (7.3 g). The crude product was used for the next step without further purification.

[0323] LCMS (ESI-MS) m / z = 293.2 [M+H]+.Step 3: 8-bromo-2-chloro-6-(trifluoromethyl)quinazoline

[0324] POCI3 (60 mL, 643 mmol) was added to a mixture of 8-bromo-6-(trifluoromethyl)quinazolin-2(12 / )-one (7.3 g, 24.9 mmol) in toluene (60 mL). The resultingmixture was stirred at 110 °C for 2 h and concentrated under reduced pressure. The residue was slowly quenched by addition of saturated anhydrous NaHCCh at 0 °C until no bubbles appeared. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 1 :20) to afford 8-bromo-2-chloro-6- (trifluoromethyl)quinazoline (1.06 g, 13.6% yield).

[0325]

[0326] LCMS (ESI-MS) m / z = 312.7 [M+H]+.Intermediate 7; 2-Methvlisoindolin-5-amine

[0327] A solution of LiAlHt (2 M in THF, 4.25 mL, 8.50 mmol) was added to 5-amino-2- methylisoindoline-1, 3-dione (500 mg, 2.83 mmol) in THF (10 mL) at 0 °C. The reaction mixture was heated to 70 °C and stirred for 1 h. After cooling to 0 °C, the reaction was quenched by the addition of ethanol and water. The resulting slurry is filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to afford crude 2-methylisoindolin-5-amine (300 mg). The crude product was used for the next step without further purification.

[0328] LCMS (ESI-MS) m / z = 149.1 [M+H]+.Intermediate 8: 8-Bromo-6-(difluoromethvD-N-(2-methvlisoindolin-5-vDauinazolin-2- amine

[0329] TFA (385 mg, 3.37 mmol) was added to a mixture of 2-methylisoindolin-5-amine (250 mg, 1.68 mmol) and 8-bromo-2-chloro-6-(difluoromethyl) quinazoline (495 mg, 1.68mmol) in propan-2-ol (5 mL). The resulting mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 10:90) to afford 8-bromo-6-(difluoromethyl)-N-(2- methylisoindolin-5-yl)quinazolin-2-amine (180 mg, 26.3% yield).

[0330] LCMS (ESI-MS) m / z = 405.0 [M+H]+.Intermediate 9: 1 -( 1 -methvlazeti din-3 -vl)- lH-pyrazol-4-amineReaction SchemeStep 11:: l-(l-methylazetidin-3-yl)-4-nitro-lH-pyrazole-(l-methylazetidin-3-yl)-lH- pyrazol-4-amine

[0331] A solution of l-(azetidin-3-yl)-4-nitro-lH-pyrazole (2 g, 7.08 mmol) and HCHO (319 mg, 10.6 mmol) in MeOH (30 mL) was stirred for 2 h at room temperature. NaBHaCN (891 mg, 14.2 mmol) was added. The resulting mixture was stirred overnight at room temperature, filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 10:90) to afford l-(l-methylazetidin-3-yl)-4-nitro-lH-pyrazole (500 mg, 33.3% yield).

[0332] LCMS (ESI-MS) m / z = 183.1 [M+H]+.Step 2: l-(l-methylazetidin-3-yl)-lH-pyrazol-4-amine

[0333] Pd / C (10% on carbon, 99.3 mg) was added to a solution of l-(l-methylazetidin-3-yl)- 4-nitro-lH-pyrazole (680 mg, 3.73 mmol) in MeOH (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under a hydrogen atmosphere, filtered and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to afford the crude title product (700 mg). The crude product was used for the next step without further purification.

[0334] LCMS (ESI-MS) m / z = 153.1 [M+H]+.Intermediate 10: !-(5-cvcloDroDvlDvrimidin-2-vl)DiDeridin-4-amineR ti S hS

[0335] CS2CO3 (4.21 g, 12.9 mmol) was added to a mixture of 2-chloro-5- cyclopropylpyrimidine (1 g, 6.46 mmol) and tert-butyl N-(piperidin-4-yl)caibamate (1.30 g, 6.46 mmol) in DMSO (20 mL). The resulting mixture was stirred overnight at 70 °C, diluted with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The residue was purified by column chromatography(EA / PE, 0:100 to 20:80) to afford the desired product tert-butyl N-[l-(5- cyclopropylpyrimidin-2-yl)piperidin-4-yl]caibamate (1.5 g, 70.3% yield).

[0336] LCMS (ESI-MS) m / z =319.2 [M+H]+.Step 2: l-(5-cydopropylpyrimidin-2-yl)piperidin-4-amine

[0337] TFA (3 mL) was added to a stirred mixture of tert-butyl N-[l-(5- cyclopropylpyrimidin-2-yl)piperidin-4-yl]caibamate (1.5 g, 4.71 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under high- 74 -vacuum to afford crude l-(5-cyclopropylpyrimidin-2-yl)piperidin-4-amine (1.5 g crude). The crude product was used for the next step without further purification.

[0338] LCMS (ESI-MS) m / z = 219.1 [M+H]+.Intermediate 11 : l-(7-cvcloDroDvl-7H-Dvrrolor2.3-dlDvrimidin-2-vl)DiDeridin-4-amineReaction Scheme

[0339] A mixture of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.0 mmol), cyclopropylboronic acid (1.12 g, 13.0 mmol), Cu(OAc)a (4.73 g, 26.0 mmol) and EfaN (2.64 g, 26.0 mmol) in DCM (20 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE, from 0:100 to 20:80) to afford the desired product 2-chloro-7-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidine (1.5 g, 59.4% yield).

[0340] LCMS (ESI-MS) m / z =194.0 [M+H]+.Step 2: Tert-butyl (l-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4- yl)carbamate

[0341] CS2CO3 (4.71 g, 14.4 mmol) was added to a mixture of 2-chloro-7- cyclopropylpyrrolo[2,3-d]pyrimidine (1.4 g, 7.23 mmol) and tert-butyl N-(piperidin-4- yl)carbamate (1.45 g, 7.23 mmol) in DMSO (15 mL). The resulting mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE, from 0:100 to 20:80) to afford the desired product tert-butyl (l-(7-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-2-yl)piperidin-4-yl)caibamate (1.5 g, 58.0% yield).

[0342] LCMS (ESI-MS) m / z =358.2 [M+H]+.Step 3: l-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine

[0343] TFA (3 mL) was added to a stirred mixture of tert-butyl (l-(7-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate (1.5 g, 4.19 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under high vacuum to afford crude l-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine (1.5 g). The crude product was used for the next step without further purification.

[0344] LCMS (ESI-MS) m / z = 258.2 [M+H]+.Intermediate 12: 2-(2-methoxvethvD-2.6-diazasDiror3 ,31heptaneReaction SchemeStep 1: Tert-butyl 6-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0345] Nal (29.5 mg, 0.19 mmol) was added to a mixture of tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (300 mg, 1.51 mmol), 2-bromoethyl methyl ether (326 mg, 2.34 mmol) and K2CO3 (544 mg, 3.93 mmol) in MeCN (15 mL). The reaction mixture was heated at 50 °C overnight, quenched by addition of water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the crude title product (150 mg). The crude product was used for the next step without further purification.

[0346] LCMS (ESI-MS) m / z = 257.2 [M+H]+.Step 2: 2-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptane

[0347] TFA (0.5 mL) was added to a stirred mixture of tert-butyl 6-(2-methoxyethyl)-2,6- diazaspiro[3.3]heptane-2 -carboxylate (150 mg, 0.58 mmol) in DCM (1.5 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under high vacuum to afford the crude title product (150 mg). The crude product was used for the next step without further purification.LCMS (ESI-MS) m / z = 157.1 [M+H]+.Intermediate 13: l-((l-methvlcvclopropvl)sulfonvDpiperidin-4-amineReaction SchemeDetailed ProcedureStep 1: Tert-butyl (l-((l-methylcyclopropyl)sulfonyl)piperidin-4-yl)carbamate

[0348] 1 -methylcyclopropane- 1 -sulfonyl chloride (463 mg, 2.99 mmol) was added dropwise to a cooled to 0 °C solution of tert-butyl piperidin-4-ylcarbamate (400 mg, 1.99 mmol) and DIEA (774 mg, 5.99 mmol) in DCM (10 mL). The resulting mixture was stirred for 1 h at room temperature, diluted with water (10 mL) and extracted with DCM (3 x 250 mL). The combined organic layers were dried over anhydrousfiltered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 1:5) to afford tert-butyl (l-((l-methylcyclopropyl)sulfonyl)piperidin-4-yl)caibamate (580 mg, 82.1% yield).

[0349] LCMS (ESI-MS) m / z = 263.2 [M+H-56]+.Step 2: l-((l-methylcyclopropyl)sulfonyl)piperidin-4-amme

[0350] TFA (2 mL) was added to a stirred mixture of tert-butyl (1-((1- methylcyclopropyl)sulfonyl)piperidin-4-yl)caibamate (500 mg, 1.57 mmol) in DCM (6 mL). The resulting mixture was stirred for 2 h at room temperature and concentrated under reduced pressure to afford the TFA salt of l-((l-methylcyclopropyl)sulfonyl)piperidin-4-amine (255 mg, 74.3% yield).

[0351] 3.07-2.94 (m, 2H), 1.95 (d, J = 12.4 Hz, 2H), 1.55-1.43 (m, 2H), 1.39 (s, 3H), 1.18-1.11 (m, 1H), 0.86-0.73 (m, 3H). LCMS (ESI-MS) m / z = 219.1 [M+H]+.Reaction Scheme

[0352] 1 -methyl- lZf-pyrazole-4- sulfonyl chloride (1.8 g, 9.96 mmol) was added to a cooled to 0 °C solution of tert-butyl piperidin-4-ylcarbamate (2.00 g, 9.96 mmol) and DIEA (3.22 g, 24.9 mmol) in DCM (40 mL). The resulting mixture was stirred at 0 °C for 1 h, quenched by addition of water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (MeOH / DCM, 0:100 to 5:95) to afford tert-butyl ( 1-((1 -methyl- \H- pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (2.2 g, 64.1% yield).

[0353] LCMS (ESI-MS) m / z = 367.1 [M+Na+H]+.Step 2: l-((l-methyl-lH-pyrazol-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate

[0354] TFA (5 mL) was added to a stirred mixture of tert-butyl (l-((l-methyl-12 / -pyrazol-4- yl)sulfonyl)piperidin-4-yl)carbamate (2 g, 5.80 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, from 0: 100 to 18:82) to afford l-((l-methyl-lH-pyrazol-4-yl)sulfonyl)piperidin-4-amine 2,2,2- trifluoroacetate (250.7 mg, 11.6% yield).

[0355] XHNMR (400 MHz, DMSO^fc) 5 8.32 (s, 1H), 8.21 (s, 3H), 3.89 (s, 3H), 3.61-3.48 (m, 2H), 3.13-3.00 (m, 1H), 2.42-2.25 (m, 2H), 2.07-1.89 (m, 2H), 1.67-1.50 (m, 2H). LCMS (ESI-MS) m / z =245.0 [M+H]+.Intermediate 15: 1 -(cyclopropylsulfonyDpiperidin-4-amineReaction Scheme

[0356] To a solution of cyclopropanesulfonyl chloride (7.02 g, 49.93 mmol) and DIEA (19.36 g, 149.79 mmol) in DCM (100 mL) was added tert-butyl N-(piperidin-4-yl)carbamate (10 g, 49.93 mmol) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (500 mL). The aqueous solution was extracted with CH2CI2 (3x500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EA (lOOmL) to afford tert-butyl (1- (cyclopropylsulfonyl)piperidin-4-yl)caibamate (10 g, 59.2% yield).

[0357] LCMS (ESI-MS) m / z = 249.1 [M+H-56]+.Step 2: l-(cyclopropylsulfonyl)piperidin-4-amine

[0358] A solution of tert-butyl (l-(cyclopropylsulfonyl)piperidin-4-yl)caibamate (10 g, 32.87 mmol) in TFA (15 mL) and DCM (45 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 1- (cyclopropylsulfonyl)piperidin-4-amine (8 g). The crude product was used for the next step without further purification.LCMS (ESI-MS) m / z = 205.1 [M+H]+.Intermediate 16: Tert-butyl 8.8-difluoro-2-hydroxy-6-azaspiror3.41octane-6-carboxylate

[0359] To a cooled to -30 °C solution of 2,2,6, 6-tetramethylpiperidine (9.62 g, 68.09 mmol) in dry THF (100 mL) was added n-BuLi (2.5 M, 27.2 mL) dropwise under an N2 atmosphere. The mixture was stirred at -30 °C for 0.5 h. The reaction was then cooled to -78 °C and a solution of bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methane (15.21 g, 56.74 mmol) in 50 mL of dry THF was added dropwise. The reaction mixture was stirred at -78 °C for 0.5 h and a solution of 3-(benzyloxy)cyclobutan-l-one (10 g, 56.74 mmol) in 50 mL of dry THF was added dropwise. The reaction mixture was then warmed to 20 °C and stirred for an additional 12 h. The reaction mixture was slowly poured into 20 mL of saturated aqueous NH4CI at 0 °C and after stirring for 1 h, the solution was diluted with H2O (200 mL) and extracted with EtOAc (400 mL x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-((3- (benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (13.7 g) which was used without further purification.LCMS (ESI-MS) m / z = 301.1 [M+H]+.Step 2: 6-benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6- azaspiro[3.4]octane

[0360] A solution of 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (13.7 g crude), N-benzyl-1 -methoxy -N-((trimethylsilyl)methyl)m ethanamine (13.00 g, 54.76 mmol) and LiF (3.55 g, 136.90 mmol) in DMSO (200 mL) was stirred at 110 °C for 1 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (1000 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude 6-benzyl-2- (benzyloxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6-azaspiro[3.4]octane (20 g) as a colorless oil. The crude product was used for the next step without further purification.

[0361] LCMS (ESI-MS) m / z = 434.2 [M+H]+.Step 3: 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol

[0362] A solution of 6-benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-6-azaspiro[3.4]octane (20 g crude), sodium perborate (4.53 g, 55.37 mmol) and LiOH (3.32 g, 138.44 mmol) in THF (50 mL) and H2O (200 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 3:97) to obtain 6-benzyl-2-(benzyloxy)-6- azaspiro[3.4]octan-8-ol (10 g, 67.0%) as colorless oil.

[0363] LCMS (ESI-MS) m / z = 324.1 [M+H]+.Step 4: 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one

[0364] To a cooled to -78°C solution of oxalyl chloride (7.85 g, 61.8 mmol) in DCM (100 mL) was added dropwise a solution of DMSO (4.83 g, 61.8 mmol) in DCM (20 mL) under a nitrogen atmosphere. The mixture was stirred at -78 °C for 20 min. A solution of 6-benzyl-2- (benzyloxy)-6-azaspiro[3.4]octan-8-ol (10 g, 30.9 mmol) in DCM (20 mL) was then added dropwise and the mixture stirred for 20 min.(12.5 g, 123 mmol) was added dropwise and the mixture stirred for 20 min. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrousfiltered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0 to 10%). The fractions with the desired mass signal were combined and concentrated under reduced pressure to afford 6- benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one (5.8 g, 58.4% yield).

[0365] LCMS (ESI-MS) m / z =322.2 [M+H]+.Step 5: 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro [3.4] octane

[0366] DAST (8.73 g, 54.1 mmol) was added to a solution of 6-benzyl-2-(benzyloxy)-6- azaspiro[3.4]octan-8-one (5.8 g, 18.0 mmol) in DCM (60 mL) at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 10%). The fractions with the desired mass signal were combined and concentrated under reduced pressure to afford 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane (1.2 g, 19.4% yield).

[0367] LCMS (ESI-MS) m / z = 344.2 [M+H]+.Step 6: Tert-butyl 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate

[0368] Pd(OH)2 / C (0.49 g, 3.49 mmol) was added to a solution of 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane (1.2 g, 3.49 mmol), BOC2O (0.92 g, 4.19 mmol) and EfcN(1.06 g, 10.48 mmol) in MeOH (120 mL). The resulting mixture was stirred 5 days at room temperature under a H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH in DCM, 0% to 5%). The fractions with the desired mass signal were combined, concentrated under reduced pressure and lyophilized to afford the tert-butyl8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (500 mg, 54.4% yield).

[0369] 3H), 3.47-3.39 (m, 2H), 2.14-2.10 (m, 1H), 2.04-1.96 (m, 1H), 1.93-1.85 (m, 1H), 1.40 (s,9H).Intermediate 17: 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyDcyclobutan-l-olReaction Scheme

[0370] A solution of LiAlHt in THF (2 M, 32.6 mL, 65.2 mmol) was added to a stirred mixture of 1,1-diethyl 3 -(benzyloxy)cyclobutane- 1,1 -dicarboxylate (5 g, 16.3 mmol) in THF (50 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 h, carefully quenched by addition of water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous filtered andconcentrated under reduced pressure to afford crude [3-(benzyloxy)-l- (hydroxymethyl)cyclobutyl] methanol (3.2 g) as colorless oil. The crude product was used for the next step without further purification.

[0371] LCMS (ESI-MS) m / z = 223.3 [M+H]+.Step 2: (3-(benzyloxy)-l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol

[0372] NaH (60% in mineral oil, 0.99 g, 24.8 mmol) was added to a cooled to 0 °C solution of [3 -(benzyloxy)- l-(hydroxymethyl)cyclobutyl]methanol (3.2 g, 14.3 mmol) in THF (40 mL). The resulting suspension was stirred at 0 °C for 1 h and TBDPSCI (3.96 g, 14.3 mmol) was slowly added. The resulting mixture was stirred at room temperature overnight, diluted with saturated aqueous NH4CI (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford crude (3-(benzyloxy)-l-(((tert- butyldiphenylsilyl)oxy) methyl)cyclobutyl)methanol (6.5 g). The crude product was used for the next step without further purification.

[0373] LCMS (ESI-MS) m / z = 461.4 [M+H]+.Step 3: 3-(benzyloxy)-l-(((tert-butyldiphenylsilyl)oxy)methyl)cydobutane-l- carbaldehyde

[0374] Dess-Martin periodinate (4.14 g, 9.76 mmol) was slowly added to a cooled to 0 °C solution of (3-(benzyloxy)-l-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (3 g crude, around 6.51 mmol) in DCM (30 mL) under a nitrogen atmosphere. After stirring for 2 h at 0 °C, the reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched by addition of saturated aqueousand extracted with DCM (3 x50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column (EA / PE, 10:90) to afford 3-(benzyloxy)-l-(((tert-butyldiphenylsilyl)oxy)methyl) cyclobutane- 1-carbaldehy de (1.8 g, 60.2% yield).

[0375] LCMS (ESI-MS) m / z = 459.2 [M+H]+.Step 4: ((3-(benzyloxy)-l-(difluoromethyl)cydobutyl)methoxy)(tert-butyl)diphenylsilane

[0376] DAST (948 mg, 5.88 mmol) was added to a stirred mixture of 3-(benzyloxy)-l-(((tert- butyldiphenylsilyl)oxy)methyl)cyclobutane-l-carbaldehyde (1.8 g, 3.92 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 h, quenched by addition of water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give ((3-(benzyloxy)-l-(difluoromethyl) cyclobutyl)methoxy)(tert- butyl)diphenylsilane (1 g, 53.0% yield).

[0377] LCMS (ESI-MS) m / z = 481.4 [M+H]+.Step 5: 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cydobutan-l-ol

[0378] Pd / C (10% on carbon, 1.11 g) was added to a mixture of (3 -(benzyloxy)- 1- (difluoromethyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane (1 g, 2.08 mmol) in MeOH (15 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give 3-(((tert- butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-l-ol (100 mg, 12.3% yield).

[0379] LCMS (ESI-MS) m / z = 391.2 [M+H]+.Intermediate 18: Racemic (3R,4R)-4-amino-l-(methylsulfonyDpiperidin-3-olReaction Scheme

[0380] To a mixture of racemic tert-butyl (3R,4R)-4-amino-3 -hydroxypiperidine- 1- carboxylate (500 mg, 2.31 mmol) in DCM (3.8 mL) and saturated aqueous Na2COs (3.8 mL) was added a solution of CbzCl (50% in toluene, 946 mg, 2.77 mmol) dropwise at 0 °C. The resulting mixture was stirred for 4 h at room temperature, diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous filtered and concentrated under reduced pressure. Theresidue was purified by Prep-TLC (EA / PE, 2: 1) to afford racemic tert-butyl (3R,4R)-4- (((benzyloxy)carbonyl)amino)-3 -hydroxypiperidine- 1 -carboxylate (800 mg, 98.7% yield). LCMS (ESI-MS) m / z = 351.2 [M+H]+.Step 2: Racemic benzyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate

[0381] A solution of racemic tert-butyl (3R,4R)-4-(((benzyloxy)carbonyl)amino)-3- hydroxypiperidine-1 -carboxylate (750 mg, 2.14 mmol) was added to a solution of HCI in 1,4- dioxane (4 M, 5 mL, 20 mmol). The resulting mixture was stirred for 2 h at room temperatureand concentrated under reduced pressure. The crude product was used for the next step without further purification.

[0382] LCMS (ESI-MS) m / z = 251.2 [M+H]+.Step 3: Racemic benzyl ((3R,4R)-3-hydroxy-l-(methylsulfonyl)piperidin-4-yl)carbamate

[0383] Methanesulfonyl chloride (549 mg, 4.79 mmol) was added to a stirred mixture of crude racemic benzyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (750 mg, 2.99 mmol) and NaHCOs (420 mg, 5 mmol) in EA (4.5 mL) at 0 °C. The resulting mixture was stirred for 1 h, quenched by addition of water (20 mL) and extracted with EA (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford racemic benzyl ((3R,4R)-3- hydroxy-l-(methylsulfonyl)piperidin-4-yl)carbamate (500 mg, 50.8% yield).

[0384] LCMS (ESI-MS) m / z = 329.1 [M+H]+.Step 4: Racemic (3R,4R)-4-amino-l-(methylsulfonyl)piperidin-3-ol

[0385] Pd / C (10% on carbon, 25 mg) was added to a mixture of racemic benzyl ((3R,4R)-3- hydroxy-l-(methylsulfonyl)piperidin-4-yl)carbamate (100 mg, 0.30 mmol) in MeOH (5 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under a hydrogen atmosphere and filtered. The filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to afford crude racemic (3R,4R)-4- amino-1 -(methyl sulfonyl)piperidin-3-ol (75.6 mg). The crude product was used for the next step without further purification.

[0386] LCMS (ESI-MS) m / z = 195.1 [M+H]+.Synthesis of Example CompoundsExample 24: 8-f2-methyl-2.6-diazaspiror3.41octan-6-yD-N-(l -Cmethvlsulfonvl)DiDeridin-4- vl)auinazolin-2-amine

[0387] To a mixture of 8-bromo-Ar-(l-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (200 mg, 0.52 mmol), 2-methyl-2,6-diazaspiro[3.4]octane (72.06 mg, 0.57 mmol) and cesium carbonate (507.40 mg, 1.55 mmol) in toluene (2 mL) was added Pd2(dba)j (47.6 mg, 0.052 mmol) and BINAP (32.3 mg, 0.052 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then filtered. The collected solid was washed with di chloromethane (5 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (dichloromethane / methanol, 10: 1). The product was further purified by preparative reverse phase HPLC (acetonitrile / water (with 10 mM NH4HCO3 and 0.1%NH3.H2O ) gradient) to afford the title compound (59.6 mg, 25.4% yield).

[0388] LCMS (ESI) m / z = 431 [M+H]+.

[0389] ^NMR (400 MHz, CDCh) 5 8.90 (s, 1H), 7.15-7.09 (m, 2H) , 6.83-6.79 (m, 1H), 5.31 (s, 1H), 4.11-4.05 (m, 3H), 3.80-3.75 (m, 2H), 3.67-3.43 (m, 6H), 3.05-2.98 (m, 2H), 2.84 (s, 3H), 2.48 (s, 3H), 2.26-2.19 (m, 4H), 1.81-1.69 (m, 2H).Example 31: N-(l-(methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2- yl)quinazolin-2-amineStep 1: tert-butyl 2-(2-((l -(methyl sulfonyl) piperidin-4-yl) amino) quinazolin-8-yl)-2,6- diazaspiro [3.4] octane-6-carboxylate

[0390] To a mixture of 8-bromo-N-(l -(methyl sulfonyl) piperidin-4-yl) quinazolin-2-amine (80 mg, 0.21 mmol), tert-butyl 2,6-diazaspiro [3.4] octane-6-carboxylate (53 mg, 0.25 mmol) and cesium carbonate (205 mg, 0.63 mmol) in 1,4-dioxane (3.0 mL) was added Pd-PEPPSI01(10.18 mg, 0.01 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. H2O (0.1 mL) was added to the mixture and the residue was purified by preparative reverse phase HPLC to provide the title compound (50 mg, 38% yield) as a yellow solid. LCMS (ESI) [M+H]+= 517.1Step 2: N-(l -(methyl sulfonyl) piperidin-4-yl)-8-(2,6-diazaspiro [3.4] octan-2-yl) quinazolin- 2-amine

[0391] To a mixture of tert-butyl 2-(2-((l -(methyl sulfonyl) piperidin-4-yl) amino) quinazolin-8-yl)-2,6-diazaspiro [3.4]octane-6-caiboxylate (50 mg, 0.10 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (0.25 mL, 3.98 mmol). The mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and dissolved in DMSO / MeOH / EtaN (1 : 1 :0.05, 3 mL). The mixture was purified by preparative reverse phase HPLC to give the title compound (12.9 mg, 32% yield) as a yellow solid. LCMS (ESI) [M+H]+= 417.1.Example 32: N-(l -(methyl sulfonyl) oioeridin-4-yl)-8-(2.6-diazaspiro [3.41 octan-2-yl) guinazolin-2-amineStep 1: Tert-butyl 2-(2-((l-(methyl sulfonyl) piperidin-4-yl) amino) quinazolin-8-yl)-2,6- diazaspiro [3.4] octane-6-carboxylate

[0392] To a mixture of 8-bromo-N-(l -(methyl sulfonyl) piperidin-4-yl) quinazolin-2-amine(80 mg, 0.21 mmol), tert-butyl 2,6-diazaspiro [3.4] octane-6-carboxylate (53 mg, 0.25 mmol)and cesium carbonate (205 mg, 0.63 mmol) in 1,4-dioxane (3.0 mL) was added Pd-PEPPSI01(10.18 mg, 0.01 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. H2O (0.1 mL) was added to a mixture and the residue was purified by preparative reverse phase HPLC to provide the title compound (50 mg, 38% yield). LCMS (ESI) [M+H]+= 517.1Step 2: N-(l-(methyl sulfonyl) piperidin-4-yl)-8-(2,6-diazaspiro [3.4] octan-2-yl) quinazolin-2-amine (Example 31)

[0393] To a mixture of tert-butyl 2-(2-((l -(methyl sulfonyl) piperidin-4-yl) amino) quinazolin-8-yl)-2,6-diazaspiro [3.4]octane-6-caiboxylate (50 mg, 0.10 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (0.25 mL, 3.98 mmol). The mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue dissolved in DMSO / MeOH / EtaN (1 : 1 :0.05, 3 mL). The mixture was purified by preparative reverse phase HPLC to give the title compound (12.9 mg, 32% yield). LCMS (ESI) [M+H]+= 417.1.Example 33: l-(7-(2-((4-(4-methvlDinerazin-l-vl)Dhenvl)amino) guinazolin-8-vl)-2.7- diazasDiror4.41nonan-2-vDethan- 1 -oneReaction SchemeDetailed ProcedureStep 1: 8-bromo-N-(4-(4-methylpiperazin-l-yl)phenyl)quinazolin-2-amine

[0394] A drop of cone. HCI was added to a mixture of 4-(4-methylpiperazin-l-yl)aniline (191 mg, 1.00 mmol) and 8-bromo-2-chloroquinazoline (243 mg, 1.00 mmol) in MeOH (4 mL). The resulting mixture was stirred at 80 °C for 4 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 0:100 to 10:90) to afford the desired product 8-bromo-N-(4-(4-methylpiperazin-l- yl)phenyl)quinazolin-2-amine (180 mg, 42.1% yield).

[0395] LCMS (ESI-MS) m / z = 398.1 [M+H]+.Step 2: l-(7-(2-((4-(4-methylpiperazin-l-yl)phenyl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4] nonan-2-yl)ethan-l-one

[0396] Pd2(dba)3 (18.4 mg, 0.02 mmol) was added to a mixture of 8-bromo-N-[4-(4- methylpiperazin-l-yl)phenyl]quinazolin-2-amine (80 mg, 0.21 mmol), l-(2,7- diazaspiro[4.4]nonan-2-yl)ethan-l-one (33.8 mg, 0.20 mmol), BINAP (12.5 mg, 0.02 mmol) and CS2CO3 (196 mg, 0.60 mmol) in 1,4-dioxane (4 mL) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to afford the desired product l-(7-(2-((4-(4- methylpiperazin-l-yl)phenyl)amino) quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-l- one (40.7 mg, 41% yield) (Example 33).

[0397] ^NMR (400 MHz, DMSO^fc) 59.32 (s, IH), 9.10 (s, IH), 7.55-7.51 (m, 2H), 7.18- 7.11 (m, 2H), 7.02-6.82 (m, 3H), 3.67-3.40 (m, 7H), 3.38-3.21 (m, 2H), 3.17-2.97 (m, 4H), 2.50-2.49 (m, 4H), 2.22 (s, 3H), 1.95-1.82 (m, 6H).LCMS (ESI-MS) m / z = 486.2 [M+H]+, .3% purity.Example 35: 1 -(7-(2-(( 1 -(methvlsulfonvl)DiDeridin-4-vl')amino)auinazolin-8-vD-2- azaspiror4.41 nonan-2-yDethan-l-oneReaction SchemeDetailed ProcedureStep 11:: Tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2- carboxylate

[0398] A solution of LiHMDS (1 M, 4.10 mL, 4.10 mmol) in THF was added to a stirred mixture of tert-butyl 7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (500 mg, 2.04 mmol) in THF (6 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under a nitrogen atmosphere and a solution of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (1.10 g, 3.07 mmol) in THF (6 mL) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, quenched by addition of saturated aqueous NH4CI (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, from 0:100 to 10:90) to afford tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate (700 mg, 73.6% yield).

[0399] LCMS (ESI-MS) m / z =372.1 [M+H]+.Step 2: Tert-butyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7- ene-2-carboxylate

[0400] A mixture of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene- 2-carboxylate (650 mg, 1.58 mmol), bis(pinacolato)diboron (606 mg, 2.36 mmol),mL) was stirred for 16 h at 80 °C under a nitrogen atmosphere. After cooled to roomtemperature, the reaction mixture was concentrated under reduced pressure directly. The residue was purified by silica-gel column chromatography (EA / PE, 0:100 to 50:50) to afford the desired product tert-butyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- azaspiro[4.4]non-7-ene-2-carboxylate (850 mg, 84.3% yield).

[0401] LCMS (ESI-MS) m / z = 350.2 [M+H]+.Step 3: Tert-butyl 7-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2- azaspiro[4.4]non-7-ene-2-carboxylate

[0402] A mixture of tert-butyl 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- azaspiro[4.4]non-7-ene-2-carboxylate (850 mg, 1.33 mmol), 8-bromo-N-(l- (m ethyl sulfonyl)piperidin-4-yl)quinazolin-2-amine (517 mg, 1.33 mmol), Pd(dppf)C12.CH2Cl2(54.7 mg, 0.06 mmol) and K2CO3 (371 mg, 2.66 mmol) in 1,4-dioxane (4 mL) and water (2 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography(EA / PE, 0:100 to 70:30) to afford the desired product tert-butyl 7-(2-((l-(methylsulfonyl)piperidin-4- yl)amino)quinazolin-8-yl)-2-azaspiro[4.4] non-7-ene-2-carboxylate (750 mg, 69.6% yield).

[0403] LCMS (ESI-MS) m / z = 528.3 [M+H]+.Step 3: Tert-butyl 7-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2- azaspiro[4.4]nonane-2-carboxylate

[0404] Pd / C (10% on carbon, 25.8 mg) was added to a mixture of tert-butyl 7-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4] non-7-ene-2- carboxylate (50 mg, 0.06 mmol) in MeOH (3 mL). The resulting mixture was stirred for 1 hat room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude product tert-butyl 7-(2-((l- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4] nonane-2-carboxylate (180 mg crude).

[0405] LCMS (ESI-MS) m / z = 530.3 [M+H]+.Step 4: N-(l-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2- amine

[0406] TFA (0.2 mL) was added to a stirred mixture of tert-butyl 7-(2-((l- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonane-2-carboxylate (50 mg, 0.06 mmol) in DCM (0.6 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure to afford crude N-(l- (methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2-amine (180 mg crude).

[0407] LCMS (ESI-MS) m / z = 430.2 [M+H]+.Step 5: l-(7-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2- azaspiro[4.4]nonan-2-yl)ethan-l-one

[0408] AC2O (6.31 mg, 0.06 mmol) was added to a stirred mixture of N-(l- (methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2-amine (35 mg, 0.06 mmol) and EfoN (24.7 mg, 0.2 mmol) in DCM (0.5 mL). The resulting mixture was stirred at 0 °C for 1 h and concentrated under reduced pressure. The residue was purified bypreparative RP-HPLC to afford the desired product l-(7-(2-((l-(methylsulfonyl)piperidin-4- yl)amino)quinazolin-8-yl)-2-azaspiro[4.4] nonan-2-yl)ethan-l-one (29.0 mg, 99.4% yield).

[0409] XHNMR (300 MHz,7.53-7.65 (m, 2H), 7.45-7.52 (m, 1H), 7.14-7.21 (m, 1H), 3.96-4.13 (m, 2H), 3.61-3.85 (m, 3H), 3.42-3.57 (m, 2H), 3.22-3.39 (m, 1H), 2.80-3.07 (m, 5H), 2.08-2.29 (m, 4H), 1.51-2.07 (m, 11H).

[0410] LCMS (ESI-MS) m / z = 472.2 [M+H]+, 98.9% purity.Example 45: l-(7-(7-fluoro-2-((l -(methyl sulfonvllpiperi din-4-vl)aminokiuinazolin-8-vl)- 2.7-diazaspiror4.41nonan-2-vl')ethan-l-one

[0411] A mixture of 8-bromo-7-fluoro-N-(l-methanesulfonylpiperidin-4-yl)quinazolin-2- amine (80 mg, 0.19 mmol), l-(2,7-diazaspiro[4.4]nonan-2-yl)ethan-l-one (33.4 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium (18.2 mg, 0.02 mmol), l.l'-Binaphthyl-2.2'- diphemyl phosphine (24.7 mg, 0.04 mmol) and sodium t-butoxide (38.1 mg, 0.39 mmol) in 1,4-dioxane (3 mL) was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrousand concentrated under reduced pressure. The residue (100 mg) was purified by preparative RP-HPLC to afford the desired product l-(7-(7-fluoro-2-((l- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan- l-one (28.5 mg, 29.2% yield).

[0412] 7.48-7.32 (m, 2H), 7.05-7.00 (m, 1H), 3.83-3.42 (m, 11H), 2.92-2.82 (m, 5H), 2.07-1.90 (m, 9H), 1.61-1.54 (m, 2H).

[0413] LCMS (ESI-MS) m / z = 491.1 [M+H]+.Example 46:

[0414] A mixture of 8-bromo-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2- yl)quinazolin-2-amine (80 mg, 0.18 mmol), l-(2,7-diazaspiro[4.4]nonan-2-yl)ethan-l-one (28.7 mg, 0.17 mmol), CS2CO3 (176 mg, 0.54 mmol), BINAP (10.6 mg, 0.017 mmol) and Pd2(dba)s (15.7 mg, 0.017 mmol) in 1,4-dioxane (1 mL) was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (2 x 5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by Prep-TLC (MeOH / DCM, 1:10). The residue was further purified purified by preparative RP-HPLC to afford the desired product l-(7-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2- yl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-l-one (19.6 mg, 22.3% yield).

[0415] XH NMR (300 MHz, Chloroform^) 59.07 (d, J = 4.2 Hz, 1H), 8.15 (dd, J = 8.8, 4.1 Hz, 1H), 7.81 (s, 1H), 7.63 (t, J = 2.7 Hz, 1H), 7.26-7.15 (m, 2H), 6.95-6.82 (m, 2H), 4.07- 3.97 (m, 4H), 3.79-3.53 (m, TH), 3.51-3.39 (m, 5H), 2.51 (dd, J = 7.2, 4.7 Hz, 2H), 2.14-2.01 (m, TH), 1.08-0.93 (m, 3H).

[0416] LCMS (ESI-MS) m / z = 513.3 [M+H]+, 99.6 % purity.Example 58: 6-(difluoromethvD-N-(2-methvlisoindolin-5-vl)-8-(6-(methvlsulfonvl)-2.6- diazaspiror 3.3 lheptan-2-vDauinazolin-2-amine

[0417] Pd-PEPPSI-IHeptCh-chloropyridine (20.4 mg, 0.02 mmol) was added to a mixture of 8-bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine (85 mg, 0.21 mmol), 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (36.9 mg, 0.21 mmol) and CS2CO3 (205 mg, 0.63 mmol) in 1,4-dioxane (2 mL) under a nitrogen atmosphere. The resultingmixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10). The product was further purified by preparative RP-HPLC to afford the desired product 6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)-8-(6- (methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)quinazolin-2-amine (23.2 mg, 21.7% yield) (Example 58) .

[0418] 1H), 7.29 (s, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.69(t, J=54.3 Hz, 2H), 4.35 (s, 4H), 4.15 (s, 4H), 4.04 (d, J = 10.9 Hz, 4H), 2.92 (s, 3H), 2.69 (s, 3H).

[0419] LCMS (ESI-MS) m / z =501.0 [M+H]+.Example 67: 6-(difluoromethvD-8-(2-methvl-2-azasDiror3.31heDtan-6-vl)-N-(l- (methylsulfonyl)DiDeridin-4-yl)auinazolin-2-amineReaction Scheme

[0420] An oven-dried 20 mL vial was charged with 4,4'-di-tert-butyl-2,2'-bipyridine (30.8 mg, 0.11 mmol) and NiCh.dme (25.2 mg, 0.11 mmol). DCE (3 mL) was added under a nitrogen atmosphere and the reaction mixture was stirred at 60 °C for 10 minutes (mixture A). Another oven-dried 40 mL vial was charged with 8-bromo-6-(difluoromethyl)-N-(l- (methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (500 mg, 1.15 mmol), tert-butyl 6-iodo-2- azaspiro[3.3]heptane-2-carboxylate (744 mg, 2.30 mmol), 1,1, 1,3,3, 3 -hexamethyl -2- (trimethylsilyl)trisilane (314 mg, 1.26 mmol), Na2CO3(243 mg, 2.30 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (16.6 mg, 0.11 mmol). DCE (5 mL) was added under a nitrogen atmosphere (mixture B). The mixture A was added to the mixture B under a nitrogen atmosphere and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 6 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2:1) to afford tert-butyl 6-(6-(difluoromethyl)-2-((l-(methylsulfonyl)piperidin-4- yl)amino)quinazolin-8-yl)-2-azaspiro[3.3]heptane-2-caiboxylate (230 mg).

[0421] LCMS (ESI-MS) m / z = 552.2 [M+H]+.Step 2: 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(2- azaspiro[3.3]heptan-6-yl)quinazolin-2-amine

[0422] TFA (1 mL) was added to a stirred mixture of tert-butyl 6-(6-(difluoromethyl)-2-((l- (methylsulfonyl) piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.41 mmol) in DCM (3 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 10:90) to afford 6-(difluoromethyl)-N-(l- (methyl sulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3 ]heptan-6-yl)quinazolin-2-amine (100 mg, 47.8% yield).LCMS (ESI-MS) m / z = 452.1 [M+H]+.Step 3: 6-(difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-N-(l-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0423] A solution of 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(2- azaspiro[3.3]heptan-6-yl) quinazolin-2-amine (70 mg, 0.15 mmol) and HCHO (23.3 mg, 0.77 mmol) in MeOH (1 mL) was stirred for 1 h at room temperature. NaBHaCN (97.4 mg, 1.55 mmol) was added and the resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1 :7). The product was further purified by preparative RP-HPLC to afford 6-(difluoromethyl)- 8-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-N-(l-(methylsulfonyl)piperidin-4-yl)quinazolin-2- amine (7.9 mg, 10.7% yield).XH NMR (400 MHz, Chloroform^) 5 8.97 (s, 1H), 7.70-7.54 (m, 2H), 6.71 (t, J = 56.4 Hz, 1H), 5.30 (d, J = 7.3 Hz, 1H), 4.14-3.95 (m, 2H), 3.80 (d, J = 12.4 Hz, 2H), 3.47 (s, 2H), 3.20 (s, 2H), 3.08-2.97 (m, 2H), 2.86 (s, 3H), 2.72-2.63 (m, 2H), 2.39-2.27 (m, TH), 1.75 (s, 1H), 1.25 (s, 1H). LCMS (ESI-MS) m / z = 466.1 [M+H]+.Example 74: N-( 1 -(cvcloDroDvlsulfonvDDiDeridin-4-vl)-6-(difluoromethvl)-8-(2.6- diazaspiror 3.41octan-2-vl)guinazolin-2-amineReaction SchemeStep 1: 8-bromo-N-(l-(cyclopropylsulfonyl)piperidin-4-yl)-6- (difluoromethyl)quinazolin-2-amine

[0424] K2CO3 (1.84 g, 13.3 mmol) was added to a mixture of 1- (cyclopropylsulfonyl)piperidin-4-amine (0.90 g, 4.42 mmol) and 8-bromo-2-chloro-6- (difluoromethyl)quinazoline (1.3 g, 4.42 mmol) in DMSO (10 mL). The resulting mixture was stirred at 100 °C for 1 h, diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(EA / PE, 4:1) to afford 8-bromo-N-(l-(cyclopropylsulfonyl)piperidin-4-yl)-6- (difluoromethyl) quinazolin-2-amine (1.2 g, 55.8% yield).

[0425] LCMS (ESI-MS) m / z = 461.2 [M+H]+.Step 2: tert-butyl 2-(2-((l-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6- (difluoromethyl)quinazolin-8-yl)-2,6-diazaspiro [3.4] octane-6-carboxylate- 103 -

[0426] A solution of 8-bromo-N-(l-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl) quinazolin-2-amine (150 mg, 0.32 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (69.0 mg, 0.32 mmol), sodium 2-methylpropan-2-olate (93.7 mg, 0.97 mmol), BINAP (20.3 mg, 0.03 mmol) and Pd2(dba)j (29.8 mg, 0.03 mmol) in 1,4-dioxane (1 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to afford tert-butyl 2-(2-((l-(cyclopropylsulfonyl)piperidin-4-yl)amino)- 6-(difluoromethyl)quinazolin-8-yl)-2,6-diazaspiro [3.4]octane-6-carboxylate (90 mg, 42.0% yield).

[0427] LCMS (ESI-MS) m / z = 593.4 [M+H]+.Step 33:: N-(l-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6- diazaspiro [3.4] octan-2-yl)quinazolin-2-amine

[0428] TFA (0.3 mL) was added to a stirred mixture of tert-butyl 2-(2-((l- (cyclopropylsulfonyl)piperidin-4-yl)amino)-6-(difluoromethyl)quinazolin-8-yl)-2,6- diazaspiro[3.4]octane-6-carboxylate (80 mg, 0.13 mmol) in DCM (1 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10). The product was further purified by preparative RP-HPLC to afford N-(l-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl) quinazolin-2-amine (18.3 mg, 27.2% yield) (Example 74).

[0429] 1H NMR (400 MHz, DMSO^fc) 59.09 (s, 1H), 7.64-7.49 (m, 1H), 7.31 (s, 1H), 6.99 (t, J = 56.1 Hz, 1H), 6.56 (d, J = 7.0 Hz, 1H), 4.14 (d, J = 9.8 Hz, 3H), 3.87 (s, 1H), 3.65 (d, J = 12.8 Hz, 2H), 3.06-2.93 (m, 4H), 2.91-2.81 (m, 2H), 2.67-2.57 (m, 2H), 2.09-1.92 (m, 4H), 1.66-1.51 (m, 2H), 1.24 (s, 1H), 1.05-0.91 (m, 4H).

[0430] LCMS (ESI-MS) m / z = 493.1 [M+H]+, 98.6 % purity.Example 89: 6-(difluoromethvD-8-(2-(2-methoxvethvl)-2-azaspiror3.31heptan-6-vD-N-(l- (methylsulfonyl)piperidin-4-yl)auinazolin-2-amine

[0431] K2CO3 (61.21 mg, 0.44 mmol) was added to a mixture of 6-(difluoromethyl)-A-(l- (methyl sulfonyl) piperidin-4-yl)-8-(2-azaspiro[3.3]heptan-6-yl)quinazolin-2-amine (100 mg, 0.22 mmol) and 2-bromoethyl methyl ether (30.8 mg, 0.22 mmol) in MeCN (4 mL). The resulting mixture was stirred for 2 days at room temperature, diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to afford 6-(difluoromethyl)-8-(2-(2- methoxyethyl)-2-azaspiro[3.3]heptan-6-yl)-Ar-(l-(methylsulfonyl) piperidin-4-yl)quinazolin- 2-amine (7.3 mg, 6.33% yield) (Example 89).

[0432] XH NMR (400 MHz, Chloroform^) 5 8.98 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 6.72 (t, J = 56.4 Hz, 1H), 5.39 (d, J = 7.3 Hz, 1H), 4.16-3.94 (m, 2H), 3.87-3.76 (m, 2H), 3.66-3.60 (m, 2H), 3.46 (t, J = 5.4 Hz, 2H), 3.36 (s, 5H), 3.13-3.01 (m, 2H), 2.89 (s, 3H), 2.79-2.64 (m, 4H), 2.42-2.24 (m, 4H), 1.83-1.67 (m, 2H).

[0433] LCMS (ESI-MS) m / z = 510.3 [M+H]+.Example 101: 6-(difluoromethyD-N-( 1 -(methylsulfonyl)piperidin-4-yl)-8-(6-(3.3.3 - trifluoropropyl)-6-azaspiror3.41octan-2-yl)auinazolin-2-amineReaction SchemeDetailed ProcedureStep 1: Tert-butyl 2-(6-(difluoromethyl)-2-((l-(methylsulfonyl)piperidin-4- yl)amino)quinazolin-8-yl)-6-azaspiro [3.4] octane-6-carboxylate

[0434] An oven-dried 20 mL vial was charged with tert-butyl 2-hydroxy-6- azaspiro[3.4]octane-6-caiboxylate (548 mg, 2.41 mmol) and 5,7-Di-tert-butyl-3- phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (871 mg, 2.21 mmol). Under nitrogen, tert-butyl methyl ether (24 mL) was added and the reaction stirred at room temperature for 5 minutes. A mixture of pyridine (401 mg, 5.10 mmol) in tert-butyl methyl ether (6 mL) was added and the mixture stirred at room temperature for 10 minutes (mixture A). Another oven- dried 40 mL vial was charged with 8-bromo-6-(difluoromethyl)-N-(l-(methyl sulfonyl)piperidin-4-yl)quinazolin-2-amine (600 mg, 1.37 mmol), NiBr2(dtbbpy)(33.56 mg, 0.06 mmol), Ir(ppy)2(dtbbpy)PF6 (18.9 mg, 0.021 mmol) and 1-azabicyclo[2.2.2]octane (Q, 268.2 mg, 2.41 mmol). DMA (30 mL) was added under nitrogen (mixture B). The mixture A was added to the mixture B under a nitrogen atmosphere and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layer was dried over anhydrous Na2,S fiOl4tered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2: 1) to afford methyl 1 -methyl-3 -(6-methyl-2-(( 1 -(methylsulfonyl)piperidin-4-yl)amino)pyrido[3 ,4-d]pyrimidin-8- yl) cyclobutane- 1 -carboxylate (700 mg).

[0435] LCMS (ESI-MS) m / z = 566.2 [M+H]+.Step 2: 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3.4]octan- 2-yl)quinazolin-2-amine

[0436] TFA (2 mL) was added to a stirred mixture of tert-butyl 2-(6-(difluoromethyl)-2-((l- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (700 mg, 1.23 mmol) in DCM (6 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to afford 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6- azaspiro[3.4]octan-2-yl)quinazolin-2-amine (500 mg, 86.8% yield).

[0437] LCMS (ESI-MS) m / z = 466.2 [M+H]+.Step 33:: 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6-(33»3- trifluoropropyl)-6-azaspiro [3.4] octan-2-yl)quinazolin-2-amine

[0438] K2CO3 (89.1 mg, 0.64 mmol) was added to a mixture of l,l,l-trifluoro-3 -iodopropane (48.1 mg, 0.21 mmol) and 6-(difhioromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6- azaspiro[3.4]octan-2-yl)quinazolin-2-amine (100 mg, 0.21 mmol) in MeCN (1 mL). The resulting mixture was stirred overnight at 50 °C, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to afford 6- (difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6-(3,3,3-trifluoropropyl)-6- azaspiro[3.4]octan-2-yl)quinazolin-2-amine (9.8 mg, 8.1% yield).

[0439] XH NMR (400 MHz, Chloroform-d) 5 8.98 (s, 1H), 7.72-7.53 (m, 2H), 6.72 (t, J = 56.4 Hz, 1H), 5.30 (d, J = 7.1 Hz, 1H), 4.2-4.02 (m, 2H), 3.78 (dd, J = 10.9, 6.0 Hz, 2H), 3.09-2.94 (m, 2H), 2.85 (s, 3H), 2.76-2.65 (m, 4H), 2.62 (s, 2H), 2.57-2.47 (m, 2H), 2.40- 2.23 (m, 6H), 2.22-2.15 (m, 2H), 1.81-1.69(m, 2H).

[0440] LCMS (ESI-MS) m / z = 562.3 [M+H]+.Example 102:6-(difluoromethvD-N-(l-(methvlsulfonvDDiDeridin-4-vD-8-(6-(oxetan-3-vl)-6- azaspiroF 3.41octan-2-vl)quinazolin-2-amine

[0441] STAB (91.1 mg, 0.43 mmol) was added to a mixture of oxetan-3-one (15.5 mg, 0.21 mmol) and 6-(difluoromethyl)-N-(l -(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3 ,4]octan- 2-yl)quinazolin-2-amine (100 mg, 0.21 mmol) in DCM (1 mL). The resulting mixture was stirred overnight at room temperature, diluted with water (10 mL) and extracted with DCM (3x 10 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP- HPLC to afford 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6-(oxetan-3-yl)- 6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine (6.2 mg, 5.5% yield) (Example 102).

[0442] XHNMR (400 MHz, Chloroform^) 59.04-8.91 (m, 1H), 7.71-7.50 (m, 2H), 6.71 (t, J = 59.2 Hz, 1H), 5.35 (s, 1H), 4.75-4.57 (m, 3H), 4.21-3.93 (m, 2H), 3.85-3.62 (m, 2H), 3.08- 2.76 (m, 4H), 2.74-2.44 (m, 5H), 2.36-1.95 (m, 6H), 1.84-1.54 (m, 2H), 1.26 (s, 3H), 0.88 (s, 1H).

[0443] LCMS (ESI-MS) m / z = 522.4 [M+H]+.Example 106: 3-(2-(6-(difluoromethyD-2-((l-(methylsulfonyDpiperidin-4- vDamino'kminazolin-8-vl')-6-azaspiror3.41octan-6-vl')-2.2-difluoropropan-l-ol

[0444] A solution of 6-(difluoromethyl)-N-(l-(methylsulfonyl)piperidin-4-yl)-8-(6- azaspiro[3.4]octan-2-yl)quinazolin-2-amine (120 mg, 0.25 mmol), K2CO3 (24.9 mg, 0.18 mmol) and 5,5-difluoro-l,3,2-dioxathiane 2,2-dioxide (45.8 mg, 0.26 mmol) in ACN (1 mL) was stirred for 4 h at 80 °C. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with MeCN (2 x 0.5 ml). To the combined filtrate was added 4-methylbenzene-l -sulfonic acid hydrate (53.9 mg, 0.28 mmol) and H2O (51.1 mg, 2.83 mmol). The resulting biphasic mixture was heated to 80 °C and stirred for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM (2 x 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to afford 3-(2-(6-(difluoromethyl)-2-((l-(methylsulfonyl)piperidin-4- yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octan-6-yl)-2,2-difluoropropan-l-ol (2.7 mg, 1.8% yield) (Example 106).

[0445] XH NMR (400 MHz, Methanol^) 59.05 (d, J = 2.1 Hz, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 6.85 (t, J = 56.3 Hz, 1H), 5.36 (t, J = 4.8 Hz, 1H), 4.18-4.04 (m, 2H), 3.83-3.70 (m, 4H), 3.08-2.97 (m, 4H), 2.91 (s, 3H), 2.85 (t, J = 6.8 Hz, 1H), 2.75 (d, J = 3.6 Hz, 2H), 2.64-2.50(m, 2H), 2.28-2.18 (m, 5H), 2.04 (d, J = 6.1 Hz, 1H), 1.90 (d, J = 2.6 Hz, 1H), 1.80-1.72 (m, 2H), 1.62 (s, 1H). LCMS (ESI-MS) m / z = 560.4 [M+H]+, 95.1 % purity.Example 116: 8-( 8.8-difluoro-2.6-diazasDiror 3.41octan-2-vl)-Ar-( 1 -(methvlsulfonvDDiDeridin-4-vl)-6-(trifluoromethvDauinazolin-2-amineReaction SchemeStep 1 : 8-bromo-7V-(l-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2- amine

[0446] K2CO3 (399 mg, 2.88 mmol) was added to a mixture of 8-bromo-2-chloro-6- (trifluoromethyl) quinazoline (300 mg, 0.96 mmol) and l-methanesulfonylpiperidin-4-amine (171 mg, 0.96 mmol) in DMSO (8 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was quenched by addition of water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 1:1) to afford 8-bromoW-(l-(methylsulfonyl) piperidin-4-yl)-6-(trifhioromethyl)quinazolin-2-amine (400 mg, 91.6% yield).

[0447] LCMS (ESI-MS) m / z = 453.0 [M+H]+.Step 2: Benzyl 8,8-difluoro-2-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)-2,6-diazaspiro [3.4] octane-6-carboxylateCb

[0448] Pd-PEPPSI-IHeptCl 3 -chloropyridine (23.6 mg, 0.02 mmol) was added to a mixture of 8-bromo-7V-(l -(methyl sulfonyl) piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine (110 mg, 0.24 mmol), benzyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (68.5 mg, 0.24 mmol) and CS2CO3 (158 mg, 0.48 mmol) in 1,4-dioxane (1 mL) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2: 1) to afford benzyl 8,8- difluoro-2-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)- 2,6-diazaspiro[3.4]octane-6-caiboxylate (110 mg, 73.0% yield).LCMS (ESI-MS) m / z = 655.2 [M+H]+.Step 3: 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-2-yl)-AL(l-(methylsulfonyl)piperidin-4- yl)-6-(trifluoromethyl)quinazolin-2-amine

[0449] Pd / C (10% on carbon, 10 mg) was added to a mixture of benzyl 8,8-difluoro-2-(2-((l- (methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)-2,6- diazaspiro[3.4]octane-6-carboxylate (100 mg, 0.15 mmol) in MeOH (8 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under a hydrogen atmosphere, filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10). The product was further purified by preparative RP-HPLC to afford 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-2-yl)-Ar-(l-(methylsulfonyl)piperidin-4-yl)-6- (trifluoromethyl)quinazolin-2-amine (9.8 mg, 12.2% yield) (Example 116).IH), 4.34 (d, J = 8.7 Hz, 2H), 4.11 (d, J = 8.7 Hz, 2H), 3.86 (s, IH), 3.68-3.52 (m, 3H), 3.26 (s, 2H), 3.17 (t, J = 14.2 Hz, 2H), 2.97-2.81 (m, 5H), 2.12-1.95 (m, 2H), 1.70-1.53 (m, 2H). LCMS (ESI-MS) m / z = 521.2 [M+H]+.Example 117: (3 S.4R)-4-((8-(8.8-difluoro-2.6-diazaspiror3.41octan-6-yD-6-(difluoromethyD auinazolin-2-yDamino)tetrahydro-2H-pyran-3-olReaction Scheme

[0450] K2CO3 (360 mg, 2.60 mmol) was added to a mixture of racemic (3S,4R)-4- aminotetrahydro-2H-pyran-3-ol hydrochloride (100 mg, 0.65 mmol) and 8-bromo-2-chloro- 6-(difluoromethyl)quinazoline (191 mg, 0.65 mmol) in DMSO (5 mL). The resulting mixture was stirred for 1 h at 100 °C. After cooling to room temperature, the reaction mixture wasquenched by addition of water (30 mL) and extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, from 80:20 to 100:0) to afford racemic (3S,4R)-4-((8- bromo-6-(difluoromethyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-3-ol (130 mg, 48.03%yield).

[0451] LCMS (ESI-MS) m / z = 374.1 [M+H]+.Step 2: Racemic tert-butyl6-(6-(difluoromethyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)quinazolin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate

[0452] Pd-PEPPSI-IPentCl (23.0 mg, 0.02 mmol) was added to a mixture of racemic (3S,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-3-ol (100 mg, 0.26 mmol), tert-butyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-caiboxylate (66.4 mg, 0.26 mmol) and CS2CO3 (174 mg, 0.53 mmol) in 1,4-dioxane (1 mL) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered, the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, from 80:20 to 100:0) to afford racemic tert-butyl 6-(6-(difluoromethyl)-2-(((3S,4R)-3-hydroxytetrahydro- 2H-pyran-4-yl)amino)quinazolin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (80 mg, 49.7% yield).LCMS (ESI-MS) m / z = 542.5 [M+H]+.Step 3: Racemic (3S,4R)-4-((8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6- (difluoromethyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0453] TFA (0.3 mL) was added to a stirred mixture of racemic tert-butyl 6-(6- (difhioromethyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)quinazolin-8-yl)- 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-caiboxylate (80 mg, 0.14 mmol) in DCM (1 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to afford racemic (3S,4R)-4-((8- (8,8-difluoro-2,6-diazaspiro[3 ,4]octan-6-yl)-6-(difhioromethyl) quinazolin-2- yl)amino)tetrahydro-2H-pyran-3-ol (13.8 mg, 21.1% yield) (Example 117).

[0454] JHNMR (400 MHz, DMSO^fc) 5 8.97 (s, 1H), 7.34-7.27 (m, 1H), 6.94-6.88 (m, 1H), 6.82-6.53 (m, 1H), 5.58 (s, 1H), 4.56-4.42 (m, 1H), 4.35-4.21 (m, 3H), 4.17-4.11 (m, 3H), 4.06-4.03 (m, 1H), 3.94-3.92 (m, 2H), 3.67-3.46 (m, 5H), 2.42-2.25 (m, 1H) , 1.78-1.60 (m, 1H), 1.35-1.22 (m, 1H).

[0455] LCMS (ESI-MS) m / z = 442.1 [M+H]+.Example 118: (3R_4R')-4-((8-(8.8-difluoro-2.6-diazasDiror3.41octan-6-vl')-6-(difluoromethvD auinazolin-2-vl) amino)-l-(methvlsulfonvlh)iDeridin-3-olReaction SchemeDetailed ProcedureStep 1: Racemic (3R,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)-l- (methylsulfonyl)piperidin-3-ol

[0456] K2CO3 (107 mg, 0.77 mmol) was added to a mixture of racemic (3R,4R)-4-amino-l- (methylsulfonyl)piperidin-3-ol (50 mg, 0.25 mmol) and 8-bromo-2-chloro-6- (difluoromethyl)quinazoline (75.6 mg, 0.25 mmol) in DMSO (2 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was quenched by addition of water (15 mL) and extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford racemic (3R,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)-l- (methylsulfonyl)piperidin-3-ol (100 mg, 86.1% yield).

[0457] LCMS (ESI-MS) m / z = 451.0 [M+H]+.Step 2: Racemic tert-butyl 6-(6-(difluoromethyl)-2-(((3R,4R)-3-hydroxy-l- (methylsulfonyl)piperidin-4-yl)amino) quinazolin-8-yl)-8,8-difluoro-2,6- diazaspiro [3.4] octane-2-carboxylate

[0458] Pd-PEPPSI-IHeptCl 3-chloropyridine (19.4 mg, 0.02 mmol) was added to a mixture of racemic (3R,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)-l- (methylsulfonyl)piperidin-3-ol (90 mg, 0.20 mmol), tert-butyl 8,8-difluoro-2,6- diazaspiro[3.4]octane-2-carboxylate (49.5 mg, 0.20 mmol) and CS2CO3 (130 mg, 0.40 mmol) in 1,4-dioxane (2 mL) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (20 mL). The filtratewas concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford racemic tert-butyl 6-(6-(difluoromethyl)-2-(((3R,4R)-3 -hydroxy- 1- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-8,8-difluoro-2,6- diazaspiro[3.4]octane-2-carboxylate (40 mg, 32.4% yield).LCMS (ESI-MS) m / z = 619.2 [M+H]+.Step 3: Racemic (3R,4R)-4-((8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6- (difluoromethyl)quinazolin-2-yl)amino)-l-(methylsulfonyl)piperidin-3-ol

[0459] TFA (0.3 mL) was added to a stirred mixture of racemic tert-butyl 6-(6- (difluoromethyl)-2-(((3R,4R)-3-hydroxy-l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin- 8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate (75 mg, 0.12 mmol) in DCM (0.9 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1 : 10) to afford racemic (3R,4R)-4-((8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-(difluoromethyl) quinazolin-2-yl) amino)-l-(methylsulfonyl)piperidin-3-ol (41.7 mg, 66.0% yield) (Example 118).

[0460] (m, 2H), 4.37-3.91 (m, 7H), 3.90-3.48 (m, TH), 3.00-2.86 (m, 4H), 2.80-2.68 (m, 1H), 2.29- 2.13 (m, 1H), 1.65-1.44 (m, 1H). LCMS (ESI-MS) m / z = 519.1[M+H]+.Example 120 l-(difluoromethvD-3-(2-((l-(methvlsulfonvDpiperidin-4-vDamino)auinazolin- 8-vlkvclobutan- 1 -olReaction SchemeDetailed ProcedureStep 1 : l-(difluoromethyl)-3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8- yl)cyclobutyl benzoate

[0461] An oven-dried 20 mL vial was charged with l-(difhioromethyl)-3-hydroxycyclobutyl benzoate (110 mg, 0.45 mmol) and 5,7-Di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (164 mg, 0.42 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction stirred at room temperature for 5 minutes. A mixture of pyridine (32.8 mg, 0.42 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture stirred at room temperature for 10 minutes (mixture A). Another oven-dried 40 mL vial was charged with 8-bromo-N-(l-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (100 mg, 0.26 mmol), flippy )a(dtbbpy)PF6 (3.56 mg, 0.004 mmol), NiBr2(dtbbpy) (9.48 mg, 0.02 mmol) and l-azabicyclo[2.2.2]octane (50.5 mg, 0.46 mmol). DMA (5 mL) was added under nitrogen (mixture B). The mixture A was added to the mixture B under a nitrogen atmosphere and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2,S fiOl4tered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2: 1) to afford 1- (difluoromethyl)-3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl benzoate (150 mg).

[0462] LCMS (ESI-MS) m / z = 531.2 [M+H]+.Step 2: l-(difluoromethyl)-3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8- yl)cyclobutan-l-ol

[0463] LiOH (33.6 mg, 1.41 mmol) was added to a mixture of l-(difluoromethyl)-3-(2-((l- (methyl sulfonyl) piperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl benzoate (150 mg, 0.28 mmol) in THF (3 mL) and H2O (1 mL). The resulting mixture was stirred overnight at room temperature, neutralized by addition of aqueous HC1 (1 N) until the pH was adjusted to 5-6 and extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous and concentrated under reduced pressure. The residue was purified by preparativeRP-HPLC to afford l-(difluoromethyl)-3-(2-((l-(methylsulfonyl)piperidin-4- yl)amino)quinazolin-8-yl)cyclobutan-l-ol (14.5 mg, 11.6% yield) (Example 120).

[0464] 7.17 (m, 1H), 6.27-5.81 (m, 2H), 4.03-3.88 (m, 1H), 3.82-3.71 (m, 1H), 3.67-3.54 (m, 2H), 2.97-2.86 (m, 5H), 2.83-2.74 (m, 2H), 2.40-2.33 (m, 1H), 2.29-2.19 (m, 1H), 2.12-2.00 (m, 2H), 1.67-1.55 (m, 2H).

[0465] LCMS (ESI-MS) m / z = 427.1[M+H]+.Example 121: ( 1 -(difluoromethyD-342-(( 1 -methanesulfonylpiperidin-4- vDamino'kiuinazolin-8-vl')cvclobutvllmethanolReaction SchemeStep 1 : 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cydobutyl)-N-(l- (methylsulfonyl) piperidin-4-yl)quinazolin-2-amine

[0466] An oven-dried 20 mL vial was charged with methyl 3-(((tert- butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-l-ol (80 mg, 0.20 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (70 mg, 0.17 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction stirred at room temperature for 5 minutes. A mixture of pyridine (13.9 mg, 0.17 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture stirred at room temperature for 10 minutes (mixture A). Another oven-dried 40 mL vial was charged with 8-bromo-N-(l- (methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (43.1 mg, 0.11 mmol), NiBr2(dtbbpy) (4 mg, 0.01 mmol), Ir(ppy)2(dtbbpy)PF6 (5.43 mg, 0.006 mmol), phatalamide (9.65 mg, 0.02 mmol) and l-azabicyclo[2.2.2]octane (77.1 mg, 0.69 mmol). DMA (5 mL) was added under nitrogen (mixture B). The mixture A was added to the mixture B under a nitrogen atmosphere and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4 filtered and concentratedunder reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2: 1) to afford 8-(3- (((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl) cyclobutyl)-N-(l- (methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (40 mg).

[0467] LCMS (ESI-MS) m / z = 679.3 [M+H]+.Step 2: (l-(difluoromethyl)-3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8- yl)cyclobutyl)methanol

[0468] A solution of TBAF in THF (1 M, 0.06 mL, 0.06 mmol) was added to a stirred mixture of 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)-N-(l - methanesulfonylpiperidin-4-yl)quinazolin-2-amine (40 mg, 0.059 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 h, quenched by addition of water (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified via Prep- TLC (EA) to afford (l-(difluoromethyl)-3-(2-((l-methanesulfonylpiperidin-4- yl)amino)quinazolin-8-yl)cyclobutyl]methanol (1.0 mg, 3.9% yield) (Example 121).

[0469] ^NMR (400 MHz, Chloroform^) 5 8.99 (s, 1H), 7.65 (s, 1H), 7.60 (s, 2H), 5.43- 5.15 (m, 2H), 4.35 (s, 1H), 4.19-3.94 (m, 2H), 3.82 (s, 2H), 3.61-3.45 (s, 1H), 3.00 (t, J=ll.l Hz, 1H), 2.85 (s, 3H), 2.68-2.44 (m, 1H), 2.27 (d, J=11.0 Hz, 2H), 2.06-1.90 (m, 1H), 1.75 (s, 2H), 1.56 (s, 2H), 1.39-1.23 (m, 2H). LCMS (ESI-MS) m / z = 441.2 [M+H]+.Example 114: 1 -cyclopropyl-3 -(2-(( 1 -(methvlsulfonvl)piperidin-4-vl)amino)-6- (trifluoromethyDauinazolin-8-yDcyclobutan- 1 -olReaction SchemeStep 1 : 3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8- yl)cyclobutan-l-one

[0470] An over-dried 20mL vial was charged with 3-hydroxycyclobutan-l-one (43 mg, 0.49 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (177 mg, 0.45 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction stirred at room temperature for 5 minutes. A mixture of pyridine (81 mg, 1.03 mmol) in tertbutyl methyl ether (1 mL) was added and the mixture stirred at room temperature for 10 minutes (mixture A). Another over-dried 40 mL vial was charged with 8-chloro-6-methyl-N- (1 -(methyl sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (200 mg, 0.56 mmol), 5,7- di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (177.72 mg, 0.45 mmol) , Ir(ppy)2(dtbbpy)PF6 (3.85 mg, 0.004 mmol), NiBr2(dtbbpy) (6.84 mg, 0.014 mmol) and l-azabicyclo[2.2.2]octane (54.68 mg, 0.49 mmol). DMA (5 mL) was added under nitrogen (mixture B). The mixture A was added to the mixture B under a nitrogen atmosphere and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for3 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to afford 3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8- yl)cyclobutan-l-one (50 mg).

[0471] LCMS (ESI-MS) m / z =443.1 [M+H]+.Step 2: l-cyclopropyl-3-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)-6- (trifluoromethyl)quinazolin-8-yl)cydobutan-l-ol

[0472] A solution of cyclopropylmagnesium bromide in THF (1 M, 0.2 mL, 0.2 mmol) was added dropwise to a cooled to -20 °C solution ofl-cyclopropyl-3-(2-((l-(methyl sulfonyl)piperidin-4-yl)amino)-6-(trifluoro-methyl)quinazolin-8-yl) cyclobutan- 1 -ol (50 mg, 0.1 mmol) in THF (30 mL) under a nitrogen atmosphere. The resulting mixture was stirred at -20 °C for 30 minutes, quenched by the addition of aqueous NH4CI (30 mL) at 0 °C and extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous htaSCh, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 1:3) to afford l-cyclopropyl-3-(2-((l-(methyl sulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)cyclobutan- 1 -ol (2 mg, 3.6% yield) (Example 114).

[0473] JHNMR (400 MHz, Chloroform^) 59.02 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 5.44 (s, 1H), 4.13 (s, 1H), 3.83 (d, J = 11.9 Hz, 2H), 3.64-3.60 (m, 1H), 3.02 (t, J = 11.8 Hz, 1H), 2.86 (d, J = 3.2 Hz,3H), 2.61-2.48 (m, 2H), 2.44-2.22 (m, 3H), 1.86-1.71 (m, 2H), 1.59 (s, 2H), 1.39-1.19 (m, 2H), 0.67-0.60 (m, 2H), 0.53-0.50 (m, 2H).

[0474] LCMS (ESI-MS) m / z =485.2 [M+H]+.Example 122: 8-(8.8-difluoro-6-azaspiror3.41octan-2-yD-N-(l-(methylsulfonyDpiperidin-4- vDauinazolin-2-amineReaction SchemeDetailed ProcedureStep 1 : Tert-butyl8,8-difluoro-2-(2-((l-(methylsulfonyl)piperidin-4-yl)amino)quinazolin- 8-yl)-6-azaspiro [3.4]octane-6-carboxylate

[0475] An oven-dried 20 mL vial was charged with tert-butyl 8,8-difluoro-2-hydroxy-6- azaspiro[3.4]octane-6-carboxylate (240 mg, 0.91 mmol) and 5,7-di-tert-butyl-3- phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (328 mg, 0.83 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction stirred at room temperature for 5 minutes. A mixture of pyridine (65.7 mg, 0.83 mmol) in tert-butyl methyl ether (1 mL) was added and the mixture stirred at room temperature for 5 minutes (mixture A). Another oven- dried 40 mL vial was charged with 8-bromo-N-(l-(methylsulfonyl)piperidin-4-yl)quinazolin- 2-amine (200 mg, 0.52 mmol), Ir(ppy )?(dtbbpy)PF6 (7.3 mg, 0.008 mmol), NiBr2(dtbbpy) (12.7 mg, 0.026 mmol), phthalimide (30.9 mg, 0.21 mmol) and l-azabicyclo[2.2.2]octane(101 mg, 0.91 mmol). DMA (5 mL) was added under nitrogen (mixture B). The mixture A was added to the mixture B under a nitrogen atmosphere and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrouNsa2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2:1) to afford tert-butyl 8,8-difluoro-2-(2-((l- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (50 mg, 17.4% yield).

[0476] LCMS (ESI-MS) m / z = 552.2 [M+H]+.Step 22:: 8-(8,8-difluoro-6-azaspiro [3.4] octan-2-yl)-N-(l-(methylsulfonyl)piperidin-4- yl)quinazolin-2-amine

[0477] TFA (0.3 mL) was added to a stirred mixture of tert-butyl 8,8-difluoro-2-(2-((l- (methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (50 mg, 0.09 mmol) in DCM (1 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to afford 8-(8,8-difluoro-6-azaspiro[3.4]octan-2-yl)-N-(l- (methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (4.3 mg, 10.6% yield).

[0478] ^NMR (400 MHz, DMSO^fc) 59.10 (s, 1H), 7.68-7.55 (m, 2H), 7.47 (s, 1H), 7.25- 7.18 (m, 1H), 4.16-3.85 (m, 2H), 3.65-3.55 (m, 2H), 3.25-3.04 (m, 3H), 2.96-2.84 (m, 6H), 2.80-2.71 (m, 2H), 2.39-2.25 (m, 2H), 2.19-2.05 (m, 3H), 1.70-1.56 (m, 2H).

[0479] LCMS (ESI-MS) m / z = 452.2 [M+H]+.

[0480] In some embodiments, compounds of the disclosure are below in Table 1.-126--- 128-- 132-- 134-- 137 -- 140-- 143-- 145-- 149--151-- 153 -154- 156-- 159 -

[0481] In some embodiments, compounds of the disclosure are below in Table 2.TABLE 2- -- 163-- 166-- 168-Biochemical AssaysCDKl / Cyclin Bl ADP-Glo Kinase Assay

[0482] The purpose of CDKl / Cyclin Bl assay is to evaluate the inhibition (% inhibition and IC50 values) of small molecule inhibitors by using a Luminescent based ADP-Glo assay. CDKl / Cyclin Bl catalyzes the production of ADP from ATP. ADP-Glo assay monitors ADP producing biochemical reactions. ADP-Glo is performed in 2 steps upon completion of kinase reaction: a combined termination of kinase reaction and depletion of remaining ATP in the first step, and conversion of generated ADP to ATP and the newly produced ATP to light output using luciferase / luciferin reaction in the second step. The luminescent signal generated is proportional to the ADP concentration produced and is correlated with the kinase activity. CDKl / Cyclin Bl was purchased from Cama (Cat 04-102). Typical reaction solutions (10 uL final reaction volume) contained 2% DMSO (± inhibitor), 10 mM MgCI2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 80 uM ATP (ATP Km = 78.6 uM), 0.01% Brig-35, 0.75 uM susbstrate, and 4.917 nM CDKl / Cyclin Bl enzyme complex in 50 mM HEPES buffer at pH 7.5. The assay was initiated with the addition of ATP-containing substrate solution, following a 30 -minute pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 90 minutes at room temperature by the addition of 10 uL of ADP-GLO Reagent. After a 90 minute incubation, 20 uL of Kinase Detection Reagent was added. Samples were incubated for 40 minutes, after which plate well luminescence was measured on a Envision microplate reader. The IC50 determinations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the 4 parameters IC50 equation.CDK2 / Cyclin El Full length ADP-Glo Kinase Assay

[0483] The purpose of CDK2 / Cyclin El assay is to evaluate the inhibition (% inhibition and IC50 values) of small molecule inhibitors by using a Luminescent based ADP-Glo assay. CDK2 / Cyclin El full length catalyzes the production of ADP from ATP. ADP-Glo assay monitors ADP producing biochemical reactions. ADP-Glo is performed in 2 steps upon completion of kinase reaction : a combined termination of kinase reaction and depletion of remaining ATP in the first step, and conversion of generated ADP to ATP and the newly produced ATP to light output using luciferase / luciferin reaction in the second step. The luminescent signal generated is proportional to the ADP concentration produced and is correlated with the kinase activity. CDK2 / Cyclin El was purchased from Eurofins (Cat 14- 475M). Typical reaction solutions (10 uL final reaction volume) contained 2% DMSO (± inhibitor), 10 mM MgCI2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 20 uM ATP (ATP Km =64.78 uM), 0.01% Brig-35, 0.75 uM susbstrate, and 0.328 nM wild-type full length CDK2 / Cyclin El enzyme complex in 50 mM HEPES buffer at pH 7. 5. The assay was initiated with the addition of ATP-containing substrate solution, following a 30 -minute pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 90 minutes at room temperature by the addition of 10 uL of ADP- GLO Reagent. After a 90 minute incubation, 20 uL of Kinase Detection Reagent was added. Samples were incubated for 40 minutes, after which plate well luminescence was measured on a Envision microplate reader. The ICso determinations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the 4 parameters ICso equation.CDK4 / Cyclin DI CHEF assay

[0484] The purpose of CDK4 / Cyclin DI assay is to evaluate the inhibition (% inhibition and ICso values) of small molecule inhibitors by using a Chelation-Enhance Fluorescence (CHEF) assay. In a CHEF assay, phosphorylation of a peptide substrate results in proportional increase in fluorescence. CHEF kinase assay use peptide substrates containing a synthetic alpha-amino acid with a side chain bearing an 8-hydroxyquinoline derivative (sulfonamido- oxide, Sox). Upon phosphorylation of a nearby serine, threonine or tyrosine and in the presence of Mg(H), the spectral properties of the Sox residue are altered, emitting 485nm wavelength light when excited with a 360nm wavelength light source. CDK4 / Cyclin DI catalyzes the phosphoryl transfer to the SOX-labeled substrate peptide AQT0258 from Assayquant Technologies. Typical reaction solutions contained 2% DMSO (+ / - inhibitor), 10 mM MgC12, 1 mM DTT, 200 uM ATP (ATP Km = 195.2 uM), 0.012% Brig-35, 10 uM AQT0258 peptide, 0.02% BSA, 1% Glycerol, 0.55mM EGTA, 2.5 nM CDK4 / Cyclin DI in 54 mM HEPES buffer at pH 7.5. The reaction was initiated with the addition of substrate solution, following a 30-minute pre-incubation of enzyme and inhibitor at 22 °C in the reaction mix. Reactions were allowed to proceed for 3 hrs at 22 °C, followed by fluorescence read of the reaction. The ICso determinations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the 4 parameters ICso equation.CDK4 / Cyclin DI mobility shift assay (MSA)

[0485] The purpose CDK4 / Cyclin DI assay is to evaluate the inhibition (% inhibition and ICso values) in the presence of small molecule inhibitors by using a fluorescence based microfluidic mobility shift assay. CDK4 / Cyclin DI catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide 5-FAM-Dyrktide (5- FAM-RRRFRPASPLRGPPK) (Perkin Elmer Peptide 34). The mobility shift assay (MSA)- 170electrophoretically separates the fluorescently labelled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured, and the ratio of these values is used to generate % conversion of substrate to product by the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO (+ / - inhibitor), 10 mM MgC12, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 0.2 mM ATP, 0.01% Brig-35, 1.5 uM 5-FAM- Dyrktide, 2.5 nM CDK4 / Cyclin DI in 50 mM HEPES buffer at pH 7.5. The reaction was initiated with the addition of substrate solution, following a 30 -minute pre-incubation of enzyme and inhibitor at 22 °C in the reaction mix. The reaction was stopped after 180 minutes by the addition of 75 uL of 500 mM EDTA and measured on a Perkin Elmer EZ reader instrument. ICso determinations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the 4 parameters ICso equation.CDK6 / Cyclin D3 ADP-Glo Kinase Assay

[0486] The purpose of the CDK6 / Cyclin D3 assay is to evaluate the inhibition (% inhibition and ICso values) in the presence of small molecule inhibitors by using a Luminescent based ADP-Glo assay. CDK6 / Cyclin D3 catalyzes the production of ADP from ATP. ADP-Glo assay monitors ADP producing biochemical reactions. ADP-Glo is performed in 2 steps upon completion of kinase reaction, a combined termination of kinase reaction and depletion of remaining ATP in the first step, and conversion of generated ADP to ATP and the newly produced ATP to light output using luciferase / luciferin reaction in the second step. The luminescent signal generated is proportional to the ADP concentration produced and is correlated with the kinase activity. CDK6 / Cyclin D3 was purchased from Cama. Typical reaction solutions (10 uL final reaction volume) contained 2% DMSO (± inhibitor), 10 mM MgCI2, 1 mM EGTA, 0.05% BSA, 2 mM DTT, 100 uM ATP (ATP Km = 291.7 uM), 0.01% Brig-35, 0.75 uM susbstrate, and 5 nM wild-type CDK6 / Cyclin D3 enzyme complex in 50 mM HEPES buffer at pH 7. 5. The assay was initiated with the addition of ATP-containing substrate solution, following a 30 -minute pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 90 minutes at room temperature by the addition of 10 uL of ADP-GLO Reagent. After a 90-minute incubation, 20 uL of Kinase Detection Reagent was added. Samples were incubated for 40 minutes, after which plate well luminescence was measured on a Envision microplate reader. The ICso determinations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the 4 parameters ICso equation.Cell growth inhibition

[0487] MCF-7 and OVCAR-3 cells were used to evaluate the anti-proliferation activity of the CDK inhibitors. MCF-7 (ATCC, HTB-22) cells are epithelial cells from a female patient with ER+ metastatic adenocarcinoma. OVCAR-3 (ATCC, HTB-161) cells were derived from malignant ascites of a patient with ovarian cancer and are known to have CCNE1 amplification. Both cell lines were maintained in RPMI media supplemented with 10% fetal bovine serum. For cell growth inhibition assay, CDK inhibitors in DMSO solution were dispensed with either Echo 655 (Beckman Coulter) or Tecan D300e (HP) into 384-well plates (Coming #3765) and the 384-well plates were UV-sterilized prior to the assay. The inhibitors were typically tested in the 10 - 10,000 nM concentration range with half-log serial dilutions. MCF-7 or OVCAR-3 (500 cells / 30 pL / well) were added to each well using Multidrop Combi (ThermoFisher) using standard cassettes. The assay plates with cells were cultured at 37"C, 5% CO2 for 6 days. At the end of the 6-day treatment, 30 pL of CellTiterdo 2.0 (Promega) was added to each well and the luminescent signal was read using CLARIOstar plus (BMG). The percentage of cell growth inhibition (% CGI) was calculated using the following formula % CGI = 100 - 100 X luminescencesampie / luminescencecontroi. The half maximal inhibitory concentration (ICSO) was determined by nonlinear curve fitting (four parameters, variable slope).

[0488] Certain compounds of the disclosure have IC50 values as in Table 3.TABLE 3- 175-

[0489] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.- 176 -

Claims

CLAIMSWe claim:

1. A method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more additional therapeutic agents or therapies, wherein Formula (I) is:wherein,R1is selected from optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolpyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;R2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle; each of R3, R4, R5, R6, is independently selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl;R7is selected from hydrogen and optionally substituted C1-6alkyl; wherein if R1is an optionally substituted pyrazole, R2is not piperidine.

2. The method according to claim 1, wherein R1is selected from optionally substituted piperidine, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substiutedf pyrrolpyrimidine, optionally substiuted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine.

3. The method according to claim 1, wherein R1is selected from optionally substituted piperidine, optionally substituted 2-pyridine, optionally substitutedazabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine.

4. The method according to claim 1, wherein R1is optionally substituted piperidine.

5. The method according to claim 1, wherein R1is optionally substituted azabicyclo[3.1.OJhexane.

6. The method according to claim 1, wherein R1is optionally substituted indole.

7. The method according to claim 1, wherein R1is optionally substituted isoindole.

8. The method according to claim 1, wherein R1is optionally substituted azetidine.

9. The method according to claim 1, wherein R1is optionally substituted indazole.

10. The method according to claim 1, wherein R1is optionally substituted tetrahydroisoquinoline.

11. The method according to any one of the preceding claims, wherein R2isY1is selected from -N- and -CR10-; each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -C(O)-wherein Z5is additionally selected from a bond; each of a, b, c, and d are independently selected from 1, 2, 3, and 4; each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R10substituents come together to form an optionally substituted heterocycle or an optionally substituted carbocycle, or R10and R11substituents come together to form an optionally substituted heterocycle; and each R11is independently selected from hydrogen and optionally substituted C1-6alkyl.

12. The method according to claim 1 or 2, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of one or more of the following Formula:wherein,R8is selected from halogen, -CN, and optionally substituted C1-6alkyl;R9is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and 3- to 6- membered heterocycloalkyl; n is selected from 0 to 9; each of X1, X2, and X3is independently selected from N and CR13;R12is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle, or R12comes together with R13to form an optionally substituted ring; and each R13is independently selected from hydrogen, halogen, -CN, and optionally substituted C1-6alkyl.R14is selected from hydrogen, halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl, or R14and R15come together to form an optionally substituted heterocycle; andR15is selected from -S(O)2R16-, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl.

13. The method according to claim 12, wherein R2is optionally substituted heterocycle.

14. The method according to claim 1, wherein R2is selected from optionally substituted C3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.

15. The method according to claim 1 or 14, wherein R2is substituted with -CN, - SO2R2*, -NR2*, oxo, C1-3 alkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, C1-3 alkylene-Cs-e cycloalkyl, oxetane, or azetidine, wherein R2* is selected from C1-6alkyl.

16. The method according to claim 1, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of one or more of the following Formula:wherein,Y1is selected from -N- and -CR10-; each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -C(O)- , -NR11-, -N(C(O)R10)-, -NS(O2)Rn, -O-, -S-, -S(O)-, and -S(O)2-, wherein Z5is additionally selected from a bond; each of a, b, c, and d are independently selected from 1, 2, 3, and 4;R8is selected from halogen, -CN, and optionally substituted C1-6alkyl;R9is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and 3- to 6- membered heterocycloalkyl; n is selected from 0 to 9;X1, X2, and X3are each CH;each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R10substituents come together to form an optionally substituted heterocycle or an optionally substituted carbocycle, or R10and R11substituents come together to form an optionally substituted heterocycle; each R11is independently selected from hydrogen and optionally substitutedCi-4 alkyl;R16is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl;R17is selected from optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl, or R13and R14come together to form an optionally substituted heterocycle; andR18is selected from halogen, -CN, optionally substituted C1-6alkyl, optionally substituted C3-6 carbocycle, and optionally substituted 3- to 6- membered heterocycloalkyl.

17. The method according to claim 11 or 16, wherein Y1is -N-.

18. The method according to claim 11 or 16, wherein Y1is -CR10-.

19. The method according to claim 11 or 16, wherein each of Z1, Z2, Z3, Z4and Z5are independently selected from -C(R10)2-, -NR11-, -N(C(O)R10)-, -NS(02)Rn, -O-, and -S(O)2-, wherein Z5is additionally selected from a bond.

20. The method according to any one of claims 11 or 16 to 19, wherein each of a, b, c, and d are independently selected from 1, 2, and 3.

21. The method according to claim 20, wherein each of a, c, and d are independently selected from 1 and 2.

22. The method according to any one of claims 11 or 16 to 21, wherein each R10is independently selected from hydrogen, halogen, -CN, -OH, -O-C1-6alkyl, optionally substituted C1-3 alkyl, and optionally substituted C3-6 cycloalkyl.

23. The method according to claim 22, wherein each R10is independently selected from hydrogen, halogen, -CN, -OH, methyl, -OMe, -CH2CH2OCH3, and cyclopropyl.

24. The method according to any one of claims 11 or 16 to 23, wherein each R11is independently selected from hydrogen and optionally substituted C1-2 alkyl.

25. The method according to claim 24, wherein each R11is independently selected from hydrogen, methyl, and ethyl, wherein the ethyl is optionally substituted with -OMe.

26. The method according to claim 1, wherein R1is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole.

27. The method according to claim 26, wherein R1is selected from optionally substituted azabicyclo[3.1.0]hexane, and optionally substituted isoindole.

28. The method according to claim 26 or 27, wherein R1is substituted with -SO2R1or C1-3 alkyl, wherein Rlais selected from C1-6 alkyl.

29. The method according to any one of claims 1, 2, 26, 27 or 28, wherein R2is selected from optionally substituted heterocycle and optionally substituted cycloalkyl.

30. The method according to claim 29, wherein R2is optionally substituted heterocycloalkyl.

31. The method according to claim 30, wherein R2is selected from optionally substituted 3- to 6- membered heterocycloalkyl.

32. The method according to claim 31, wherein R2is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, and optionally substituted morpholine.

33. The method according to any one of claims 29 to 32, wherein R2is substituted with halogen, -SChR2*, -NR2*, -C(O)CH3, -CN, optionally substituted 3- to 6- membered hterocycloalkyl, optionally substituted C3-5 carbocycle, oxo, and optionally substituted C1-3 alkyl, wherein R2* is selected from C1-6 alkyl.

34. The method according to claim 32, wherein R2is substituted with fluoro, -SO2Me, oxo, and methyl.

35. The method according to any one of claims 1-10, 12, or 29, wherein R2is selected from37. The method according to any one of claims 1-10 or 12, wherein R2is optionally substituted heterocycloalkyl.

38. The method according to any one of the preceding claims, wherein R3is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

39. The method according to claim 38, wherein R3is selected from hydrogen, fluoro, - CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

40. The method according to claim 38, wherein R3is selected from hydrogen, fluoro, and -CN.

41. The method according to claim 40, wherein R3is selected from hydrogen and -CN.

42. The method according to any one of the preceding claims, wherein R4is selected from hydrogen, halogen, -CN, optionally substituted Ci alkyl, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

43. The method according to claim 42, wherein R4is selected from hydrogen, -CN, - CHF2, -CF3, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

44. The method according to claim 43, wherein R4is selected from hydrogen, -CN, and -CHF2.

45. The method according to any one of the preceding claims, wherein R5is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

46. The method according to claim 45, wherein R5is selected from hydrogen, fluoro, - CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

47. The method according to claim 46, wherein R5is hydrogen.

48. The method according to any one of the preceding claims wherein R6is selected from hydrogen, halogen, -CN, optionally substituted C3-4 carbocycle, and optionally substituted 3- to 4 membered heterocycloalkyl.

49. The method according to claim 48, wherein R6is selected from hydrogen, fluoro, - CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

50. The method according to claim 49, wherein R6is hydrogen.

51. The method according to any one of the preceding claims, wherein R7is hydrogen.

52. The method according to claim 1 selected from the compounds in Table I.

53. The method according to claim 12 selected from the compounds in Table I.

54. The method according to claim 16 selected from the compounds in Table I.

55. The method of treating a disease or condition according to any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that further comprises one or more pharmaceutically acceptable excipients.

56. The method of treating a disease or condition according to any one of the preceding claims wherein the one or more additional therapeutic agents are selected from the group consisting of a platinum compound, a taxane, apigenin, a Wee-1 inhibitor, a PRMT5 inhibitor, an MDM2 inhibitor, a Src inhibitor, a Raf inhibitor, a MEKinhibitor, an XP01 inhibitor, a vitamin D analog, a type-I TGF-b receptor inhibitor, a TRK inhibitor, a tankyrase inhibitor, a senolytic agent, a RET inhibitor, a proteosome inhibitor, a menin inhibitor, an LC 3 -KAT inhibitor, a KIT inhibitor, a KIFC inhibitor, an IGF-1R inhibitor, an HEF-2 alpha inhibitor, an HER2 antibody drug conjugate, a heat shock protein, an HDAC inhibitor, a GLI1 inhibitor, a F0XM1 inhibitor, an EZH2 inhibitor, an estrogen receptor antagonist, an estrogen receptor alpha antagonist, an elF4A inhibitor, a dihydrofolate reductase inhibitor, a CD73 inhibitor, a BTK inhibitor a BMI inhibitor, a beta-catenin inhibitor, a CBP / p300 dual inhibitor, an ALDH1 A3 inhibitor, a dual c-Met / Trk inhibitor, an antrogen receptor inhibitor, a Bcl-2 inhibitor, glyoxalase 1 inhibitor, a KIFC1 inhibitor, a USP10 inhibitor, an antioxidant defense inhibitor, RANKL inhibitor, a FLT3 inhibitor, a notch inhibitor, a BRAF inhibitor, a HER2 inhibitor, an eIF4A inhibitor, SHP2 inhibitor, an ERK1 / 2 inhibitor, an EGFR inhibitor, an IKK beta inhibitor, a PAK inhibitor, a steroid, a steroidogenesis inhibitor, a KIT D816V inhibitor, BET inhibitor, a PI3K inhibitor, an mTOR inhibitor, an FGFR inhibitor, a pan-ERBB inhibitor, an ALK-inhibitor, an anti-PD-1 monoclonal antibody, an anti- PD-L1 monoclonal antibody, an autophagy inhibitor, a YAP-inhibitor, an androgen receptor inhibitor, a PARP inhibitor, a F0XM1 inhibitor, an aromatase inhibitor, a CDK2 inhibitor, a CDK4 inhibitor, and a CDK4 / 6 inhibitor.

57. The method according to claim 56, wherein the one or more agents are selected from the group consisting of mTOR inhibitors, PI3K inhibitors, PARP inhibitors, Her2 antibody drug conjugates, anti-PD-1 monoclonal antibodies, anti-PD-Ll monoclonal antibodies, and Trop2 antibody drug conjugates.

58. The method of claim 56 or 57, further comprising hormone therapy.

59. The method of treating a disease or condition according to any one of claims 1-58, wherein the one or more additional therapeutic agents are selected from the group consisting of carboplatin, cisplatin, oxaliplatin, nedaplatin, phenanthriplatin, lobaplatin, enloplatin, paclitaxel, docetaxel, apigenin, adavosertib, pemrametosta, AZD1775, inecalcitol, SNDX-50469, NVP-CGM097, idasanutlin, nutlin-3, siremadlin, brigimadlin, saracatinib, bosutinib, dasatinib, sorafenib, trametinib, binimetinib, cobimetinib, KPT-330, SB-505124, entrectinib, MSC2504877, alectinib. bortezomib, selumetinib, PD0325901, trimetazidine, midostaurin, avapritinib, nintedanibispinesib, SR31527, ganitumab, NVP-AEW541, PT2399, T- DM1, SHetA2, tucidinostat, suberanilohydroxamic acid, vorinostat, valproate,GANT61, NB55, NB73, NB115AQB, lasofoxifene, CR-1-31-B, celastrol, gambogic acid, pralatrexate, ibmtinib, tirabrutinib, PTC-209, ICG-001, NEO2734, N,N- di ethylaminobenzaldehyde, altiratinib, seviteronel, RAD 140, MLN0128, temsirolimus, sapanisertib, navitoclax, venetoclax, BBGC, ispinesib, spautin-1, auranofin, neratinib, pyrotinib, tucatinib, OPG-Fc, quizartinib, CB-103, encorafenib, vemurafenib, dabrafenib, trastuzumab, CR-1-31-B, TNO155, SCH772984, LY3214996, cetuximab, PF-0647775, erlotinib, Bay 11-7082, PF03758309, progesterone, mitotane, midostaurin, avapritinib, JQ1, ZEN-3694, ARV-825, alpelisib, pictilisib, vistusertib, everolimus, infigratinib, LY2874455, rogaratinib, BLU9931, H3B-6527, FIIN-2, FUN-3, lenvatinib, ponatinib, regorafenib. Pemigatinib, buparlisib, paxalisib, futibatinib, infigratinib, afatinib, ceritinib, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, hydroxychloroquine, chloroquine, verteporfin, pyrvinium pamoate, enzalutamide, N-desmethyl enzalutamide, darolutamide, apalutamide, ralaniten, EPI-7170, abiraterone, bafilomycin Al, albendazole, letrozole, fulvestrant, olaparib, talazoparib, NB55, NB73, NB115, gedatolisib, eribulin, temozolomide, cytarabine, doxorubicin, gemcitabine, pemetrexed, dexamethasone, L-asparaginase, vincristine, 5-FU, sunitinib, and irinotecan.

60. The method according to any one of claims 1-53, wherein the one or more agents are selected from the group consisting of a Trop2 antibody drug conjugate, a cytokine, an oncolytic virus, a bi-specific immune checkpoint inhibitor, a T-cell engager, a cancer vaccine, a cell therapy, a CD73 inhibitor, HER3 antibody drug conjugates such as patritumab deruxtecan, or a TLR agonist.

61. The method according to any one of claims 1-53, wherein the one or more additional therapies is a cancer gene therapy.

62. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of vistusertib, MLN0128, alpelisib, buparlisib, paxalisib, gedatolisib, pictilisib, talazoparib, laparib, T-DM1, sacituzumab govtecan, and datopotamab deruxtecan.

63. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of carboplatin, cisplatin, oxaliplatin, nedaplatin, phenanthriplatin, lobaplatin, and enloplatin.

64. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of paclitaxel and docetaxel.

65. The method according to claim 59, wherein the one or more additional therapeutic agents is apigenin.

66. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of adavosertib, pemrametosta, nutlin- 3, saracatinib, and dasatinib.

67. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of sorafenib, trametinib, cobimetinib, alpelisib, pictilisib, vistusertib, and irinotecan.

68. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of FHN-2, FHN-3, lenvatinib, ponatinib, regorafenib, pemigatinib, futibatinib, and infigratinib.

69. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of afatinib and ceritinib.

70. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

71. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of hydroxychloroquine, verteporfm, and olaparib.

72. The method according to claim 59, wherein the one or more additional therapeutic agents are selected from the group consisting of enzalutamide, N-desmethyl enzalutamide, darolutamide, apalutamide, and abiraterone.

73. The method of treating a disease or condition according to any one of claims 1-58, wherein the therapy is radiotherapy or ultrasound therapy.

74. The method according to any of the preceding claims, wherein the disease or condition is cancer.

75. The method according to claim 72, wherein the cancer is a solid tumor.

76. The method according to claim 72, wherein the cancer is ovarian cancer, pancreatic cancer, bladder cancer, brain cancer, sarcoma, melanoma, lung cancer, urothelial carcinoma mantle cell lymphoma, large B-cell lymphoma, leukemia, colorectal cancer, adenocarcinoma, adrenocortical carcinoma, breast cancer, medulloblastoma, cholangiocarcinoma, glioma, esophageal squamous cell carcinoma, meningioma, Ewing sarcoma, well-differentiated liposarcoma, dedifferentiated liposarcoma, clear cell renal cell carcinoma, lung squamous cell carcinoma, endometrial cancer, gastriccancer, pediatric astrocytoma, rare pediatric undifferentiated sarcoma, mastocytosis, glioblastoma, glioblastoma multiforme, esophageal carcinoma, thyroid cancer, neuroblastoma, colon cancer, rectal cancer, esophageal carcinoma, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, well-differentiated liposarcoma, dedifferentiated liposarcoma, advanced dedifferentiated liposarcoma, leiomyosarcoma, neuroendocrine tumor, peripheral nerve sheath tumors, pediatric cancer, mesothelioma, myeloma, chordomas, bladder cancer, nasopharyngeal carcinoma, cervical cancer, testicular germ cell tumors, brain metastasis, head and neck squamous cell carcinoma, oral squamous cell carcinoma, osteosarcoma, or prostate cancer.

77. The method according to claim 74, wherein the cancer is metastatic triple-negative breast cancer, non-small cell lung cancer, small cell lung cancer, metastatic urothelial carcinoma, HR+ HER2- metastatic breast cancer, colorectal cancer, esophageal carcinoma, endometrial cancer, pancreatic ductal adenocarcinoma, castrate-resistant prostate cancer, epithelial ovarian cancer, gastric adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, cervical cancer, or renal cell carcinoma.

78. The method according to claim 74, wherein the cancer is osteosarcoma, glioma, cholangiocarcinoma, glioblastoma, head and neck squamous cell carcinoma, medulloblastoma, advanced dedifferentiated liposarcoma, leiomyosarcoma, chordomas, breast cancer, or pediatric cancer.

79. The method according to claim 74, wherein the cancer is medulloblastoma, head and neck squamous cell cancer, chorodomas, mesothelioma, colorectal cancer, chordomas, medulloblastoma, pancreatic ductal adenocarcinoma, thyroid cancer, or oral squamous cell carcinoma.

80. The method according to claim 74, wherein the cancer is colorectal cancer, prostate cancer, castration-resistant prostate cancer, or neuroendocrine prostate cancer.

81. The method according to any of the preceding claims, wherein the compound inhibits CDK 2, CDK 4, CD6, or any combination thereof.

82. The method according to claim 79, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK 2 / 4 / 6.-

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