Quinazoline compounds and methods of use

Abstract

Disclosed herein are substituted quinazoline compounds, conjugates, and pharmaceutical compositions for the treatment of cancer. The disclosed compounds are particularly useful for inhibiting CDK. In certain aspects, the disclosure generally relates to substituted quinolinone amide compounds or salts of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) and pharmaceutical compositions thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 390,250, filed on July 18, 2022, and U.S. Provisional Patent Application No. 63 / 402,857, filed on August 31, 2022. The entire contents of the above patent applications are incorporated herein by reference. Background Art

[0003] Cell cycle-mediated mammalian cell division and proliferation is an important and fundamental biological process that controls the generation and production of cells with critical biological functions. The cell cycle is a highly regulated process and responds to a complex set of cellular signals from within and outside the cell. Complex cell signaling networks, including components that promote and suppress cancer, play a key role in controlling the cell cycle. Gain of function of tumor-promoting components or loss of function of tumor suppressor products can lead to cell cycle dysregulation and thus tumorigenesis.

[0004] Cyclins and cyclin-dependent kinases (CDKs) are essential for driving and controlling cell cycle transitions and cell division (34176404). Cyclins are a family of proteins whose expression levels vary at different stages in the cell cycle. Cyclins bind and activate CDKs at different stages of the cell cycle, and the progression of the cell cycle is tightly synchronized, involving the sequential activation of multiple cyclin-CDK complexes. Of the more than 20 CDKs discovered to date, CDK1, 2, 4, and 6 are reported to play a direct role in cell cycle progression. The CDK4-cyclin D and CDK6-cyclin D complexes are essential for entry into the G1 phase of the cell cycle. The CDK2-cyclin E complex regulates progression from the G1 phase into the S phase, while CDK2-cyclin A is required during the S phase. The CDK1-cyclin A complex promotes entry into the M phase, and mitosis is further regulated by the CDK1-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 entry into S phase. Activation of CDK2-cyclin A during early S phase promotes phosphorylation of endogenous substrates, allowing DNA replication and inactivation of E2F, thereby completing S phase.

[0005] Dysregulation of the cell cycle machinery is a hallmark of cancer, leading to overactivation of CDKs and uncontrolled cell division and proliferation. Genetic alterations in genes encoding cyclin D, CDK4 / 6, and CDK4 / 6 inhibitory proteins (e.g., p21, p27) can all lead to tumorigenesis. Cyclin E is a regulatory cyclin of CDK2 and is frequently overexpressed in cancer. Since tumor development is closely associated with genetic mutations and dysregulation of CDKs and their regulators, CDK inhibitors can be used for anticancer therapy. Since the early 1990s, CDK inhibitors have been developed for cancer therapy, with a variety of FDA-approved drugs (palbociclib, ribociclib, and abemaciclib). However, these early generation CDK inhibitors on the market had poor selectivity and high toxicity (e.g., bone marrow suppression), leading to adverse effects that limited clinical dose levels and prevented further benefit to patients. The development of new CDK inhibitors with better selectivity for normal cells and fewer side effects remains an unmet medical need. Summary of the invention

[0006] The present disclosure generally relates to substituted quinazoline compounds or salts of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) and pharmaceutical compositions thereof. The substituted quinazoline compounds or salts of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) disclosed herein can be used to treat abnormal cell growth, such as cancer, in a subject in need thereof.

[0007] In some aspects, a method of treating cancer may comprise administering to an individual in need thereof a compound or pharmaceutically acceptable salt of any of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA).

[0008] In certain aspects, the present disclosure provides a compound represented by formula (I):

[0009]

[0010] in,

[0011] R 1 is selected from the group consisting of optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;

[0012] R 2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;

[0013] R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0014] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl;

[0015] If R 1 is an optionally substituted pyrazole, then R 2 Not piperidine.

[0016] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0017] In some aspects, the present disclosure provides a method of treating cancer, comprising administering a compound or pharmaceutical composition described herein to a subject in need thereof. In some aspects, the present disclosure provides a method of inhibiting cyclin-dependent kinases (CDKs) in cells using a compound or pharmaceutically acceptable salt or pharmaceutical composition described herein.

[0018] Incorporation by reference

[0019] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0020] Although preferred embodiments of the present invention have been shown and described herein, it will be appreciated by those skilled in the art that these embodiments are provided by way of example only. Those skilled in the art will now appreciate that many variations, changes and substitutions will not depart from the present invention. It should be understood that in practicing the present invention, various alternatives to the embodiments of the present invention described herein may be adopted. The appended claims are intended to define the scope of the present invention, and thus encompass methods and structures within the scope of these claims and their equivalents.

[0021] The basic functions of cell regulation, cell division, and cell proliferation are controlled by cyclin-dependent kinases (CDKs), which are activated by regulatory subunits such as cyclins. Due to the role of CDKs in cell regulation, CDK inhibitors can be used to treat cancer. Studies have shown that increased CDK activity or transient abnormal activation leads to tumor development; tumor development is often associated with changes in CDKs or CDK regulators.

[0022] CDK binds to cyclins (which are regulatory proteins.), and without cyclins, CDK has almost no kinase activity. The cyclin-CDK complex is an active kinase, usually regulated by phosphorylation and other binding proteins. Currently, 21 CDKs and 5 CDK-like genes are known in the human genome. Although many CDKs are related to transcription, CDK2, CDK4 and CDK6 are related to the cell cycle. CDK2 is related to DNA replication in higher eukaryotes, while CDK4 and CDK6 are related to various growth regulatory signals.

[0023] Overexpression of CDK2 is associated with abnormal cell cycle regulation. Cyclin E, the cyclin partner of CDK2, binds to CDK2 to form an active kinase complex. The CDK2-cyclin E complex plays an important role in regulating the G1 / S transition, centrosome duplication, and histone biosynthesis. Processive phosphorylation can release the G1 transcription factor E2F and promote entry into the S phase. Cyclin A, another cyclin partner of CDK2, can bind and activate CDK2 at the initial stage of the S phase and promote phosphorylation of endogenous substrates, thereby inactivating DNA replication and E2F to complete the S phase.

[0024] CDK4 and CDK6 are also involved in the cell cycle. CDK4 and CDK6 inhibitors can arrest the cell cycle from G1 to S phase by blocking the phosphorylation of Rb protein and inhibiting the proliferation of Rb-positive tumor cells. In addition to cell cycle activity, CDK4 and CDK6 inhibitors can also inhibit tumor growth through other mechanisms, including but not limited to inducing senescence, promoting anti-tumor immune responses, regulating cell metabolism, and enhancing cell arrest caused by signal transduction pathway inhibitors.

[0025] definition

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0027] As used in the specification and claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0028] As used in the specification and the appended claims, the following terms have the following meanings unless otherwise specified.

[0029] "Amino" refers to the -NH2 group.

[0030] "Cyano" refers to a -CN group.

[0031] "Nitro" refers to a -NO2 group.

[0032] "Oxa" refers to an -O- group.

[0033] "Oxo" refers to a =0 group.

[0034] "Thio" refers to a =S group.

[0035] "Imino" refers to a =NH group.

[0036] "Oximo" refers to a =N-OH group.

[0037] "Hydrazino" refers to the =N-NH2 radical.

[0038] "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-C 15 In certain embodiments, an alkyl group contains from one to thirteen carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group comprises methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond.

[0039] "Heteroalkyl" refers to an alkyl group as defined above, one or more of which is replaced by a heteroatom, for example, wherein the heteroatom is selected from N, O and S at each substitution position. Other heteroatoms may also be used, including but not limited to B, Al, Si and P. The heteroatom may also be oxidized, such as but not limited to -S(O)- and -S(O)2-. For example, heteroalkyl groups may include ethers, thioethers and alkylamines. The heteroalkyl group consists of a specified number of carbon atoms and may include one or more heteroatoms selected from O, N, Si and S, wherein the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N and S may be located at any interior position of the heteroalkyl group. The heteroatom Si may be located at any position of the heteroalkyl group, including the position where the alkyl group is connected to the rest of the molecule. Two heteroatoms may be consecutive, for example, -CH2NHOCH3 and -CH2OSi(CH3)3. The heteroalkyl group may include any number of carbon atoms specified herein and in the definition of alkyl.

[0040] "Alkoxy" refers to a group bonded through an oxygen atom, of the formula -O-alkyl, wherein alkyl is an alkyl chain as defined above.

[0041] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In certain embodiments, alkenyl comprises two to eight carbon atoms. In other embodiments, alkenyl comprises two to four carbon atoms. Alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc.

[0042] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having two to twelve carbon atoms. In certain embodiments, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group comprises two to six carbon atoms. In other embodiments, the alkynyl group comprises two to four carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0043] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, which is composed only of carbon and hydrogen, does not contain unsaturation, and has one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The connection point of the alkylene chain to the rest of the molecule and to the group is through a carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene group comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene).

[0044] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, the chain consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond, and is connected to the group by a single bond. In certain embodiments, the alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene comprises three to five carbon atoms (eg, C3-C5 alkenylene).

[0045] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, the chain consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. In certain embodiments, the alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, the alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene).

[0046] "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain that connects the rest of the molecule to a group, the chain consisting of heteroatoms such as N, O and S. Other heteroatoms may also be used, including but not limited to B, Al, Si and P. The heteroalkylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. In certain embodiments, the heteroalkylene contains one heteroatom. In certain embodiments, the heteroalkylene contains two heteroatoms. In certain embodiments, the heteroalkylene contains three heteroatoms. In certain embodiments, the heteroalkylene contains four heteroatoms. In certain embodiments, the heteroalkylene contains five heteroatoms. In certain embodiments, the heteroatom can be N, O, S, Si or P, or a combination thereof. In certain embodiments, the heteroatom can be N, O or S, or a combination thereof. In certain embodiments, the heteroatom can be N, O, or a combination thereof.

[0047] The term "C x-y " or "C x -C y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is intended to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups containing from one to six carbon atoms.

[0048] The term "C x-y "Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively.

[0049] As used herein, the term "carbocycle" refers to a saturated, unsaturated or aromatic ring, wherein each atom of the ring is carbon.Carbocycles include 3-10-membered monocycles, 5-12-membered bicyclic rings, 5-12-membered spiral bicyclic rings, and 5-12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as a phenyl, can be fused with a saturated or unsaturated ring (such as cyclohexane, cyclopentane, or cyclohexene). Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as long as the valence number allows. Bicyclic carbocycles also include spiral bicyclic rings, such as spiropentane. Bicyclic carbocycles include combinations of any ring size, such as 3-3 spiral ring systems, 4-4 spiral 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 bicyclo[1.1.1]pentanyl.

[0050] The term "aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π electron system that conforms to the Hückel theory. Ring systems derived from aryl groups include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0051] The term "cycloalkyl" refers to a saturated ring in which each atom on the ring is carbon. Cycloalkyl can include monocyclic and polycyclic rings, such as 3-10-membered monocyclic rings, 5-12-membered bicyclic rings, 5-12-membered spirobicyclic rings, and 5-12-membered bridged rings. In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl can be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7 dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, etc.

[0052] The term "cycloalkenyl" refers to a saturated ring, wherein each atom of the ring is carbon, and there is at least one double bond between two ring carbons. Cycloalkenyl can include monocycles and polycycles, such as 3 to 10 monocycles, 6 to 12 bicycles, and 5 to 12 bridged rings. In other embodiments, cycloalkenyl comprises 5 to 7 carbon atoms. Cycloalkenyl can be connected to the rest of the molecule by a single bond. The example of monocyclic cycloalkenyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0053] The term "halo," or alternatively, "halogen" or "halide" refers to fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0054] The term "haloalkyl" refers to an alkyl group as defined above, substituted with one or more halo groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

[0055] As used herein, the term "heterocycle" refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycles include 3 to 10-membered monocycles, 6 to 12-membered bicyclics, 5 to 12-membered spiral bicyclics and 5 to 12-membered bridged rings. Monocyclic heterocycles include any saturated, unsaturated and aromatic rings, as long as the valence number allows. Monocyclic heterocycles include but are not limited to oxetanes, azetidines, furans, tetrahydrofurans, pyrroles, pyrrolidines, pyrans, piperidines, piperazines, imidazoles, thiazoles, morpholines, pyridines and pyrimidines. Bicyclic heterocycles include any combination of saturated, unsaturated and aromatic bicyclics, as long as the valence number allows. In exemplary embodiments, aromatic rings (e.g., pyridyl) can be fused with saturated or unsaturated rings (e.g., cyclohexane, cyclopentane, morpholine, piperidines or cyclohexene). Bicyclic heterocycles include any combination of ring sizes, such as a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. 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. Bicyclic heterocycles also include spiro bicyclic rings, such as 5- to 12-membered spiro bicyclic rings, 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, 1-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-thia-6-azaspiro[3.3]hept ... [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.

[0056] The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π electron system that conforms to the Huckel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through any atom in the ring. Examples of heteroaryls include, but are not limited to, aza- benzothiazolyl, benzoimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, pyrrolyl, pyrazolyl, pyridyl, pyridopyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, and thiophenyl (i.e., thienyl).

[0057] 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 can include monocycles and polycycles, such as 3 to 10 monocycles, 6 to 12 bicycles, 5 to 12 spiral bicycles and 5 to 12 bridged rings. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If there are one or more nitrogen-atoms, it is optionally quaternized. Heterocycloalkyl is connected to the rest of the molecule by any atom (valence number allows, such as any carbon or nitrogen atom of heterocycloalkyl) of heterocycloalkyl. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, dioxolanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, 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, 1-thia-6-aza Spiro[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.

[0058] The term "heterocycloalkenyl" refers to an unsaturated ring having a carbon atom and at least one heteroatom, and at least one double bond is present between two ring carbons. Heterocycloalkenyl does not include a heteroaryl ring. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycloalkenyl can 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, the heterocycloalkenyl includes five to seven ring atoms. The heterocycloalkenyl can be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), -10-ydrazine-10-ne (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazolin (dihydroisothiazole), oxadiazolin (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0059] The term "replacement" refers to a portion with a substituent that replaces one or more carbons or hydrogen on a replaceable heteroatom, such as NH or NH2 of a compound. It should be understood that "replacement" or "replaced by..." includes implicit conditions, i.e., such substitutions meet the allowed valences of the substituted atoms and substituents, and the substitutions produce stable compounds, i.e., compounds that do not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.). In certain embodiments, substitution refers to a portion with a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thio group. As used herein, the term "replacement" is intended to include all allowed substituents of an organic compound. Broadly speaking, the substituents allowed in an organic compound include non-cyclic and cyclic, branched and non-branched, carbocyclic and heterocyclic, spirocyclic and non-spirocyclic, aromatic and non-aromatic substituents. For appropriate organic compounds, the allowed substituents may be one or more, and may be the same or different.

[0060] In some embodiments, each substituent can individually include any substituent described herein, for example: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), -11-ydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-ORa , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which is optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), R a、 -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -Rb -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); wherein each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a (if the valence permits) may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c-C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0061] 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)".

[0062] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0063] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and with a reasonable benefit / risk ratio.

[0064] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to 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 that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (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, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0065] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, etc. 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, etc. 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, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium and magnesium salts.

[0066] As used herein, "treatment" or "treating" refers to a method of obtaining a beneficial or desired result for a disease, disorder, or medical condition, including but not limited to a therapeutic benefit and / or a preventive benefit. Therapeutic benefit may include, for example, eradication or improvement of the underlying disorder being treated. In addition, therapeutic benefit may include, for example, eradication or improvement of one or more physiological symptoms associated with the underlying disorder, thereby observing improvement in the subject, although the subject may still suffer from the underlying disorder. In certain embodiments, in order to obtain a preventive benefit, the composition is administered to a subject at risk for a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even though the disease may not have been diagnosed. Treatment by administering the compounds described herein does not require the involvement of a medical professional.

[0067] Abbreviations

[0068]

[0069]

[0070] Compound

[0071] The following is a discussion of compounds and salts thereof that can be used in the disclosed methods. In certain embodiments, the compounds and salts are described by Formula (I0), (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA).

[0072] In one aspect, disclosed herein is a compound represented by formula (I):

[0073]

[0074] in,

[0075] R 1 Selected from optionally substituted piperidine, optionally substituted phenyl, optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;

[0076] A is selected from optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings;

[0077] R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;

[0078] R 3 , R 4 , R5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0079] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl

[0080] R z is selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle; and

[0081] m is selected from 0 to 9,

[0082] If R 1 is an optionally substituted pyrazole, then R 2 Not piperidine.

[0083] In one aspect, disclosed herein is a compound represented by formula (I):

[0084]

[0085] in,

[0086] R 1 is selected from the group consisting of optionally substituted indole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;

[0087] R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;

[0088] R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0089] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl.

[0090] In one aspect, disclosed herein is a compound represented by formula (I):

[0091]

[0092] in,

[0093] R 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;

[0094] R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;

[0095] R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0096] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl.

[0097] R 1 Can be any suitable functional group known to those skilled in the art. 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted pyridine, optionally substituted azetidine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole. 1 is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole. 1 is selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole. 1 SO2R 1a or C 1-3 Alkyl substituted, where R 1a Selected from C 1-6 alkyl.

[0098] In some embodiments, R1 is selected from the group consisting of optionally substituted piperidine, optionally substituted phenyl, optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, 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, R 1 is selected from optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole and optionally substituted azetidine.

[0099] In some embodiments, R 1 yes In some embodiments, A is selected from optionally substituted C 3-6 In some embodiments, A is selected from optionally substituted C 5-6 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, R z is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle. z Selected from optionally substituted C 1-3 alkyl and an optionally substituted 5- to 8-membered heterocyclic ring. z Selected from C 1-3 Alkyl and substituted 5- to 8-membered heterocyclic ring.

[0100] In some embodiments, R 1 is selected from the group consisting of optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, 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, R 1is selected from the group consisting of optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. 1 is an optionally substituted piperidine. 1 is optionally substituted azabicyclo[3.1.0]hexane. In some embodiments, R 1 is an optionally substituted indole. 1 is an optionally substituted isoindole. 1 is an optionally substituted azetidine. 1 is an optionally substituted indazole. 1 is an optionally substituted tetrahydroisoquinoline.

[0101] R 2 Can be any suitable functional group known to those skilled in the art. 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. 2 Selected from optionally substituted C 3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.

[0102] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. 2 In some embodiments, R 2 In some embodiments, R 2 Selected from optionally substituted C 3-6 In some embodiments, R 2 Selected from optionally substituted C 5-6 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. 2is selected from the group consisting of 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 1-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 [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, R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0103] In some embodiments, R 2 Halogen, -SO2R 2a 、-NR 2a , oxo, -COR 2a , C 1-4 Alkyl, C 1-3 Alkylene-C 1-3 Alkoxy, -OR 2a , -CN, -CH2-CN and optionally substituted 3- to 6-membered heterocycloalkyl, wherein R 2a Selected from hydrogen and C 1-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, piperidine, piperazine or azetidine, wherein R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a , oxo and C 1-4Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a and-NR 2a , oxo and C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, propyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -(CH2)2OEt, -OH, -OMe, -OEt, -CN, -C-CN, oxetane, and azetidine. In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo and methyl. 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, methylpiperidine or azetidine, wherein R 2a Selected from C 1-6 alkyl.

[0104] In some embodiments, R 2 yes

[0105]

[0106] Y 1 Selected from -N- and -CR 10 -;

[0107] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11, -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0108] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0109] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0110] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0111] In some embodiments, R 2 Selected from:

[0112]

[0113]

[0114] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 Selected from

[0115] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN. 3 is selected from hydrogen and -CN.

[0116] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4 R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0117] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0118] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0119] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0120] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IA):

[0121]

[0122] in,

[0123] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0124] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; and

[0125] n is selected from 0 to 9.

[0126] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. 2 In some embodiments, R 2 In some embodiments, R 2 Selected from optionally substituted C 3-6 In some embodiments, R2 Selected from optionally substituted C 5-6 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. 2 is selected from the group consisting of 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 1-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 [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, R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0127] In some embodiments, R 2 Halogen, -SO2R 2a 、-NR 2a , oxo, -COR 2a , C 1-4 Alkyl, C 1-3 Alkylene-C 1-3 Alkoxy, -OR 2a , -CN, -CH2-CN and optionally substituted 3- to 6-membered heterocycloalkyl, wherein R 2a Selected from hydrogen and C1-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, piperidine, piperazine or azetidine, wherein R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a , oxo and C 1-4 Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a and-NR 2a , oxo and C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, propyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -(CH2)2OEt, -OH, -OMe, -OEt, -CN, -C-CN, oxetane, and azetidine. In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo and methyl. 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, methylpiperidine or azetidine, wherein R 2a Selected from C 1-6 alkyl.

[0128] In some embodiments, R 2 Selected from optionally substituted C3-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane or azetidine, wherein R 2a Selected from C 1-6 In some embodiments, R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0129] In some embodiments, R 2 Selected from:

[0130]

[0131]

[0132] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 Selected from

[0133] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN.3 is selected from hydrogen and -CN.

[0134] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4 R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0135] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0136] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0137] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0138] The variable n can be any suitable number known to those skilled in the art. In some embodiments, n is from 0 to 9. In some embodiments, n is from 0 to 5. In some embodiments, n is from 0 to 3. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0139] R 8 Can be any suitable functional group known to those skilled in the art. 8 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 8 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 8 is fluorine, chlorine, bromine, methyl, ethyl or propyl.

[0140] R 9 Can be any suitable functional group known to those skilled in the art. 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 9 Selected from optionally substituted C 1-4 In some embodiments, R 9 Selected from methyl, ethyl and propyl.

[0141] In some embodiments, the compound is selected from:

[0142]

[0143] In some embodiments, the compound is selected from:

[0144]

[0145] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IAA):

[0146]

[0147] in,

[0148] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0149] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl;

[0150] n is selected from 0 to 9;

[0151] Y 1 Selected from -N- and -CR 10 -;

[0152] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0153] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0154] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0155] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0156] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN. 3 is selected from hydrogen and -CN.

[0157] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4 R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0158] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0159] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0160] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0161] The variable n can be any suitable number known to those skilled in the art. In some embodiments, n is from 0 to 9. In some embodiments, n is from 0 to 5. In some embodiments, n is from 0 to 3. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0162] R 8 Can be any suitable functional group known to those skilled in the art. 8 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 8 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 8 is fluorine, chlorine, bromine, methyl, ethyl or propyl.

[0163] R 9 Can be any suitable functional group known to those skilled in the art. 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 9 Selected from optionally substituted C 1-4 In some embodiments, R 9 Selected from methyl, ethyl and propyl.

[0164] Y 1 Can be any suitable atom known to those skilled in the art. 1 Selected from -N- and -CR 10 -. In some embodiments, Y 1 In some embodiments, Y 1 Yes-CR 10 -.

[0165] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each is independently any suitable atom known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10)-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0166] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, and 3. In some embodiments, each of a, c, and d is independently selected from 1 and 2.

[0167] R 10 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents are taken together to form an optionally substituted heterocycle. 10 are independently selected from hydrogen, halogen, -OH, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 In some embodiments, each R 10 R is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, methyl, ethyl, propyl, cyclopropyl and cyclobutyl. 10 Independently selected from hydrogen, fluorine, -OH, methyl and cyclopropyl.

[0168] R 11 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 11 are independently selected from hydrogen and optionally substituted C 1-4 In some embodiments, each R 11are independently selected from hydrogen and optionally substituted C 1-2 In some embodiments, each R 11 R is independently selected from hydrogen, methyl and ethyl, wherein methyl and ethyl are optionally substituted with -OMe, -OEt and -OPr. 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0169] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IAAA):

[0170]

[0171] in,

[0172] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; and

[0173] R 2 is an optionally substituted cycloalkyl and an optionally substituted heterocycle. In some embodiments of compounds of Formula (IAAA), R 2 Selected from:

[0174]

[0175]

[0176] In some embodiments, the compound is selected from:

[0177]

[0178]

[0179] In some embodiments, the compound is selected from:

[0180]

[0181]

[0182] In some embodiments, the compound is selected from:

[0183]

[0184]

[0185] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IB):

[0186]

[0187] in,

[0188] X 1 , X 2 , X 3 Each of which is independently selected from N and CR 13 ;

[0189] R 12 is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle, or R 12 With R 13 together form an optionally substituted ring; and

[0190] Each R 13 are independently selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl.

[0191] In some embodiments, R 2 is an optionally substituted heterocycle.

[0192] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. 2 In some embodiments, R 2 In some embodiments, R 2 Selected from optionally substituted C 3-6 In some embodiments, R 2 Selected from optionally substituted C 5-6 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. 2is selected from the group consisting of 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 1-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 [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, R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0193] In some embodiments, R 2 Halogen, -SO2R 2a 、-NR 2a , oxo, -COR 2a , C 1-4 Alkyl, C 1-3 Alkylene-C 1-3 Alkoxy, -OR 2a , -CN, -CH2-CN and optionally substituted 3- to 6-membered heterocycloalkyl, wherein R 2a Selected from hydrogen and C 1-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, piperidine, piperazine or azetidine, wherein R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a , oxo and C 1-4Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a and-NR 2a , oxo and C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, propyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -(CH2)2OEt, -OH, -OMe, -OEt, -CN, -C-CN, oxetane, and azetidine. In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo and methyl. 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, methylpiperidine or azetidine, wherein R 2a Selected from C 1-6 alkyl.

[0194] In some embodiments, R 2 Selected from optionally substituted C 3-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane or azetidine, wherein R 2a Selected from C 1-6 In some embodiments, R 2It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0195] In some embodiments, R 2 Selected from:

[0196]

[0197]

[0198] In some embodiments, R 2 Selected from:

[0199]

[0200] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN. 3 is selected from hydrogen and -CN.

[0201] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4 R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4is selected from hydrogen, -CN and -CHF2.

[0202] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0203] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0204] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0205] X 1 , X 2 and X 3 Each of X can be any suitable atom known to those skilled in the art. 1 , X 2 and X 3 Each of which is independently selected from N and CR 13 In some embodiments, X 1 , X 2 and X 3 Each of X is independently N. In some embodiments, X 1 , X 2 and X 3 Each of which is independently selected from CR 13 In some embodiments, X 1 , X 2 and X 3 Each is CH.

[0206] R 12 Can be any suitable functional group known to those skilled in the art. 12 is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle, or R 12 With R 13 Together they form an optionally substituted ring. 12 is an optionally substituted heterocycle. 12 is an optionally substituted 3- to 8-membered heterocyclic ring. 12 is an optionally substituted 5- to 8-membered heterocyclic ring. 12 is an optionally substituted 6- to 7-membered heterocyclic ring.

[0207] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IBB):

[0208]

[0209] in,

[0210] Y 1 Selected from -N- and -CR 10 -;

[0211] Z 1 , Z 2 , Z3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0212] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0213] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0214] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0215] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN. 3 is selected from hydrogen and -CN.

[0216] R 4 Can be any suitable functional group known to those skilled in the art.4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4 R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0217] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0218] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0219] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0220] X 1 , X 2 and X 3 Each of X can be any suitable atom known to those skilled in the art. 1 , X 2 and X 3 Each of which is independently selected from N and CR 13 In some embodiments, X 1 , X 2 and X 3 Each of X is independently N. In some embodiments, X 1 , X 2 and X 3 Each of which is independently selected from CR 13 In some embodiments, X 1 , X 2 and X 3 Each is CH.

[0221] R 12 Can be any suitable functional group known to those skilled in the art. 12 is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle, or R 12 With R 13 Together they form an optionally substituted ring. 12 is an optionally substituted heterocycle. 12 is an optionally substituted 3- to 8-membered heterocyclic ring. 12 is an optionally substituted 5- to 8-membered heterocyclic ring.12 is an optionally substituted 6- to 7-membered heterocyclic ring.

[0222] Each R 13 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 13 are independently selected from hydrogen, halogen, -CN and optionally substituted C 1-4 Alkyl, or R 12 With R 13 Together they form an optionally substituted ring. In some embodiments, each R 13 R is independently selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, and propyl. 13 is independently selected from hydrogen, fluorine, -CN, methyl and ethyl. 13 are independently hydrogen.

[0223] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each is independently any suitable atom known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0224] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0225] R 10 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents are taken together to form an optionally substituted heterocycle. 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl and optionally substituted C 1-3 In some embodiments, each R 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, -OEt, methyl, ethyl, propyl, and -CH2CH2OCH3. 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3. 10 Independently selected from hydrogen, fluorine, -CN, -OH, -OMe, methyl and -CH2CH2OCH3.

[0226] R 11 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 11 are independently selected from hydrogen and optionally substituted C 1-4 In some embodiments, each R 11 are independently selected from hydrogen and optionally substituted C 1-2 In some embodiments, each R 11 R is independently selected from hydrogen, methyl and ethyl, wherein methyl and ethyl are optionally substituted with -OMe, -OEt and -OPr. 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0227] In some embodiments, the compound is selected from:

[0228]

[0229] In some embodiments, the compound is selected from:

[0230]

[0231] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IC):

[0232]

[0233] in,

[0234] R 14 is selected from halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 15 together form an optionally substituted heterocyclic ring; and

[0235] R 15 Selected from -S(O)2R 16 -, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0236] In some embodiments, R 2 is an optionally substituted heterocycle.

[0237] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. 2 In some embodiments, R 2 In some embodiments, R 2 Selected from optionally substituted C 3-6 In some embodiments, R 2 Selected from optionally substituted C 5-6 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. 2is selected from optionally substituted 3- to 6-membered heterocycloalkyl. 2 is selected from the group consisting of 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 1-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 [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, R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0238] In some embodiments, R 2 Halogen, -SO2R 2a 、-NR 2a , oxo, -COR 2a , C 1-4 Alkyl, C 1-3 Alkylene-C 1-3 Alkoxy, -OR 2a , -CN, -CH2-CN and optionally substituted 3- to 6-membered heterocycloalkyl, wherein R 2a Selected from hydrogen and C 1-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, piperidine, piperazine or azetidine, wherein R 2a Selected from C 1-6 In some embodiments, R 2Halogen, -SO2R 2a , oxo and C 1-4 Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 Halogen, -SO2R 2a and-NR 2a , oxo and C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 In some embodiments, R 2 is substituted with fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, propyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -(CH2)2OEt, -OH, -OMe, -OEt, -CN, -C-CN, oxetane, and azetidine. In some embodiments, R 2 In some embodiments, R is substituted by fluorine, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R is substituted by fluorine, -SO2Me, oxo, and methyl. In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane, methylpiperidine or azetidine, wherein R 2a Selected from C 1-6 alkyl.

[0239] In some embodiments, R 2 Selected from optionally substituted C 3-6 In some embodiments, R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane or azetidine, wherein R 2a Selected from C1-6 In some embodiments, R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0240] In some embodiments, R 2 Selected from:

[0241]

[0242]

[0243] In some embodiments, R 2 Selected from:

[0244]

[0245] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN. 3 is selected from hydrogen and -CN.

[0246] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0247] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0248] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0249] R 7 Can be any suitable functional group known to those skilled in the art.7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0250] R 14 Can be any suitable functional group known to those skilled in the art. 14 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 15 Together they form an optionally substituted heterocyclic ring. 14 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 14 Selected from fluorine, chlor, bromine, methyl, ethyl and propyl.

[0251] R 15 Can be any suitable functional group known to those skilled in the art. 15 Selected from -S(O)2R 16 -, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 15 and R 14 Together they form an optionally substituted heterocyclic ring. 15 Selected from -S(O)2R 16 - and optionally substituted C 1-4 In some embodiments, R 15 is an optionally substituted C 3-6 In some embodiments, R 15 is an optionally substituted 3- to 6-membered heterocycloalkyl group.

[0252] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (ICC):

[0253]

[0254] in,

[0255] Y 1 Selected from -N- and -CR 10 -;

[0256] Z 1 , Z2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0257] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0258] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring;

[0259] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 Alkyl; and

[0260] R 16 Selected from -S(O)2R 16 -, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0261] R 3 It can be any suitable functional group known to those skilled in the art. In some embodiments, it is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN. 3 is selected from hydrogen and -CN.

[0262] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is 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, R 4 R is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0263] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 5 It's hydrogen.

[0264] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 6 It's hydrogen.

[0265] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0266] X 1 , X 2 and X 3 Each of X can be any suitable atom known to those skilled in the art. 1 , X 2 and X 3 Each of which is independently selected from N and CR 13 In some embodiments, X 1 , X 2 and X 3 Each of X is independently N. In some embodiments, X 1 , X 2 and X 3 Each of which is independently selected from CR 13 In some embodiments, X 1 , X 2 and X 3 Each is CH.

[0267] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each is independently any suitable atom known to those skilled in the art. 1 , Z2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0268] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0269] R 14 Can be any suitable functional group known to those skilled in the art. 14 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 14 Selected from fluorine, chlor, bromine, methyl, ethyl and propyl.

[0270] R 16 Can be any suitable functional group known to those skilled in the art. 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 16 Selected from optionally substituted C 1-4 In some embodiments, R 16 is methyl, ethyl or propyl.16 It is methyl.

[0271] In some embodiments, the compound is selected from:

[0272]

[0273] In some embodiments, the compound is selected from:

[0274]

[0275]

[0276]

[0277]

[0278] In some embodiments, the compound is selected from:

[0279]

[0280] In one aspect, disclosed herein are compounds represented by formula (II):

[0281]

[0282] in,

[0283] A is selected from optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings;

[0284] R 1 is selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle;

[0285] m is selected from 0 to 9;

[0286] R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0287] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl;

[0288] Y 1 Selected from -N- and -CR 10 -;

[0289] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0290] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0291] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0292] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0293] Ring A can be any suitable carbocyclic or heterocyclic ring known to those skilled in the art. In some embodiments, A is selected from optionally substituted C 3-6 In some embodiments, A is selected from optionally substituted C 5-6 In some embodiments, A is selected from phenyl, pyridine, pyrimidine, imidazole, pyrazole, tetrazole, thiazole, furan, pyran, tetrahydrofuran, dioxane, morpholine, piperidine and tetrahydroisoquinoline. In some embodiments, A is selected from phenyl, pyridine, pyrimidine, imidazole, pyrazole, tetrazole, thiazole, furan, pyran, tetrahydrofuran, dioxane, morpholine, piperidine and tetrahydroisoquinoline. In some embodiments, A is selected from phenyl, pyridine, pyrimidine, imidazole, pyrazole, tetrazole, thiazole, furan, pyran, tetrahydrofuran, dioxane, morpholine, piperidine and tetrahydroisoquinoline. In some embodiments, A is selected from phenyl, pyridine, pyrimidine, imidazole, pyrazole, furan, pyran, dioxane, morpholine, piperidine and tetrahydroisoquinoline. In some embodiments, A is selected from phenyl, pyridine, pyrimidine, imidazole, pyrazole, furan, pyran, dioxane, morpholine, piperidine and tetrahydroisoquinoline.

[0294] The variable m can be any suitable number known to those skilled in the art. In some embodiments, m is selected from 0 to 9. In some embodiments, m is selected from 0 to 4. In some embodiments, m is selected from 0 to 2. In some embodiments, m is 1.

[0295] R 1 It can be any suitable functional group known to those skilled in the art. 1 Can be any functional group described herein above. In some embodiments, R 1 is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle. 1 Selected from optionally substituted C 1-3 alkyl and an optionally substituted 5- to 8-membered heterocyclic ring. 1 Selected from C 1-3 In some embodiments, R 1 It is methyl, ethyl, propyl, isopropyl, In some embodiments, R 1 is methyl, isopropyl,

[0296] R 3 It can be any suitable functional group known to those skilled in the art. 3 Can be any functional group described herein above. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN.

[0297] R 4 It can be any suitable functional group known to those skilled in the art. 4 Can be any functional group described herein above. In some embodiments, R 4is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, fluorine, chlorine, bromine, -CN, optionally substituted methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 4 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0298] R 5 It can be any suitable functional group known to those skilled in the art. 5 Can be any functional group described herein above. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is hydrogen, fluorine or -CN. In some embodiments, R 5 It's hydrogen.

[0299] R 6 It can be any suitable functional group known to those skilled in the art. 6 Can be any functional group described herein above. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4In some embodiments, R 56 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is hydrogen, fluorine or -CN. In some embodiments, R 6 It's hydrogen.

[0300] R 7 It can be any suitable functional group known to those skilled in the art. 7 Can be any functional group described herein above. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0301] Y 1 Can be any suitable atom known to those skilled in the art. 1 Choose rom-N- and -CR 10 -. In some embodiments, Y 1 In some embodiments, Y 1 Yes-CR 10 -.Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Z is independently any suitable atom known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 can be any atom previously described herein. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11-、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0302] The variables a, b, c, and d can be any suitable number known to those skilled in the art. The variables a, b, c, and d can be any number described above herein. The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0303] R 10 R may be any suitable functional group known to those skilled in the art. 10 Can be any functional group described herein above. In some embodiments, each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl and optionally substituted C 1-3 In some embodiments, each R 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, -OEt, methyl, ethyl, propyl, and -CH2CH2OCH3. 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3. 10 Independently selected from hydrogen, fluorine, -CN, -OH, -OMe, methyl and -CH2CH2OCH3.

[0304] R 11 It can be any suitable functional group known to those skilled in the art. 11 Can be any functional group described herein above. In some embodiments, each R 11are independently selected from hydrogen and optionally substituted C 1-2 In some embodiments, each R 11 R is independently selected from hydrogen, methyl and ethyl, wherein methyl and ethyl are optionally substituted with -OMe, -OEt and -OPr. 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0305] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IIA):

[0306]

[0307] in,

[0308] R 13 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 together form an optionally substituted heterocyclic ring; and

[0309] R 14 is selected from halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0310] R 3 It can be any suitable functional group known to those skilled in the art. 3 Can be any functional group described herein before. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from hydrogen, fluorine and -CN.

[0311] R4 It can be any suitable functional group known to those skilled in the art. 4 Can be any functional group described herein above. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, fluorine, chlorine, bromine, -CN, optionally substituted methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 4 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 4 is selected from hydrogen, -CN and -CHF2.

[0312] R 5 It can be any suitable functional group known to those skilled in the art. 5 Can be any functional group described herein above. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 5 is hydrogen, fluorine or -CN. In some embodiments, R 5 It's hydrogen.

[0313] R 6 It can be any suitable functional group known to those skilled in the art. 6 Can be any functional group described herein above. In some embodiments, R6 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 56 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 6 is hydrogen, fluorine or -CN. In some embodiments, R 6 It's hydrogen.

[0314] R 7 It can be any suitable functional group known to those skilled in the art. 7 Can be any functional group described herein above. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0315] Y 1 Can be any suitable atom known to those skilled in the art. 1 Selected from -N- and -CR 10 -. In some embodiments, Y 1 In some embodiments, Y 1 For-CR 10 -.Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Z is independently any suitable atom known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 can be any atom previously described herein. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0316] The variables a, b, c, and d can be any suitable number known to those skilled in the art. The variables a, b, c, and d can be any number described above herein. The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0317] R 10 It can be any suitable functional group known to those skilled in the art. 10 Can be any functional group described herein above. In some embodiments, each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl and optionally substituted C 1-3 In some embodiments, each R 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, -OEt, methyl, ethyl, propyl, and -CH2CH2OCH3. 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3. 10 Independently selected from hydrogen, fluorine, -CN, -OH, -OMe, methyl and -CH2CH2OCH3.

[0318] R 11It can be any suitable functional group known to those skilled in the art. 11 Can be any functional group described herein above. In some embodiments, each R 11 are independently selected from hydrogen and optionally substituted C 1-2 In some embodiments, each R 11 R is independently selected from hydrogen, methyl and ethyl, wherein methyl and ethyl are optionally substituted with -OMe, -OEt and -OPr. 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0319] R 13 Can be any suitable functional group known to those skilled in the art. 13 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 Together they form an optionally substituted heterocyclic ring. 13 Selected from optionally substituted C 1-4 In some embodiments, R 13 Selected from optionally substituted C 3-6 In some embodiments, R 13 Selected from optionally substituted C 3-6 In some embodiments, R 13 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. 13 and R 14 Together they form an optionally substituted heterocyclic ring.

[0320] R 14 Can be any suitable functional group known to those skilled in the art. 14 is selected from halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 13 Together they form an optionally substituted heterocyclic ring. 14 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 14 Selected from optionally substituted C 3-6 In some embodiments, R 14 and R13 Together they form an optionally substituted heterocyclic ring.

[0321] In some embodiments, the compound is selected from:

[0322]

[0323] In some embodiments, the compound is selected from:

[0324]

[0325] Additional embodiments of the compounds of the present disclosure include the following:

[0326] Embodiment 1 of the present disclosure relates to a compound having a structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0327]

[0328] in,

[0329] R 1 Selected from optionally substituted piperidine, optionally substituted phenyl, optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;

[0330] A is selected from optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings;

[0331] R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;

[0332] R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0333] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl

[0334] R z is selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle; and

[0335] m is selected from 0 to 9.

[0336] Embodiment 2 of the present disclosure relates to the compound of embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from optionally substituted piperidine, optionally substituted phenyl, optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole and optionally substituted azetidine.

[0337] Embodiment 3 of the present disclosure relates to the compound of embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 yes

[0338] Embodiment 4 of the present disclosure relates to the compound of embodiment 3 or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from optionally substituted C 5-6 carbocyclic ring and optionally substituted 5- to 10-membered heterocyclic ring.

[0339] Embodiment 5 of the present disclosure relates to the compound of embodiment 4 or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from phenyl, pyrazole and tetrahydroisoquinoline.

[0340] Embodiment 6 of the present disclosure relates to the compound of any one of Embodiments 3 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein m is selected from 0 to 4.

[0341] Embodiment 7 of the present disclosure relates to the compound of Embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, wherein m is selected from 0 to 2.

[0342] Embodiment 8 of the present disclosure relates to a compound according to any one of Embodiments 3 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R z is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocycle and optionally substituted heterocycle.

[0343] Embodiment 9 of the present disclosure relates to the compound of embodiment 8 or a pharmaceutically acceptable salt or solvate thereof, wherein R z Selected from optionally substituted C 1-3 alkyl and optionally substituted 5- to 8-membered heterocyclic ring.

[0344] Embodiment 10 of the present disclosure relates to the compound of embodiment 9 or a pharmaceutically acceptable salt or solvate thereof, wherein R z Selected from C 1-3 Alkyl and substituted 5- to 8-membered heterocyclic ring.

[0345] Embodiment 11 of the present disclosure relates to a compound according to any of the preceding embodiments or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 yes

[0346]

[0347] Y 1 Selected from -N- and -CR 10 -;

[0348] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0349] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0350] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0351] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0352] Embodiment 12 of the present disclosure relates to a compound of Embodiment 1 or 2 or a pharmaceutically acceptable salt or solvate thereof, which has a structure of one or more of the following formulae:

[0353]

[0354] in,

[0355] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0356] R 9Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl;

[0357] n is selected from 0 to 9;

[0358] X 1 , X 2 and X 3 Each of which is independently selected from N and CR 13 ;

[0359] R 12 is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle, or R 12 With R 13 together form an optionally substituted ring; and

[0360] Each R 13 are independently selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl.

[0361] R 14 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 15 together form an optionally substituted heterocyclic ring; and

[0362] R 15 Selected from -S(O)2R 16 -, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0363] Embodiment 12(a) of the present disclosure is directed to a compound of Embodiment 12 having a structure of Formula (IA) or a pharmaceutically acceptable salt or solvate thereof.

[0364] Embodiment 12(b) of the present disclosure is directed to a compound of Embodiment 12 having the structure of Formula (IB) or a pharmaceutically acceptable salt or solvate thereof.

[0365] Embodiment 12(c) of the present disclosure relates to a compound of Embodiment 12 having a structure of Formula (IC) or a pharmaceutically acceptable salt or solvate thereof.

[0366] Embodiment 13 of the present disclosure relates to a compound of any one of Embodiments 12, 12(a), 12(b) or 12(c), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted heterocycle.

[0367] Embodiment 14 of the present disclosure relates to a compound of any one of Embodiments 12, 12(a), 12(b) or 12(c), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from optionally substituted C 3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.

[0368] Embodiment 15 of the present disclosure relates to the compound of embodiment 13 or 14 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane or azetidine, wherein R 2a Selected from C 1-6 alkyl.

[0369] Embodiment 16 of the present disclosure relates to a compound of Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, which has a structure of one or more of the following formulae:

[0370]

[0371] in,

[0372] Y 1 Selected from -N- and -CR 10 -;

[0373] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0374] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0375] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0376] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl;

[0377] n is selected from 0 to 9;

[0378] X 1 , X 2 and X 3 Each is CH;

[0379] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring;

[0380] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl;

[0381] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl;

[0382] R 17 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 together form an optionally substituted heterocyclic ring; and

[0383] R 18 is selected from halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0384] Embodiment 16(a) of the present disclosure relates to a compound of Embodiment 16 having a structure of Formula (IAA) or a pharmaceutically acceptable salt or solvate thereof.

[0385] Embodiment 16(b) of the present disclosure relates to a compound of Embodiment 16 having a structure of Formula (IBB) or a pharmaceutically acceptable salt or solvate thereof.

[0386] Embodiment 16(c) of the present disclosure relates to a compound of Embodiment 16 having a structure of Formula (ICC) or a pharmaceutically acceptable salt or solvate thereof.

[0387] Embodiment 16(d) of the present disclosure relates to a compound of Embodiment 16 having a structure of Formula (IDD) or a pharmaceutically acceptable salt or solvate thereof.

[0388] Embodiment 17 of the present disclosure relates to a compound of any one of Embodiments 11, 16, 16(a), 16(b), 16(c) or 16(d), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Yes-N-.

[0389] Embodiment 18 of the present disclosure relates to a compound of any one of Embodiments 11, 16, 16(a), 16(b), 16(c) or 16(d), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Yes-CR 10 -.

[0390] Embodiment 19 of the present disclosure relates to a compound of any one of Embodiments 11, 16, 16(a), 16(b), 16(c) or 16(d), or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0391] Embodiment 20 of the present disclosure is directed to a compound of any one of embodiments 11, 16, 16(a), 16(b), 16(c), 16(d), 17, 18 or 19, or a pharmaceutically acceptable salt or solvate thereof, wherein each of a, b, c and d is independently selected from 1, 2 and 3.

[0392] Embodiment 21 of the present disclosure relates to the compound of Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, wherein each of a, c and d is independently selected from 1 and 2.

[0393] Embodiment 22 of the present disclosure relates to a compound of any one of Embodiments 11, 16, 16(a), 16(b), 16(c), 16(d), 17, 18, 19, 20 or 21, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl.

[0394] Embodiment 23 of the present disclosure relates to the compound of embodiment 22 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 independently selected from hydrogen, halogen, -CN, -OH, methyl, -OMe, -CH2CH2OCH3, and cyclopropyl.

[0395] Embodiment 24 of the present disclosure is directed to a compound of any one of embodiments 11, 16, 16(a), 16(b), 16(c), 16(d), 17, 18, 19, 20, 21, 22, or 23, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 11 are independently selected from hydrogen and optionally substituted C 1-2 alkyl.

[0396] Embodiment 25 of the present disclosure relates to the compound of embodiment 24 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0397] Embodiment 26 of the present disclosure relates to the compound of embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole and optionally substituted indole.

[0398] Embodiment 27 of the present disclosure relates to the compound of embodiment 26 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole.

[0399] Embodiment 28 of the present disclosure relates to the compound of embodiment 26 or 27 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 SO2R1a or C 1-3 Alkyl substituted, where R 1a Selected from C 1-6 alkyl.

[0400] Embodiment 29 of the present disclosure relates to a compound of any one of embodiments 1, 2, 26, 27 or 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from optionally substituted heterocycle and optionally substituted cycloalkyl.

[0401] Embodiment 30 of the present disclosure relates to the compound of embodiment 29 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted heterocycloalkyl.

[0402] Embodiment 31 of the present disclosure relates to the compound of embodiment 30 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl.

[0403] Embodiment 32 of the present disclosure relates to the compound of embodiment 31 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine and optionally substituted morpholine.

[0404] Embodiment 33 of the present disclosure relates to a compound of any one of Embodiments 29 to 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Halogen, -SO2R 2a 、-NR 2a , -C(O)CH3, -CN, optionally substituted 3- to 6-membered terocycloalkyl, optionally substituted C 3-5 Carbocyclic, oxo and optionally substituted C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 alkyl.

[0405] Embodiment 34 of the present disclosure relates to the compound of embodiment 32 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Substituted by fluorine, -SO2Me, oxo and methyl.

[0406] Embodiment 35 of the present disclosure relates to a compound of any one of Embodiments 1-10, 12, 12(a), 12(b), 12(c) or 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from

[0407]

[0408] Embodiment 36 of the present disclosure relates to the compound of embodiment 35 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Selected from

[0409]

[0410]

[0411] Embodiment 37 of the present disclosure relates to a compound of any one of Embodiments 1-10, 12, 12(a), 12(b) or 12(c), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted heterocycloalkyl.

[0412] Embodiment 38 of the present disclosure relates to a compound of any of the preceding embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0413] Embodiment 39 of the present disclosure relates to the compound of embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0414] Embodiment 40 of the present disclosure relates to the compound of embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from hydrogen, fluorine and -CN.

[0415] Embodiment 41 of the present disclosure relates to the compound of embodiment 40 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from hydrogen and -CN.

[0416] Embodiment 42 of the present disclosure relates to a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0417] Embodiment 43 of the present disclosure relates to the compound of embodiment 42 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from hydrogen, -CN, -CHF2, -CF3, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0418] Embodiment 44 of the present disclosure relates to the compound of embodiment 43 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from hydrogen, -CN and -CHF2.

[0419] Embodiment 45 of the present disclosure relates to the compounds of the preceding embodiments or pharmaceutically acceptable salts or solvates thereof, wherein R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0420] Embodiment 46 of the present disclosure relates to the compound of embodiment 45 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0421] Embodiment 47 of the present disclosure relates to the compound of embodiment 46 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It's hydrogen.

[0422] Embodiment 48 of the present disclosure relates to a compound according to any of the preceding embodiments or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0423] Embodiment 49 of the present disclosure relates to the compound of embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0424] Embodiment 50 of the present disclosure relates to the compound of embodiment 49 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It's hydrogen.

[0425] Embodiment 51 of the present disclosure relates to a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 It's hydrogen.

[0426] Embodiment 52 of the present disclosure relates to a compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, which is selected from one or more compounds in Table 1.

[0427] Embodiment 52(a) of the present disclosure is directed to a compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0428] Embodiment 53 of the present disclosure relates to a compound of Embodiment 12 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0429] Embodiment 53(a) of the present disclosure is directed to Formula (IA) or a pharmaceutically acceptable salt thereof of Embodiment 53, which is selected from the compounds in Table 1.

[0430] Embodiment 53(b) of the present disclosure is directed to Embodiment 53, Formula (IB) or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0431] Embodiment 53(c) of the present disclosure is directed to a compound of formula (IC) of Embodiment 53 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0432] Embodiment 54 of the present disclosure is directed to a compound of Embodiment 16 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0433] Embodiment 54(a) of the present disclosure is directed to a compound of formula (IAA) of Embodiment 54 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0434] Embodiment 54(b) of the present disclosure relates to Formula (IBB) or a pharmaceutically acceptable salt thereof of Embodiment 54, which is selected from the compounds in Table 1.

[0435] Embodiment 54(c) of the present disclosure relates to Formula (ICC) of Embodiment 54 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

[0436] Embodiment 54(d) of the present disclosure relates to Formula (IDD) or a pharmaceutically acceptable salt thereof of Embodiment 54, which is selected from the compounds in Table 1.

[0437] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14 C content. In a specific embodiment, the compound is deuterated at at least one position. This deuterated form can be prepared by the methods 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 metabolic stability and or efficacy, thereby increasing the duration of action of the drug.

[0438] Unless otherwise stated, compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having the present structure may differ except for the replacement of hydrogen with deuterium or tritium, or with 13 C- or 14 All other carbon-rich carbons are within the scope of the present disclosure.

[0439] The compounds of the invention optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br and 125 Isotopic substitutions of I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0440] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for the synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0441] Deuterium substituted compounds are synthesized using various methods, such as those described in Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10)] 2000, p. 110; 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.

[0442] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to synthesize deuterated compounds. A large number of deuterated reagents and building blocks can be purchased from chemical suppliers (eg, Aldrich Chemical Co.).

[0443] The compounds of the present invention also include crystalline and amorphous forms of these 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 and mixtures thereof.

[0444] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficient acidity, sufficient basicity, or both functional groups can react with any of a variety of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds (e.g., those with quaternary nitrogen) can form salts with appropriate counterions (e.g., halides, such as bromide, chloride, or fluoride, particularly bromide).

[0445] In some cases, the compounds described herein can exist as diastereomers, enantiomers, or other stereoisomers. The compounds described herein include all diastereomers, enantiomers, and epimers, as well as appropriate mixtures thereof. The separation of stereoisomers can 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, incorporated herein by reference for the present disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0446] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms of the compounds described herein are also considered to be disclosed herein.

[0447] In certain embodiments, the compound or the salt of the compound can be a prodrug, for example, wherein the hydroxyl group in the parent compound exists in the form of an ester or carbonate, or the carboxylic acid present in the parent compound exists in the form of an ester. The term "prodrug" is intended to include compounds that are converted into medicaments of the present disclosure under physiological conditions. One method of making a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to display the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, such as a specific target cell in the host animal. For example, esters or carbonates (for example, esters of alcohol or carboxylic acids or carbonates and phosphonates) are preferred prodrugs of the present disclosure.

[0448] Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce a compound as hereinbefore described, are included within the scope of the claims. In certain cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0449] Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. Prodrugs may also have a higher solubility in a pharmaceutical composition than the parent drug. Prodrugs can be designed as reversible drug derivatives and used as modifiers to enhance drug transport to specific site tissues or to increase the residence time of a drug within a cell.

[0450] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (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 et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series; and Edward B.Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for disclosure). According to another embodiment, the present disclosure provides methods for preparing the aforementioned compounds. These compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0451] Synthetic chemistry transformations and methods that can be used to synthesize the compounds described herein are known in the art, and include, for example, those described in R. Larock, Comprehensive Organic Transformation (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd Edition (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).

[0452] Therapeutic applications

[0453] The methods of administering a compound of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt discussed herein can be used to treat cancer. In some embodiments, methods of treating solid tumors are disclosed herein. Examples of cancer include, but are not limited to, ovarian cancer, breast cancer, colon cancer, and brain cancer.

[0454] In some embodiments, disclosed herein are methods of treating cancer by administering a compound of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA), or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein are methods of treating cancer comprising administering a pharmaceutical composition described herein to a subject in need thereof.

[0455] In some embodiments, disclosed herein is a method of inhibiting a cyclin-dependent kinase (CDK) in a cell by administering a compound or a pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA). In some embodiments, disclosed herein is a method of inhibiting a cyclin-dependent kinase (CDK) in a cell using a compound or a pharmaceutically acceptable salt of any of the compounds described herein or a pharmaceutical composition described herein.

[0456] The CDK can be any suitable CDK known to those skilled in the art. In some embodiments, the CDK is selected from CDK 2, CDK 4, CD6, or any combination thereof. In some embodiments, the CDK is selected from CDK2, CDK4, CDK6, CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK 2 / 4 / 6. In some embodiments, the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK 2 / 4 / 6.

[0457] Additional embodiments of therapeutic applications of the present disclosure include the following:

[0458] Embodiment 56 of the present disclosure relates to a method of treating cancer, comprising administering the pharmaceutical composition of embodiment 54 to a subject in need thereof.

[0459] Embodiment 57 of the present disclosure relates to the method of embodiment 56, wherein the cancer is a solid tumor.

[0460] Embodiment 58 of the present disclosure relates to the method of embodiment 56 or 57, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain cancer.

[0461] Embodiment 59 of the present disclosure relates to the method of embodiment 58, wherein the cancer is ovarian cancer or breast cancer.

[0462] Embodiment 60 of the present disclosure relates to a method of inhibiting cyclin-dependent kinase (CDK) in a cell using the compound or pharmaceutically acceptable salt of any one of Embodiments 1 to

[0399] or the pharmaceutical composition of Embodiment 54.

[0463] Embodiment 61 of the present disclosure relates to the method of embodiment 59, wherein the CDK is selected from CDK 2, CDK 4, CD6, or any combination thereof.

[0464] Embodiment 62 of the present disclosure relates to the method of embodiment 60, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK4 / 6 and CDK 2 / 4 / 6.

[0465] Embodiment 63 of the present disclosure relates to the method of embodiment 62, wherein the CDK is CDK 2 / 4 / 6.

[0466] Pharmaceutical preparations

[0467] The compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical composition may comprise at least one compound or pharmaceutically acceptable salt of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents and / or thickening agents. In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and a pharmaceutically acceptable excipient. In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and a pharmaceutically acceptable excipient.

[0468] Pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) can be formulated using one or more physiologically acceptable carriers (including excipients and adjuvants). The formulation can be modified depending on the selected route of administration. Pharmaceutical compositions comprising the compound, salt or conjugate can be manufactured by, for example, lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or embedding the conjugate. The pharmaceutical composition can also include the compound, salt or conjugate in free base form or in pharmaceutically acceptable salt form.

[0469] Methods of formulating a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) may include formulating any compound, salt or conjugate with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semisolid or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, solid compositions also contain non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, the compound, salt or conjugate may be in lyophilized or powdered form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0470] A pharmaceutical composition comprising a compound of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) or a pharmaceutically acceptable salt thereof may comprise at least one active ingredient (e.g., a compound, salt or conjugate and another agent). The active ingredient may be embedded in a microcapsule (prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), a colloidal drug delivery system (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or a macroemulsion.

[0471] The compositions and formulations may be sterilized. Sterilization may be achieved by filtration via sterile filtration.

[0472] Compositions comprising a compound of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) or a pharmaceutically acceptable salt thereof can be formulated as an injection for administration. Non-limiting examples of injections can include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. The suspension can also contain a suitable stabilizer. The injection can be formulated for bolus injection or continuous infusion. Alternatively, the composition can be in lyophilized or powdered form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0473] For parenteral administration, the compound of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) or a pharmaceutically acceptable salt can be formulated into a unit dose injectable form (e.g., solution, suspension, emulsion) together with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be essentially non-toxic and non-therapeutic. The vehicle can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain small amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0474] In one embodiment, the invention relates to methods and compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) for oral delivery to a subject in need thereof. In one embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the oral cavity or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the stomach and / or intestine.

[0475] In one embodiment, the composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) is provided in a modified release dosage form. 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, multi-particulate devices, and combinations thereof. The composition may also contain a non-release controlling excipient.

[0476] In another embodiment, the composition of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) is provided in an enteric coated dosage form. These enteric coated dosage forms may also contain non-release controlling excipients. In one embodiment, the composition is in the form of enteric coated granules as a controlled release capsule for oral administration. The composition may also contain cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric coated pellets as a controlled release capsule for oral administration. The composition may also contain glyceryl monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc or triethyl citrate.

[0477] In another embodiment, the composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) is an enteric coated controlled release tablet for oral administration. The composition may also contain carnauba wax, crospovidone, diacetylated monoglycerides, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide or yellow iron oxide.

[0478] Sustained release formulations comprising a compound or a pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) can also be prepared. Examples of sustained release formulations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of molded articles (e.g., films or microcapsules). Examples of sustained release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or polyvinyl alcohol), polylactic acid, copolymers of L-glutamic acid and ethyl gamma-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (e.g., LUPRON DEPO TM ) (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(–)-3-hydroxybutyric acid.

[0479] Pharmaceutical formulations comprising a compound of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) or a pharmaceutically acceptable salt may be prepared by mixing the compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient and / or stabilizer for storage. The formulation may be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients and / or stabilizers may be non-toxic to the recipient at the dosages and concentrations used. Acceptable carriers, excipients and / or stabilizers may include: buffers, such as phosphates, citrates 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 counterions, such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycols.

[0480] In another embodiment, the composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) may 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.

[0481] In another embodiment, the composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) is provided in an effervescent dosage form. These effervescent dosage forms may also contain non-release controlling excipients.

[0482] In another embodiment, the composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) can be provided in a dosage form having at least one component that can promote immediate release of the active agent and at least one component that can promote controlled release of the active agent. In a further embodiment, the dosage form can release the compound discontinuously in the form of at least two consecutive pulses separated by a time interval of from 0.1 hour to up to 24 hours. The composition can contain one or more release-controlling and non-release-controlling excipients, such as those suitable for destructible semipermeable membranes and swellable materials.

[0483] In another embodiment, a composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) is provided to a subject in a dosage form for oral administration, the dosage form comprising one or more pharmaceutically acceptable excipients or carriers, encapsulated in an intermediate reaction layer and a gastro-resistant outer layer, the intermediate reaction layer comprising a gastro-resistant polymer layered material partially neutralized with a base and having cation exchange capacity.

[0484] In some embodiments, the compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) provided herein can be in unit dosage form or multiple dosage form. As used herein, unit dosage form refers to physically discrete units suitable for administration to a human or non-human animal subject and individually packaged. Each unit dose can contain a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, and a desired pharmaceutical carrier or excipient. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, a unit dosage form can be administered in parts or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, which can be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, tablet or capsule bottles, or pint or gallon bottles. In another embodiment, multiple dosage forms contain different pharmaceutically active agents.

[0485] In some embodiments, the composition of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II) or (IIA) can also be formulated into modified release dosage forms, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended-, accelerated-, and fast-, targeted-, programmed-, 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, NY, 2002; Vol. 126, incorporated herein in its entirety).

[0486] Additional embodiments of the pharmaceutical formulations disclosed herein include the following:

[0487] Embodiment 55 of the present disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of embodiments 1 to 54 or any sub-embodiment thereof, and a pharmaceutically acceptable excipient.

[0488] Combination therapy

[0489] Combination therapy is also contemplated herein, e.g., co-administering a disclosed compound and an additional active agent as part of a specific treatment regimen intended to provide a beneficial effect of the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions produced by the combination of therapeutic agents. The combined administration of these therapeutic agents is typically performed over a specified time period (typically hours, days, weeks, months, or years, depending on the selected combination). Combination therapy is intended to include administering multiple therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, and administering these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0490] Substantially simultaneous administration is achieved, for example, by administering to a subject a single formulation or composition (e.g., a tablet or capsule of each therapeutic agent in a fixed ratio, or multiple single formulations of each therapeutic agent (e.g., capsules). The sequential or substantially simultaneous administration of each therapeutic agent is performed by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents are administered by the same route or different routes. For example, the first therapeutic agent in the selected combination is administered by intravenous injection, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0491] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that the components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially.

[0492] Additional Implementation

[0493] Embodiment 101. A compound or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (I):

[0494]

[0495] in,

[0496] R 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine;

[0497] R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle;

[0498] R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0499] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl.

[0500] Embodiment 102. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IA):

[0501]

[0502] in,

[0503] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0504] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; and

[0505] n is selected from 0 to 9.

[0506] Embodiment 103. The compound or salt thereof of Embodiment 2, wherein R 2 Selected from optionally substituted C 3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.

[0507] Embodiment 104. The compound or salt thereof of Embodiment 13, wherein R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane or azetidine, wherein R 2a Selected from C 1-6 alkyl.

[0508] Embodiment 105. The compound or salt thereof of Embodiment 13, wherein R 2 It is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0509] Embodiment 106. The compound or salt thereof of any one of Embodiments 1 to

[0310] , wherein the compound is selected from:

[0510]

[0511] Embodiment 107. The compound or salt thereof of any one of Embodiments 1 to

[0310] , wherein the compound is selected from:

[0512]

[0513] Embodiment 108. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IAA):

[0514]

[0515] in,

[0516] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0517] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl;

[0518] n is selected from 0 to 9;

[0519] Y 1 Selected from -N- and -CR 10 -;

[0520] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0521] Each of a, b, c, d is independently selected from 1, 2, 3, 4;

[0522] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0523] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0524] Embodiment 109. The compound or salt thereof of Embodiment

[0312] , wherein Y1 Yes-N-.

[0525] Embodiment 110. The compound or salt thereof of Embodiment 16, wherein Y 1 Yes-CR 10 -.

[0526] Embodiment 111. The compound or salt thereof of Embodiment 16, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0527] Embodiment 112. The compound or salt thereof of any one of Embodiments 16 to

[0316] , wherein each of a, b, c and d is independently selected from 1, 2 and 3.

[0528] Embodiment 113. The compound of Embodiment

[0317] or a salt thereof, wherein each of a, c and d is independently selected from 1 and 2.

[0529] Embodiment 114. A compound or salt thereof according to any one of Embodiments 16 to

[0318] , wherein each R 10 are independently selected from hydrogen, halogen, -OH, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl.

[0530] Embodiment 115. The compound or salt thereof of Embodiment

[0319] , wherein each R 10 Independently selected from hydrogen, fluorine, -OH, methyl and cyclopropyl.

[0531] Embodiment 116. A compound or salt thereof according to any one of Embodiments 16 to

[0320] , wherein each R 11 are independently selected from hydrogen and optionally substituted C 1-2 alkyl.

[0532] Embodiment 117. The compound or salt thereof of Embodiment

[0321] , wherein each R 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0533] Embodiment 118. The compound or salt thereof of any one of Embodiments 16 to 25, wherein the compound is selected from:

[0534]

[0535]

[0536]

[0537] Embodiment 119. The compound or salt thereof of Embodiment

[0323] , wherein the compound is selected from:

[0538]

[0539]

[0540] Embodiment 120. The compound or salt thereof according to embodiment

[0323] , wherein the compound is selected from:

[0541]

[0542] Embodiment 121. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IB):

[0543]

[0544] in,

[0545] X 1 , X 2 , X 3 Each of which is independently selected from N and CR 13 ;

[0546] R 12 is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle, or R 12 With R 13 together form an optionally substituted ring; and

[0547] Each R 13 are independently selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl.

[0548] Embodiment 122. The compound of Embodiment

[0325] or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted heterocycle.

[0549] Embodiment 123. The compound of Embodiment

[0325] or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IBB):

[0550]

[0551] in,

[0552] Y 1 Selected from -N- and -CR 10 -;

[0553] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0554] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0555] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0556] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0557] Embodiment 124. Compound Embodiment

[0328] , wherein X 1 , X 2 and X 3 Each is CH.

[0558] Embodiment 125. The compound or salt thereof of Embodiment

[0328] or

[0329] , wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11, -O- and -S(O)2-, where Z 5 Also selected from keys.

[0559] Embodiment 126. The compound or salt thereof of any one of Embodiments

[0329] to

[0330] , wherein each of a, b, c and d is independently selected from 1 and 2.

[0560] Embodiment 127. A compound or salt thereof according to any one of Embodiments

[0328] to

[0331] , wherein each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl and optionally substituted C 1-3 alkyl.

[0561] Embodiment 128. The compound or salt thereof of Embodiment

[0332] , wherein each R 10 Independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl and -CH2CH2OCH3.

[0562] Embodiment 129. A compound or salt thereof according to any one of Embodiments

[0328] to

[0333] , wherein each R 11 are independently selected from hydrogen and optionally substituted C 1-2 alkyl.

[0563] Embodiment 130. The compound or salt thereof of Embodiment

[0334] , wherein each R 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0564] Embodiment 131. The compound or salt thereof of any one of Embodiments

[0328] to

[0335] , wherein the compound is selected from:

[0565]

[0566]

[0567] Embodiment 132. The compound or salt thereof of Embodiment

[0336] , wherein the compound is selected from:

[0568]

[0569] Embodiment 133. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IC):

[0570]

[0571] in,

[0572] R 14is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 15 are joined together to form an optionally substituted heterocyclic ring; and

[0573] R 15 Selected from -S(O)2R 16 -, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0574] Embodiment 134. The compound of Embodiment

[0336] or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (ICC):

[0575]

[0576] in,

[0577] Y 1 Selected from -N- and -CR 10 -;

[0578] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0579] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0580] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring;

[0581] Each R 11 are independently selected from hydrogen and optionally substituted C1-4 Alkyl; and

[0582] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0583] Embodiment 135. The compound of Embodiment 1 or a salt thereof, wherein R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole and optionally substituted indole.

[0584] Embodiment 136. The compound or salt thereof of Embodiment 26, wherein R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole.

[0585] Embodiment 137. The compound or salt thereof of Embodiment 26 or 27, wherein R 1 SO2R 1a or C 1-3 Alkyl substituted, where R 1a Selected from C 1-6 alkyl.

[0586] Embodiment 138. The compound of any one of Embodiments 26 to 27, wherein the compound is selected from:

[0587]

[0588] Embodiment 139. A compound or salt thereof according to any one of Embodiments 1, 2,

[0326] or 26 to 27, wherein R 2 is selected from optionally substituted heterocycle and optionally substituted cycloalkyl.

[0589] Embodiment 140. The compound or salt thereof of Embodiment 29, wherein R 2 is selected from optionally substituted heterocycloalkyl.

[0590] Embodiment 141. The compound of Embodiment 29 or a salt thereof, wherein R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl.

[0591] Embodiment 142. The compound of Embodiment 30 or a salt thereof, wherein R 2 is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine and optionally substituted morpholine.

[0592] Embodiment 143. A compound or salt thereof according to any one of Embodiments 29 to 42, wherein R 2 Halogen, -SO2R2a 、-NR 2a , -C(O)CH3, -CN, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C 3-5 Carbocyclic, oxo and optionally substituted C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 alkyl.

[0593] Embodiment 144. The compound of Embodiment 32 or a salt thereof, wherein R 2 Substituted by fluorine, -SO2Me, oxo and methyl.

[0594] Embodiment 145. The compound of Embodiment 31 or a salt thereof, wherein R 2 Selected from

[0595]

[0596] Embodiment 146. The compound or salt thereof of Embodiment 29, wherein R 2 is selected from optionally substituted cycloalkyl.

[0597] Embodiment 147. The compound or salt thereof of Embodiment 29, wherein R 2 is selected from optionally substituted cyclopentanes.

[0598] Embodiment 148. The compound or salt thereof of Embodiment 29, wherein R 2 Selected from

[0599] Embodiment 149. A compound or salt thereof according to any one of Embodiments 1-

[0310] , 16-25,

[0325] -

[0335] or

[0338] -33, wherein R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0600] Embodiment 150. The compound of Embodiment 38 or a salt thereof, wherein R 3 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0601] Embodiment 151. The compound of Embodiment 39 or a salt thereof, wherein R 3 is selected from hydrogen, fluorine and -CN.

[0602] Embodiment 152. The compound of Embodiment 39 or a salt thereof, wherein R 3 is selected from hydrogen and -CN.

[0603] Embodiment 153. A compound or salt thereof according to any one of Embodiments 1-

[0310] , 16-25,

[0325] -

[0335] ,

[0338] -33 or 38-40, wherein R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0604] Embodiment 154. The compound of Embodiment 42 or a salt thereof, wherein R 4 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0605] Embodiment 155. The compound of Embodiment 43 or a salt thereof, wherein R 4 is selected from hydrogen, -CN and -CHF2.

[0606] Embodiment 156. A compound or salt thereof according to any one of Embodiments 1-

[0310] , 16-25,

[0325] -

[0335] ,

[0338] -33 or 38-43, wherein R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0607] Embodiment 157. The compound of Embodiment 44 or a salt thereof, wherein R 5 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0608] Embodiment 158. The compound of Embodiment 46 or a salt thereof, wherein R 5 It's hydrogen.

[0609] Embodiment 159. A compound or salt thereof according to any one of Embodiments 1-

[0310] , 16-25,

[0325] -

[0335] ,

[0338] -33 or 38-46, wherein R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0610] Embodiment 160. The compound of Embodiment 47 or a salt thereof, wherein R 6 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0611] Embodiment 161. The compound of Embodiment 48 or a salt thereof, wherein R 6 It's hydrogen.

[0612] Embodiment 162. A compound or salt thereof according to any one of Embodiments 1-

[0310] , 16-25,

[0325] -

[0335] ,

[0338] -33 or 38-49, wherein R 7 It's hydrogen.

[0613] Embodiment 163. The compound of Embodiment 1 or a salt thereof, wherein the compound is selected from:

[0614]

[0615]

[0616]

[0617]

[0618] Embodiment 164. The compound of Embodiment 1 or a salt thereof, wherein the compound is selected from:

[0619]

[0620] Embodiment 165. A compound or a pharmaceutically acceptable salt or solvate thereof having the structure of formula (II):

[0621]

[0622] in,

[0623] A is selected from optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 12-membered heterocyclic rings;

[0624] R 1 is selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle;

[0625] m is selected from 0 to 9;

[0626] R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN and optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0627] R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl;

[0628] Y 1 Selected from -N- and -CR 10 -;

[0629] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys;

[0630] Each of a, b, c and d is independently selected from 1, 2, 3 and 4;

[0631] Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and

[0632] Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

[0633] Embodiment 166. The compound or salt thereof of Embodiment 51, wherein A is selected from optionally substituted C 5-6 Carbocyclic and optionally substituted 5- to 10-membered heterocyclic rings.

[0634] Embodiment 167. The compound or salt thereof of Embodiment

[0371] , wherein A is selected from phenyl, pyrazole and tetrahydroisoquinoline.

[0635] Embodiment 168. The compound or salt thereof of any one of Embodiments 51 to 5, wherein m is selected from 0 to 4.

[0636] Embodiment 169. The compound of Embodiment 6 or a salt thereof, wherein m is selected from 0 to 2.

[0637] Embodiment 170. The compound or salt thereof of any one of Embodiments 51 to 7, wherein R 1 is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocycle and optionally substituted heterocycle.

[0638] Embodiment 171. The compound of Embodiment 8 or a salt thereof, wherein R 1 Selected from optionally substituted C 1-3 alkyl and optionally substituted 5- to 8-membered heterocyclic ring.

[0639] Embodiment 172. The compound of Embodiment 9 or a salt thereof, wherein R 1 Selected from C 1-3 Alkyl and substituted 5- to 8-membered heterocyclic ring.

[0640] Embodiment 173. The compound of Embodiment 51 or a pharmaceutically acceptable salt or solvate thereof has the structure of Formula (IIA):

[0641]

[0642] in,

[0643] R 13 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 are joined together to form an optionally substituted heterocyclic ring; and

[0644] R 14 is selected from halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0645] Embodiment 174. A compound or salt thereof according to any one of Embodiments 51 to

[0378] , wherein R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0646] Embodiment 175. The compound or salt thereof of Embodiment

[0379] , wherein R 3 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0647] Embodiment 176. The compound or salt thereof of Embodiment

[0380] , wherein R 3 is selected from hydrogen, fluorine and -CN.

[0648] Embodiment 177. A compound or salt thereof according to any one of Embodiments 51 to

[0381] , wherein R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0649] Embodiment 178. The compound or salt thereof of Embodiment

[0382] , wherein R 4 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0650] Embodiment 179. The compound or salt thereof of Embodiment

[0383] , wherein R 4 is selected from hydrogen, -CN and -CHF2.

[0651] Embodiment 180. A compound or salt thereof according to any one of Embodiments 51 to

[0384] , wherein R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0652] Embodiment 181. The compound or salt thereof of Embodiment

[0385] , wherein R 5 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0653] Embodiment 182. The compound or salt thereof of Embodiment

[0386] , wherein R 5 It's hydrogen.

[0654] Embodiment 183. A compound or salt thereof according to any one of Embodiments 51 to

[0387] , wherein R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0655] Embodiment 184. The compound or salt thereof of Embodiment

[0388] , wherein R 6 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0656] Embodiment 185. The compound or salt thereof of Embodiment

[0389] , wherein R 6 It's hydrogen.

[0657] Embodiment 186. A compound or salt thereof according to any one of Embodiments 51 to

[0390] , wherein R 7 It's hydrogen.

[0658] Embodiment 187. A compound or salt thereof according to any one of Embodiments 51 to

[0391] , wherein Z 1 , Z 2 , Z 3 , Z4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys.

[0659] Embodiment 188. A compound or salt thereof according to any one of Embodiments 51 to

[0392] , wherein each of a, b, c and d is independently selected from 1 and 2.

[0660] Embodiment 189. A compound or salt thereof according to any one of Embodiments 51 to

[0393] , wherein each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl and optionally substituted C 1-3 alkyl.

[0661] Embodiment 190. The compound or salt thereof of Embodiment

[0394] , wherein each R 10 Independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl and -CH2CH2OCH3.

[0662] Embodiment 191. A compound or salt thereof according to any one of Embodiments 51 to

[0395] , wherein each R 11 are independently selected from hydrogen and optionally substituted C 1-2 alkyl.

[0663] Embodiment 192. The compound or salt thereof of Embodiment

[0396] , wherein each R 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

[0664] Embodiment 193. A compound or salt thereof according to any one of Embodiments 51 to

[0397] , wherein the compound is selected from:

[0665]

[0666]

[0667] Embodiment 194. The compound or salt thereof of Embodiment

[0398] , wherein the compound is selected from:

[0668]

[0669] Embodiment 195. A pharmaceutical composition comprising a compound or salt of any one of Embodiments 1 to

[0399] and a pharmaceutically acceptable excipient.

[0670] Embodiment 196. A method of treating cancer, comprising administering the pharmaceutical composition of embodiment 54 to a subject in need thereof.

[0671] Embodiment 197. The method of Embodiment 196, wherein the cancer is a solid tumor.

[0672] Embodiment 198. The method of embodiment 196 or 197, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain cancer.

[0673] Embodiment 199. The method of Embodiment 198, wherein the cancer is ovarian cancer or breast cancer.

[0674] Embodiment 200. A method of inhibiting cyclin-dependent kinases (CDKs) in a cell using a compound or salt of any one of Embodiments 1 to

[0399] or a pharmaceutical composition of Embodiment 54.

[0675] Embodiment 201. The method of Embodiment 59, wherein the CDK is selected from CDK 2, CDK 4, CD6, or any combination thereof.

[0676] Embodiment 202. The method of embodiment 60, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6 and CDK2 / 4 / 6.

[0677] Embodiment 203. The method of Embodiment 202, wherein the CDK is CDK 2 / 4 / 6.

[0678] Example

[0679] Having now generally described the invention, the invention will be more readily understood by reference to the following examples, which are provided for the purpose of illustrating certain aspects and embodiments of the invention only and are not intended to limit the invention in any way.

[0680] The following synthetic schemes are provided for illustrative purposes, not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art can prepare in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as needed. Typically, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0681] General Synthesis Schemes 1-4

[0682] Solution 1

[0683]

[0684] Solution 2

[0685]

[0686] Solution 3

[0687]

[0688] Solution 4

[0689]

[0690] Intermediates

[0691] Intermediate 1: 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0692] Reaction scheme

[0693]

[0694] Detailed steps

[0695] Step 1: 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0696]

[0697] 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-diisopropylethylamine (31.8 g, 246.3 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (1000 mL) and extracted with ethyl acetate (3×1000 mL). The combined organic layer was washed with brine (1000 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to provide a crude product. The residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate) to provide 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (5.04 g, 13.09 mmol, 15.9% yield).

[0698] LCMS (ESI) m / z = 385 [M+H] + .

[0699] 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.04 (d, J = 7.6Hz, 1H), 7.83-7.72 (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).

[0700] Intermediate 2: 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl- 1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0701] Reaction scheme

[0702]

[0703] Detailed steps

[0704] Step 1: tert-Butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0705]

[0706] 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 (3×500 mL). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide a crude product. The residue was purified by grinding with 100 mL of 1:5 EA / PE to provide the desired product, tert-butyl 6-(6-nitropyridine-3-yl)-2,6-diazaspiro [3.3] heptane-2-carboxylate (6.78 g, 83.7% yield).

[0707] LCMS (ESI) m / z = 321.1 [M+H] + .

[0708] Step 2: tert-Butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0709]

[0710] Under nitrogen atmosphere, Pd / C (10% carbon load, 200 mg) is added to a mixture of 6-(6-nitropyridine-3-yl)-2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1 g, 3.12 mmol) in EtOH (25 mL). Under hydrogen atmosphere, the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to provide crude 6-(6-aminopyridine-3-yl)-2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (800 mg, 83.8% yield). LCMS (ESI-MS) m / z=291.2 [M+H] + .

[0711] Step 3: tert-Butyl 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0712]

[0713] A mixture of 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4.7 g, 16.2 mmol) and 1H-benzo[d][1,2,3]triazole-1-carboxaldehyde (2.62 g, 17.8 mmol) in THF (50 mL) was heated to 80 ° C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to provide a crude product. The residue was purified by silica gel column chromatography (EA / PE, 7:3) to provide the desired product 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (5.2 g, 95.8% yield).

[0714] LCMS (ESI-MS) m / z = 319.2 [M+H] + .

[0715] Step 4: tert-Butyl 6-(6-((8-bromoquinazolin-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0716]

[0717] NaH (60% in mineral oil, 0.23 g, 9.42 mmol) was added to a stirred mixture of tert-butyl 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1 g, 3.14 mmol) in DMF (10 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C for 2 hours 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 hour. The reaction mixture was quenched by adding water (100 mL) and extracted with EA (3×200 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide a crude product. The residue was purified by trituration with DCM (40 mL) to afford the desired product, tert-butyl 6-(6-((8-bromoquinazolin-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (800 mg, 46.1% yield).

[0718] LCMS (ESI-MS) m / z = 497.2 [M+H] + .

[0719] Step 5: N-(5-(2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-8-bromoquinazolin-2-amine

[0720]

[0721] TFA (3mL) was added to a stirred mixture of 6-(6-((8-bromoquinazoline-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (800mg, 1.60mmol) in DCM (9mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to provide crude N-(5-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-2-yl)-8-bromoquinazoline-2-amine (1g). The crude product was used in the next step without further purification.

[0722] LCMS (ESI-MS) m / z = 397.1 [M+H] + .

[0723] Step 6: 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0724]

[0725] To a solution of N-(5-(2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-8-bromoquinazoline-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 NaBH3CN (1.74 g, 27.7 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×100 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 and the residue was purified by silica gel column chromatography (MeOH / DCM, 1:10) to provide the desired product, 8-bromo-N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)quinazolin-2-amine (200 mg, 15.3% yield).

[0726] LCMS (ESI) m / z = 425.1 [M+H] + .

[0727] Intermediate 3: N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)carboxamide

[0728] Reaction scheme

[0729]

[0730] Detailed steps

[0731] Step 1: tert-Butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0732]

[0733] 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 added 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 cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3×500 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 provide a crude product. The residue was purified by trituration with petroleum ether / ethyl acetate (5:1, 100 mL) to afford tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield).

[0734] LCMS (ESI) m / z = 321 [M+H] + .

[0735] Step 2: 2-(6-Nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0736]

[0737] Trifluoroacetic acid (16 mL) was added to a stirred mixture of 6-(6-nitropyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6.78 g, 21.16 mmol) in dichloromethane (80 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL) and concentrated under vacuum again to provide crude 2-(6-nitropyridine-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g). The crude product can be used in the next step without further purification.

[0738] LCMS (ESI) m / z = 221 [M+H] + .

[0739] Step 3: 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0740]

[0741] A solution of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (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 at room temperature for 3 hours and concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3×500 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 provide a 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).

[0742] LCMS (ESI) m / z = 249 [M+H] + .

[0743] Step 4: 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine

[0744]

[0745] A solution of 2-ethyl-6-(6-nitropyridine-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 at 80 ° C for 1 hour. The resulting mixture was filtered and the filter cake was washed with ethanol (100 mL). The filtrate was concentrated under vacuum to provide a crude product. The residue was purified by reverse phase flash chromatography (C18 silica gel, acetonitrile / water (containing 10 mmol / L NH4HCO3) gradient) to provide 5-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)pyridine-2-amine (2 g, 56.6% yield).

[0746] LCMS (ESI) m / z = 219 [M+H] + .

[0747] Step 5: N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)formamide

[0748]

[0749] A solution of acetic anhydride (2mL) in formic acid (4mL) was stirred at room temperature for 1 hour, followed by addition of 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridine-2-amine (400mg, 1.83mmol) in batches at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized to pH=7 with saturated aqueous sodium bicarbonate (200mL) and extracted with ethyl acetate (3×100mL). 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 (containing 10mM NH4HCO3 and 0.1% NH3.H2O) gradient) to provide the title compound (70mg, 15.3% yield).

[0750] LCMS (ESI) m / z = 247 [M+H] + .

[0751] Intermediate 4: 8-Bromo-7-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0752] Reaction scheme

[0753]

[0754] Detailed steps

[0755] Step 1: 8-Bromo-7-fluoroquinazolin-2-amine

[0756]

[0757] 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 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EA (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide a crude product. The residue was purified by silica gel column chromatography (EA / PE, 2: 1) to provide the desired product 8-bromo-7-fluoroquinazoline-2-amine (800 mg, 14.6% yield).

[0758] LCMS (ESI-MS) m / z = 242.0 [M+H] + .

[0759] Step 2: 8-Bromo-2-chloro-7-fluoroquinazoline

[0760]

[0761] A mixture of tert-butyl nitrite (511 mg, 4.95 mmol) and cuprous chloride (490 mg, 4.95 mmol) in acetonitrile (10 mL) was stirred at 60 ° C for 1 hour. 8-bromo-7-fluoroquinazoline-2-amine (800 mg, 3.30 mmol) was added in batches at room temperature within 1 minute. 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 provide 8-bromo-2-chloro-7-fluoroquinazoline (300 mg, 34.7% yield).

[0762] LCMS (ESI-MS) m / z = 261.0 [M+H] + .

[0763] Step 3: 8-Bromo-7-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0764]

[0765] 1,8-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 provide the desired product 8-bromo-7-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (120 mg, 25.8% yield).

[0766] LCMS (ESI-MS) m / z = 403.1 [M+H] + .

[0767] Intermediate 5: 8-Bromo-2-chloro-6-(difluoromethyl)quinazoline

[0768] Reaction scheme

[0769]

[0770] Detailed steps

[0771] Step 1: 2-Bromo-4-(difluoromethyl)-1-fluorobenzene

[0772]

[0773] At 0 ° C, DAST (47.6 g, 296 mmol) was added dropwise to a stirred mixture of 3-bromo-4-fluorobenzaldehyde (30 g, 148 mmol) in DCM (300 mL). The resulting mixture was stirred overnight at 40 ° C and quenched by adding saturated aqueous NaHCO (500 ml) at 0 ° C. The mixture was extracted with DCM (3 × 500 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide crude 2-bromo-4-(difluoromethyl)-1-fluorobenzene (32.2 g, 96.8% yield).

[0774] LCMS (ESI-MS) m / z = 225.0 [M+H] + .

[0775] Step 2: 3-Bromo-5-(difluoromethyl)-2-fluorobenzaldehyde

[0776]

[0777] Under a nitrogen atmosphere, LDA (2M in THF, 24.4 mL, 48.8 mmol) was added dropwise to a mixture of 2-bromo-4-(difluoromethyl)-1-fluorobenzene (10 g, 44.4 mmol) in 100 mL of THF cooled to -78 ° C. The mixture was stirred at -78 ° C for 0.5 hours. DMF (3.89 g, 53.3 mmol) was added dropwise, and the resulting mixture was stirred at -78 ° C for another hour. The reaction mixture was slowly poured into 200 mL of saturated aqueous NH4Cl at 0 ° C and stirred for 1 hour. The solution was diluted with H2O (200 mL) and extracted with EA (400 mL×3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide crude 3-bromo-5-(difluoromethyl)-2-fluorobenzaldehyde (15 g). The crude product can be used in the next step without further purification. Step 3: 8-bromo-6-(difluoromethyl)quinazoline-2-amine

[0778]

[0779] Guanidine (3.85 g, 65.21 mmol) was added to a mixture of 3-bromo-5-(difluoromethyl)-2-fluorobenzaldehyde (15 g, 59.28 mmol) in NMP (13 mL). The mixture was stirred at 150 ° C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL). The organic layer was washed with brine (2 × 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 provide 8-bromo-6-(difluoromethyl)quinazoline-2-amine (0.9 g, 5.54% yield).

[0780] LCMS (ESI-MS) m / z = 274.0 [M+H] + .

[0781] Step 4: 8-Bromo-2-chloro-6-(difluoromethyl)quinazoline

[0782]

[0783] Tert-butyl nitrite (3.9 mL) was added to a mixture of 8-bromo-6-(difluoromethyl)quinazoline-2-amine (3 g, 10.94 mmol), TBA-Cl (5.4 mL) in TMSCl and t-BuOH (15 mL). The mixture was stirred at 60 ° C overnight. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 6:94) to provide 8-bromo-2-chloro-6-(difluoromethyl)quinazoline (1.03 g, 31.9% yield).

[0784] 1 H NMR (400 MHz, DMSO-d6) δ9.79-9.76(m,1H),8.57-8.54(m,2H),7.43-7.16(m,1H). LCMS(ESI-MS)m / z=292.9[M+H] + .

[0785] Intermediate 6: 8-Bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine

[0786] Reaction scheme

[0787]

[0788] Detailed steps

[0789] Step 1: 2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde

[0790]

[0791] Under nitrogen atmosphere, n-BuLi (2.5 M in hexane, 52.6 mL, 131.5 mmol) solution 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. 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 hours, quenched by adding water (500 mL) and extracted with EA (2×500 mL). The combined organic layers were washed with brine (2×1000 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide crude 2-amino-3-bromo-5-(trifluoromethyl)benzaldehyde (10.2 g, 60.7% yield).

[0792] LCMS (ESI-MS) m / z = 268.1 [M+H] + .

[0793] Step 2: 8-Bromo-6-(trifluoromethyl)quinazolin-2(1H)-one

[0794]

[0795] A mixture of 2-amino-3-bromo-5-(trifluoromethyl)benzaldehyde (10.2 g, 38.2 mmol) and urea (34.4 g, 57.3 mmol) was heated to 180 ° C and stirred for 5 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with water (2×200 mL) and EA (2×200 mL). The collected solid was dried under high vacuum to provide crude 8-bromo-6-(trifluoromethyl)quinazoline-2(1H)-one (7.3 g). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z=293.2[M+H] + .

[0796] Step 3: 8-Bromo-2-chloro-6-(trifluoromethyl)quinazoline

[0797]

[0798] POCl3 (60mL, 643mmol) was added to a mixture of 8-bromo-6-(trifluoromethyl)quinazoline-2(1H)-one (7.3g, 24.9mmol) in toluene (60mL). The resulting mixture was stirred at 110°C for 2 hours and concentrated under reduced pressure. The residue was slowly quenched by adding saturated anhydrous NaHCO3 at 0°C until no bubbles appeared. The resulting mixture was extracted with EA (3×200mL). The combined organic layers were washed with brine (2×300mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 1:20) to provide 8-bromo-2-chloro-6-(trifluoromethyl)quinazoline (1.06g, 13.6% yield).

[0799] 1 H NMR (400MHz, DMSO-d6) δ9.80(s,1H),8.80(s,1H),8.74(s,1H). LCMS(ESI-MS)m / z=312.7[M+H] + .

[0800] Intermediate 7: 2-Methylisoindolin-5-amine

[0801]

[0802] At 0 ° C, LiAlH4 solution (2M in THF, 4.25mL, 8.50mmol) was added to 5-amino-2-methylisoindoline-1,3-dione (500mg, 2.83mmol) in THF (10mL). The reaction mixture was heated to 70 ° C and stirred for 1 hour. After cooling to 0 ° C, the reaction was quenched by adding ethanol and water. The resulting slurry was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to provide crude 2-methylisoindoline-5-amine (300mg). The crude product can be used in the next step without further purification.

[0803] LCMS (ESI-MS) m / z = 149.1 [M+H] + .

[0804] Intermediate 8: 8-Bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine

[0805]

[0806] 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, 1.68 mmol) 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 provide 8-bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazoline-2-amine (180 mg, 26.3% yield).

[0807] LCMS (ESI-MS) m / z = 405.0 [M+H] + .

[0808] Intermediate 9: 1-(1-Methylazetidin-3-yl)-1H-pyrazol-4-amine

[0809] Reaction scheme

[0810]

[0811] Detailed steps

[0812] Step 1: 1-(1-methylazetidin-3-yl)-4-nitro-1H-pyrazole-(1-methylazetidin-3-yl)-1H-pyrazol-4-amine

[0813]

[0814] A solution of 1- (azetidine -3- bases) -4- nitro -1H- pyrazole (2g, 7.08mmol) and HCHO (319mg, 10.6mmol) in MeOH (30mL) was stirred at room temperature for 2 hours. NaBH3CN (891mg, 14.2mmol) was added. The resulting mixture was stirred at room temperature overnight, filtered and the filter cake was washed with MeOH (20mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 10: 90) to provide 1- (1- methylazetidine -3- bases) -4- nitro -1H- pyrazole (500mg, 33.3% yield).

[0815] LCMS (ESI-MS) m / z = 183.1 [M+H] + .

[0816] Step 2: 1-(1-methylazetidin-3-yl)-1H-pyrazol-4-amine

[0817]

[0818] Under a nitrogen atmosphere, Pd / C (10% carbon loading, 99.3 mg) was added to a solution of 1-(1-methylazetidine-3-yl)-4-nitro-1H-pyrazole (680 mg, 3.73 mmol) in MeOH (10 mL). Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature for 1 hour, filtered and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to provide a crude title product (700 mg). The crude product can be used in the next step without further purification. LCMS (ESI-MS) m / z=153.1 [M+H] + .

[0819] Intermediate 10: 1-(5-Cyclopropylpyrimidin-2-yl)piperidin-4-amine

[0820] Reaction scheme

[0821]

[0822] Detailed steps

[0823] Step 1: tert-Butyl (1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)carbamate

[0824]

[0825] 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)carbamate (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 × 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude product. The residue was purified by column chromatography (EA / PE, 0:100 to 20:80) to provide the desired product, tert-butyl N-[1-(5-cyclopropylpyrimidine-2-yl)piperidin-4-yl]carbamate (1.5 g, 70.3% yield). LCMS (ESI-MS) m / z=319.2[M+H] + .

[0826] Step 2: 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-amine

[0827]

[0828] TFA (3mL) is added to the stirred mixture of tert-butyl N-[1-(5-cyclopropylpyrimidine-2-yl)piperidin-4-yl]carbamate (1.5g, 4.71mmol) in DCM (10mL). The resulting mixture is stirred at room temperature for 2 hours and concentrated under high vacuum to provide crude 1-(5-cyclopropylpyrimidine-2-yl)piperidin-4-amine (1.5g crude product). The crude product can be used in the next step without further purification.

[0829] LCMS (ESI-MS) m / z = 219.1 [M+H] + .

[0830] Intermediate 11: 1-(7-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine

[0831] Reaction scheme

[0832]

[0833] Detailed steps

[0834] Step 1: 2-Chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine

[0835]

[0836] 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)2 (4.73 g, 26.0 mmol) and Et3N (2.64 g, 26.0 mmol) in DCM (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×50 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 provide the desired product, 2-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 59.4% yield).

[0837] LCMS (ESI-MS) m / z = 194.0 [M+H] + .

[0838] Step 2: tert-Butyl (1-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate

[0839]

[0840] 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 at 100 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layer was 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 provide the desired product, tert-butyl (1-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate (1.5 g, 58.0% yield).

[0841] LCMS (ESI-MS) m / z = 358.2 [M+H] + .

[0842] Step 3: 1-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine

[0843]

[0844] TFA (3 mL) was added to a stirred mixture of tert-butyl (1-(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 hours and concentrated under high vacuum to provide crude 1-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine (1.5 g). The crude product was used in the next step without further purification.

[0845] LCMS (ESI-MS) m / z = 258.2 [M+H] + .

[0846] Intermediate 12: 2-(2-Methoxyethyl)-2,6-diazaspiro[3.3]heptane

[0847] Reaction scheme

[0848]

[0849] Detailed steps

[0850] Step 1: tert-Butyl 6-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0851]

[0852] NaI (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 adding water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude title product (150 mg). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z=257.2[M+H] + .

[0853] Step 2: 2-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptane

[0854]

[0855] 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 at room temperature for 1 hour and concentrated under high vacuum to provide the crude title product (150 mg). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z=157.1 [M+H] + .

[0856] Intermediate 13: 1-((1-Methylcyclopropyl)sulfonyl)piperidin-4-amine

[0857] Reaction scheme

[0858]

[0859] Detailed steps

[0860] Step 1: tert-Butyl (1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)carbamate

[0861]

[0862] 1-Methylcyclopropane-1-sulfonyl chloride (463mg, 2.99mmol) was added dropwise to a solution of tert-butyl piperidin-4-ylcarbamate (400mg, 1.99mmol) and DIEA (774mg, 5.99mmol) in DCM (10mL) cooled to 0°C. The resulting mixture was stirred at room temperature for 1 hour, diluted with water (10mL) and extracted with DCM (3×250mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 1:5) to provide tert-butyl (1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)carbamate (580mg, 82.1% yield).

[0863] LCMS(ESI-MS)m / z=263.2[M+H-56] + .

[0864] Step 2: 1-((1-methylcyclopropyl)sulfonyl)piperidin-4-amine

[0865]

[0866] TFA (2 mL) was added to a stirred mixture of tert-butyl (1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.57 mmol) in DCM (6 mL). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to provide the TFA salt of 1-((1-methylcyclopropyl)sulfonyl)piperidin-4-amine (255 mg, 74.3% yield).

[0867] 1 H NMR (400MHz, DMSO-d6) δ8.09 (s, 3H), 3.69 (d, J = 12.5Hz, 2H), 3.20 (s, 1H), 3.07-2.94 (m, 2H), 1.95(d,J=12.4Hz,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] + .

[0868] Intermediate 14: 1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate

[0869] Reaction scheme

[0870]

[0871] Detailed steps

[0872] Step 1: tert-Butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate

[0873]

[0874] 1-Methyl-1H-pyrazole-4-sulfonyl chloride (1.8 g, 9.96 mmol) was added to a 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) cooled to 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour, quenched by adding water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM, 0:100 to 5:95) to provide tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (2.2 g, 64.1% yield).

[0875] LCMS (ESI-MS)m / z=367.1[M+Na+H] + .

[0876] Step 2: 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate

[0877]

[0878] TFA (5mL) is added to a stirred mixture of tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (2g, 5.80mmol) in DCM (30mL). The resulting mixture is stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (MeOH / DCM, from 0:100 to 18:82) to provide 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate (250.7mg, 11.6% yield).

[0879] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.21(s,3H),3.89(s,3H),3.61-3.48(m,2 H),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] + .

[0880] Intermediate 15: 1-(Cyclopropylsulfonyl)piperidin-4-amine

[0881] Reaction scheme

[0882]

[0883] Detailed steps

[0884] Step 1: tert-Butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate

[0885]

[0886] 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 dropwise N-(piperidin-4-yl)carbamic acid tert-butyl ester (10 g, 49.93 mmol) 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 CH2Cl2 (3×500 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by grinding with EA (100 mL) to provide tert-butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, 59.2% yield).

[0887] LCMS(ESI-MS)m / z=249.1[M+H-56] + .

[0888] Step 2: 1-(Cyclopropylsulfonyl)piperidin-4-amine

[0889]

[0890] A solution of tert-butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, 32.87 mmol) in TFA (15 mL) and DCM (45 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to provide 1-(cyclopropylsulfonyl)piperidin-4-amine (8 g). The crude product was used in the next step without further purification.

[0891] LCMS (ESI-MS) m / z = 205.1 [M+H] + .

[0892] Intermediate 16: 8,8-Difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester

[0893] Reaction scheme

[0894]

[0895] Detailed steps

[0896] Step 1: 2-((3-(Benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0897]

[0898] Under N2 atmosphere, n-BuLi (2.5M, 27.2mL) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (9.62g, 68.09mmol) in anhydrous THF (100mL) cooled to -30°C. The mixture was stirred at -30°C for 0.5 hours. The reaction was then cooled to -78°C and a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methane (15.21g, 56.74mmol) in 50mL anhydrous THF was added dropwise. The reaction mixture was stirred at -78°C for 0.5 hours, and a solution of 3-(benzyloxy)cyclobutane-1-one (10g, 56.74mmol) in 50mL anhydrous THF was added dropwise. The reaction mixture was then warmed to 20°C and stirred for another 12 hours. The reaction mixture was slowly poured into 20 mL of saturated aqueous NH4Cl at 0°C, and after stirring for 1 hour, the solution was diluted with H2O (200 mL) and extracted with EtOAc (400 mL×3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide crude 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.7 g), which was used without further purification.

[0899] LCMS (ESI-MS) m / z = 301.1 [M+H] + .

[0900] Step 2: 6-Benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro[3.4]octane

[0901]

[0902] A solution of 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.7 g crude), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (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 hour. 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 provide crude 6-benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro[3.4]octane (20 g) as a colorless oil. The crude product was used in the next step without further purification.

[0903] LCMS (ESI-MS) m / z = 434.2 [M+H] + .

[0904] Step 3: 6-Benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol

[0905]

[0906] A solution of 6-benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-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 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (3×500 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 provide 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol (10 g, 67.0%) as a colorless oil.

[0907] LCMS (ESI-MS) m / z = 324.1 [M+H] + .

[0908] Step 4: 6-Benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one

[0909]

[0910] Under a nitrogen atmosphere, a solution of DMSO (4.83 g, 61.8 mmol) in DCM (20 mL) was added dropwise to a solution of oxalyl chloride (7.85 g, 61.8 mmol) in DCM (100 mL) cooled to -78 ° C. The mixture was stirred at -78 ° C for 20 minutes. 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 was stirred for 20 minutes. Et3N (12.5 g, 123 mmol) was added dropwise, and the mixture was stirred for 20 minutes. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3 × 200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0 to 10%). Fractions with the desired mass signal were combined and concentrated under reduced pressure to provide 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one (5.8 g, 58.4% yield). LCMS (ESI-MS) m / z=322.2 [M+H] + .

[0911] Step 5: 6-Benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane

[0912]

[0913] 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 at room temperature overnight. 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 provide 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro [3.4] octane (1.2 g, 19.4% yield).

[0914] LCMS (ESI-MS) m / z = 344.2 [M+H] + .

[0915] Step 6: 8,8-Difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester

[0916]

[0917] Pd(OH)2 / C (0.49 g, 3.49 mmol) is 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 Et3N (1.06 g, 10.48 mmol) in MeOH (120 mL). The resulting mixture was stirred at room temperature for 5 days under 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 merged, concentrated under reduced pressure and freeze-dried to provide 8,8-difluoro-2-hydroxy-6-azaspiro [3.4] octane-6-tert-butyl formate (500 mg, 54.4% yield).

[0918] 1 H NMR(400MHz,DMSO-d6)δ5.3-5.06(m,1H),4.20-4.00(m,1H),3.69-3.50(m,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).

[0919] Intermediate 17: 3-(((tert-Butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-1-ol

[0920] Reaction scheme

[0921]

[0922] Detailed steps

[0923] Step 1: (3-(Benzyloxy)cyclobutane-1,1-diyl)dimethanol

[0924]

[0925] At 0 ° C, a solution of LiAlH4 in THF (2M, 32.6 mL, 65.2 mmol) was added dropwise to a stirred mixture of 1,1-diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate (5 g, 16.3 mmol) in THF (50 mL). The resulting mixture was stirred at room temperature for 3 hours, carefully quenched by adding water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude [3-(benzyloxy)-1-(hydroxymethyl)cyclobutyl]methanol (3.2 g) as a colorless oil. The crude product was used in the next step without further purification.

[0926] LCMS (ESI-MS) m / z = 223.3 [M+H] + .

[0927] Step 2: (3-(Benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol

[0928]

[0929] NaH (60% in mineral oil, 0.99 g, 24.8 mmol) was added to a solution of [3-(benzyloxy)-1-(hydroxymethyl)cyclobutyl]methanol (3.2 g, 14.3 mmol) in THF (40 mL) cooled to 0°C. The resulting suspension was stirred at 0°C for 1 hour, and TBDPSCl (3.96 g, 14.3 mmol) was slowly added. The resulting mixture was stirred at room temperature overnight, diluted with saturated aqueous NH4Cl (100 mL), and extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide crude (3-(benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (6.5 g). The crude product was used in the next step without further purification.

[0930] LCMS (ESI-MS) m / z = 461.4 [M+H] + .

[0931] Step 3: 3-(Benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbaldehyde

[0932]

[0933] Under nitrogen atmosphere, Dess-Martin periodinate (4.14 g, 9.76 mmol) was slowly added to a solution of (3-(benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (3 g crude, ca. 6.51 mmol) in DCM (30 mL) cooled to 0°C. After stirring at 0°C for 2 hours, the reaction was warmed to room temperature and stirred for 4 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 (50 mL) and extracted with DCM (3×50 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 provide 3-(benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbaldehyde (1.8 g, 60.2% yield).

[0934] LCMS (ESI-MS) m / z = 459.2 [M+H] + .

[0935] Step 4: ((3-(Benzyloxy)-1-(difluoromethyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane

[0936]

[0937] DAST (948 mg, 5.88 mmol) was added to a stirred mixture of 3-(benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbaldehyde (1.8 g, 3.92 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 hours, quenched by the addition of water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide ((3-(benzyloxy)-1-(difluoromethyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane (1 g, 53.0% yield). LCMS (ESI-MS) m / z=481.4 [M+H] + .

[0938] Step 5: 3-(((tert-Butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutane-1-ol

[0939]

[0940] Under nitrogen atmosphere, Pd / C (10% carbon loading, 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). The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to provide 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutane-1-ol (100 mg, 12.3% yield).

[0941] LCMS (ESI-MS) m / z = 391.2 [M+H] + .

[0942] Intermediate 18: Racemic (3R,4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol

[0943] Reaction scheme

[0944]

[0945] Step 1: Racemic (3R,4R)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1-carboxylate

[0946]

[0947] To a mixture of racemic (3R, 4R)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.31 mmol) in DCM (3.8 mL) and saturated aqueous Na2CO3 (3.8 mL) was added CbzCl solution (50% in toluene, 946 mg, 2.77 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for 4 hours, diluted with water (20 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2:1) to provide racemic (3R, 4R)-4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (800 mg, 98.7% yield).

[0948] LCMS (ESI-MS) m / z = 351.2 [M+H] + .

[0949] Step 2: Racemic ((3R,4R)-3-hydroxypiperidin-4-yl)carbamic acid benzyl ester

[0950]

[0951] A solution of racemic (3R,4R)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1-carboxylate (750 mg, 2.14 mmol) was added to a solution of HCl in 1,4-dioxane (4 M, 5 mL, 20 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0952] LCMS (ESI-MS) m / z = 251.2 [M+H] + .

[0953] Step 3: Racemic ((3R,4R)-3-hydroxy-1-(methylsulfonyl)piperidin-4-yl)carbamic acid benzyl ester

[0954]

[0955] Methanesulfonyl chloride (549 mg, 4.79 mmol) was added to a stirred mixture of crude racemic ((3R, 4R)-3-hydroxypiperidin-4-yl)benzylcarbamate (750 mg, 2.99 mmol) and NaHCO3 (420 mg, 5 mmol) in EA (4.5 mL) at 0 ° C. The resulting mixture was stirred for 1 hour, quenched by adding water (20 mL) and extracted with EA (2×20 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 provide racemic ((3R, 4R)-3-hydroxy-1-(methylsulfonyl)piperidin-4-yl)benzylcarbamate (500 mg, 50.8% yield).

[0956] LCMS (ESI-MS) m / z = 329.1 [M+H] + .

[0957] Step 4: Racemic (3R,4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol

[0958]

[0959] Under nitrogen atmosphere, Pd / C (10% carbon loading, 25 mg) was added to a mixture of racemic ((3R, 4R)-3-hydroxy-1-(methylsulfonyl)piperidin-4-yl)benzylcarbamate (100 mg, 0.30 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere and filtered. The filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to provide crude racemic (3R, 4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol (75.6 mg). The crude product can be used in the next step without further purification.

[0960] LCMS (ESI-MS) m / z = 195.1 [M+H] + .

[0961] Example 31: N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0962]

[0963] Step 1 : tert-Butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[0964]

[0965] To a mixture of 8-bromo-N-(1-(methylsulfonyl)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-PEPPSI under nitrogen atmosphere. Cl (10.18 mg, 0.01 mmol). 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] + =517.1 Step 2 :N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0966]

[0967] To a mixture of tert-butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (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 hours. The solvent was removed under reduced pressure and dissolved in DMSO / MeOH / Et3N (1:1:0.05, 3 mL). The mixture was purified by preparative reverse phase HPLC to provide the title compound (12.9 mg, 32% yield) as a yellow solid. LCMS(ESI)[M+H] + =417.1.

[0968] Example compounds

[0969] Embodiment 24: 8-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 1-(2-YL)quinazolin-2-amine

[0970]

[0971] Under nitrogen atmosphere, to 8- bromo-N- (1- (methylsulfonyl) piperidin-4-yl) quinazoline-2-amine (200mg, 0.52mmol), 2- methyl -2,6- diazaspiro [3.4] octane (72.06mg, 0.57mmol) and cesium carbonate (507.40mg, 1.55mmol) in toluene (2mL) mixture, add Pd2 (dba) 3 (47.6mg, 0.052mmol) and BINAP (32.3mg, 0.052mmol). The resulting mixture was heated to 100 ° C and stirred overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with dichloromethane (5mL), 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 (containing 10 mM NH4HCO3 and 0.1% NH3.H2O) gradient) to provide the title compound (59.6 mg, 25.4% yield).

[0972] LCMS (ESI) m / z = 431 [M+H] + .

[0973] 1 H NMR(400MHz, CDCl3)δ8.90(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).

[0974] Embodiment 32: N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)

[0975] Quinazolin-2-amine

[0976]

[0977] Step 1: tert-Butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[0978]

[0979] To a mixture of 8-bromo-N-(1-(methylsulfonyl)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-PEPPSI under nitrogen atmosphere. Cl (10.18 mg, 0.01 mmol). 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). LCMS (ESI) [M+H] + =517.1

[0980] Step 2: N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine (Example 31)

[0981]

[0982] To a mixture of tert-butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (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 hours. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO / MeOH / Et3N (1:1:0.05, 3 mL). The mixture was purified by preparative reverse phase HPLC to provide the title compound (12.9 mg, 32% yield). LCMS(ESI)[M+H] + =417.1. Example 35: 1-(7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinoline (2-azaspiro[4.4]nonan-2-yl)ethan-1-one

[0983] Reaction scheme

[0984]

[0985] Detailed steps

[0986] Step 1: tert-Butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate

[0987]

[0988] Under nitrogen atmosphere, a solution of LiHMDS (1M, 4.10mL, 4.10mmol) in THF was added to a stirred mixture of 7-oxo-2-azaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester (500mg, 2.04mmol) in THF (6mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 1 hour under a nitrogen atmosphere, and a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (1.10g, 3.07mmol) in THF (6mL) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, quenched by adding saturated aqueous NH4Cl (50mL) and extracted with EA (3 × 50mL). The combined organic layer was washed with brine (50mL), 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).

[0989] LCMS (ESI-MS) m / z = 372.1 [M+H] + .

[0990] Step 2: tert-Butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate

[0991]

[0992] Under nitrogen atmosphere, 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), Pd(dppf)Cl2.CH2Cl2 (64.8 mg, 0.08 mmol) and KOAc (312 mg, 3.15 mmol) in 1,4-dioxane (8 mL) was stirred at 80° C. for 16 hours. After cooling to room temperature, the reaction mixture was directly concentrated under reduced pressure. 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-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (850 mg, 84.3% yield).

[0993] LCMS (ESI-MS) m / z = 350.2 [M+H] + .

[0994] Step 3: tert-Butyl 7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate

[0995]

[0996] Under nitrogen atmosphere, a mixture of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (850 mg, 1.33 mmol), 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (517 mg, 1.33 mmol), Pd(dppf)Cl2.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. 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-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (750 mg, 69.6% yield).

[0997] LCMS (ESI-MS) m / z = 528.3 [M+H] + .

[0998] Step 3: tert-Butyl 7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonane-2-carboxylate

[0999]

[1000] Pd / C (10% carbon loading, 25.8 mg) was added to a mixture of tert-butyl 7-(2-((1-(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 at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide the crude product tert-butyl 7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonane-2-carboxylate (180 mg crude).

[1001] LCMS (ESI-MS) m / z = 530.3 [M+H] + .

[1002] Step 4: N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2-amine

[1003]

[1004] TFA (0.2 mL) was added to a stirred mixture of tert-butyl 7-(2-((1-(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 at room temperature for 1 hour and concentrated under reduced pressure to provide crude N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2-amine (180 mg crude).

[1005] LCMS (ESI-MS) m / z = 430.2 [M+H] + .

[1006] Step 5: 1-(7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonan-2-yl)ethan-1-one

[1007]

[1008] Ac2O (6.31 mg, 0.06 mmol) was added to a stirred mixture of N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]non-7-yl)quinazoline-2-amine (35 mg, 0.06 mmol) and Et3N (24.7 mg, 0.2 mmol) in DCM (0.5 mL). The resulting mixture was stirred at 0 ° C for 1 hour and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to provide the desired product 1-(7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-2-azaspiro[4.4]non-2-yl)ethane-1-one (29.0 mg, 99.4% yield).

[1009] 1H NMR(300MHz,DMSO-d6)δ9.09(s,1H),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).

[1010] LCMS (ESI-MS) m / z = 472.2 [M+H] + , 98.9% purity.

[1011] Embodiment 33: 1-(7-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2,7-diazo Heterospiro[4.4]nonan-2-yl)ethane-1-one

[1012] Reaction scheme

[1013]

[1014] Detailed steps

[1015] Step 1: 8-Bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine

[1016]

[1017] A drop of concentrated HCl was added to a mixture of 4-(4-methylpiperazine-1-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 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 0: 100 to 10: 90) to provide the desired product 8-bromo-N-(4-(4-methylpiperazine-1-yl)phenyl)quinazoline-2-amine (180 mg, 42.1% yield). LCMS (ESI-MS) m / z=398.1[M+H] + .

[1018] Step 2: 1-(7-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one

[1019]

[1020] Under nitrogen atmosphere, Pd2(dba)3 (18.4 mg, 0.02 mmol) was added to a mixture of 8-bromo-N-[4-(4-methylpiperazine-1-yl)phenyl]quinazoline-2-amine (80 mg, 0.21 mmol), 1-(2,7-diazaspiro[4.4]nonan-2-yl)ethane-1-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). The resulting mixture was heated to 100 ° C and stirred overnight under 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 provide the desired product, 1-(7-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one (40.7 mg, 41% yield) (Example 33). 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),9.10(s,1H),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).

[1021] LCMS (ESI-MS) m / z = 486.2 [M+H] + , .3% purity.

[1022] Embodiment 46: 1-(7-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino) Quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one

[1023]

[1024] A mixture of 8-bromo-N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)quinazolin-2-amine (80 mg, 0.18 mmol), 1-(2,7-diazaspiro[4.4]nonan-2-yl)ethane-1-one (28.7 mg, 0.17 mmol), Cs2CO3 (176 mg, 0.54 mmol), BINAP (10.6 mg, 0.017 mmol) and Pd2(dba)3 (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 (2×5 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 by preparative RP-HPLC to afford the desired product, 1-(7-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one (19.6 mg, 22.3% yield).

[1025] 1 H NMR (300MHz, chloroform-d) δ9.07 (d, J=4.2Hz, 1H), 8.15 (dd, J=8.8, 4.1Hz, 1H), 7.81 (s, 1H), 7.63 (t, J=2.7Hz, 1H), 7.26-7.15 (m, 2H), 6.95-6. 82(m,2H),4.07-3.97(m,4H),3.79-3.53(m,7H),3.51-3.39(m,5H),2.51(dd,J=7.2,4.7Hz,2H),2.14-2.01(m,7H),1.08-0.93(m,3H). LCMS(ESI-MS)m / z=513.3[M+H] + , 99.6% purity.

[1026] Embodiment 45: 1-(7-(7-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2, 7-diazaspiro[4.4]nonan-2-yl)ethan-1-one

[1027]

[1028] A mixture of 8-bromo-7-fluoro-N-(1-methylsulfonylpiperidin-4-yl)quinazolin-2-amine (80 mg, 0.19 mmol), 1-(2,7-diazaspiro[4.4]nonan-2-yl)ethane-1-one (33.4 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium (18.2 mg, 0.02 mmol), 1.1'-binaphthyl-2.2'-diphemylphosphine (24.7 mg, 0.04 mmol) and sodium tert-butoxide (38.1 mg, 0.39 mmol) in 1,4-dioxane (3 mL) was heated to 100 °C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EA (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue (100 mg) was purified by preparative RP-HPLC to provide the desired product, 1-(7-(7-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one (28.5 mg, 29.2% yield).

[1029] 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),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).

[1030] LCMS (ESI-MS) m / z = 491.1 [M+H] + .

[1031] Embodiment 58: 6-(Difluoromethyl)-N-(2-methylisoindolin-5-yl)-8-(6-(methylsulfonyl)-2,6- diazaspiro[3.3]hept-2-yl)quinazolin-2-amine

[1032]

[1033] Under nitrogen atmosphere, Pd-PEPPSI-IHeptCl3-chloropyridine (20.4mg, 0.02mmol) was added to a mixture of 8-bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazoline-2-amine (85mg, 0.21mmol), 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (36.9mg, 0.21mmol) and Cs2CO3 (205mg, 0.63mmol) in 1,4-dioxane (2mL). The resulting mixture was heated to 100°C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (20mL). 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 provide the desired product, 6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)-8-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)quinazolin-2-amine (23.2 mg, 21.7% yield) (Example 58).

[1034] 1 H NMR (300MHz, chloroform-d) δ9.06(s,1H),7.60(s,1H),7.38(d,J=8.4Hz,1H),7.29(s,2H),7.24(d,J=8.1Hz,1H ), 6.69 (t, J = 54.3Hz, 2H), 4.35 (s, 4H), 4.15 (s, 4H), 4.04 (d, J = 10.9Hz, 4H), 2.92 (s, 3H), 2.69 (s, 3H).

[1035] LCMS (ESI-MS) m / z = 501.0 [M+H] + .

[1036] Embodiment 67: 6-(Difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]hept-6-yl)-N-(1-(methylsulfonyl)- 4-Yl)piperidin-4-yl)quinazolin-2-amine

[1037] Reaction scheme

[1038]

[1039] Detailed steps

[1040] Step 1: tert-Butyl 6-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[1041]

[1042] 4,4'-di-tert-butyl-2,2'-bipyridine (30.8 mg, 0.11 mmol) and NiCl2.dimethyl ether (25.2 mg, 0.11 mmol) were charged into an oven-dried 20 mL vial. DCE (3 mL) was added under nitrogen atmosphere and the reaction mixture was stirred at 60°C for 10 minutes (Mixture A). 8-bromo-6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (500mg, 1.15mmol), 6-iodo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (744mg, 2.30mmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (314mg, 1.26mmol), Na2CO3 (243mg, 2.30mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (16.6mg, 0.11mmol) were loaded into another oven dried 40mL cillin bottle. DCE (5mL) (mixture B) was added under nitrogen atmosphere. Mixture A was added to mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with 450nm LED lamp under fan for 6 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2:1) to provide tert-butyl 6-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg).

[1043] LCMS (ESI-MS) m / z = 552.2 [M+H] + .

[1044] Step 2: 6-(Difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]hept-6-yl)quinazolin-2-amine

[1045]

[1046] TFA (10mL) is added to the stirred mixture of 6-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (230mg, 0.41mmol) in DCM (3mL). The resulting mixture is stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (MeOH / DCM, 10:90) to provide 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]heptane-6-yl)quinazoline-2-amine (100mg, 47.8% yield).

[1047] LCMS (ESI-MS) m / z = 452.1 [M+H] + .

[1048] Step 3: 6-(Difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]hept-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[1049]

[1050] A solution of 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]hept-6-yl)quinazoline-2-amine (70 mg, 0.15 mmol) and HCHO (23.3 mg, 0.77 mmol) in MeOH (1 mL) was stirred at room temperature for 1 hour. NaBHCN (97.4 mg, 1.55 mmol) was added, and the resulting mixture was stirred at room temperature overnight 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 provide 6-(difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]hept-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (7.9 mg, 10.7% yield).

[1051] 1H NMR (400MHz, chloroform-d) δ8.97 (s, 1H), 7.70-7.54 (m, 2H), 6.71 (t, J = 56.4Hz, 1H), 5.30 (d, J = 7.3Hz, 1H), 4.14-3.95 (m, 2H), 3.80 (d, J = 12. 4Hz,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,7H),1.75(s,1H),1.25(s,1H). LCMS(ESI-MS)m / z=466.1[M+H] + .

[1052] Embodiment 74: N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro [3.4]Oct-2-yl)quinazolin-2-amine

[1053] Reaction scheme

[1054]

[1055] Detailed steps

[1056] Step 1: 8-Bromo-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)quinazolin-2-amine

[1057]

[1058] 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 hour, diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 4:1) to provide 8-bromo-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)quinazoline-2-amine (1.2 g, 55.8% yield).

[1059] LCMS (ESI-MS) m / z = 461.2 [M+H] + .

[1060] Step 2: tert-Butyl 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-(difluoromethyl)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[1061]

[1062] Under nitrogen atmosphere, a solution of 8-bromo-N-(1-(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-ol (93.7 mg, 0.97 mmol), BINAP (20.3 mg, 0.03 mmol) and Pd2(dba)3 (29.8 mg, 0.03 mmol) in 1,4-dioxane (1 mL) was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (2×5 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-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-(difluoromethyl)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (90 mg, 42.0% yield).

[1063] LCMS (ESI-MS) m / z = 593.4 [M+H] + .

[1064] Step 3: N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[1065]

[1066] TFA (0.3 mL) was added to a stirred mixture of tert-butyl 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-(difluoromethyl)quinazoline-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (80 mg, 0.13 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour 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 provide N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazoline-2-amine (18.3 mg, 27.2% yield) (Example 74).

[1067] 1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.64-7.49(m,1H),7.31(s,1H),6.99( t,J=56.1Hz,1H),6.56(d,J=7.0Hz,1H),4.14(d,J=9.8Hz,3H),3.87(s,1H), 3.65(d,J=12.8Hz,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).

[1068] LCMS (ESI-MS) m / z = 493.1 [M+H] + , purity 98.6%.

[1069] Embodiment 89:

[1070]

[1071] K2CO3 (61.21 mg, 0.44 mmol) was added to a mixture of 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]hept-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 at room temperature for 2 days, diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, 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]hept-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (7.3 mg, 6.33% yield) (Example 89).

[1072] 1H NMR (400MHz, chloroform-d) δ8.98 (s, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.58 (s, 1H), 6.72 (t,J=56.4Hz,1H),5.39(d,J=7.3Hz,1H),4.16-3.94(m,2H),3.87-3.76(m, 2H),3.66-3.60(m,2H),3.46(t,J=5.4Hz,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).

[1073] LCMS (ESI-MS) m / z = 510.3 [M+H] + .

[1074] Embodiment 101:

[1075] Reaction scheme

[1076]

[1077] Detailed steps

[1078] Step 1: tert-Butyl 2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

[1079]

[1080] 2-Hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (548mg, 2.41mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (871mg, 2.21mmol) were loaded into a dried 20mL cillin bottle. Under nitrogen, tert-butyl methyl ether (24mL) was added, and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (401mg, 5.10mmol) in tert-butyl methyl ether (6mL) was added, and the mixture was stirred at room temperature for 10 minutes (Mixture A). 8-Bromo-6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-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) were loaded into another dried 40 mL cillin bottle. DMA (30 mL) (mixture B) was added under nitrogen. Mixture A was added to 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 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (3×200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered 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).

[1081] LCMS (ESI-MS) m / z = 566.2 [M+H] + .

[1082] Step 2: 6-(Difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine

[1083]

[1084] TFA (2mL) is added to the stirred mixture of 2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (700mg, 1.23mmol) in DCM (6mL). The resulting mixture is stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue is purified by Prep-TLC (MeOH / DCM, 1:10) to provide 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3.4]octan-2-yl)quinazoline-2-amine (500mg, 86.8% yield).

[1085] LCMS (ESI-MS) m / z = 466.2 [M+H] + .

[1086] Step 3: 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-(3,3,3-trifluoropropyl)-6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine

[1087]

[1088] K2CO3 (89.1 mg, 0.64 mmol) was added to a mixture of 1,1,1-trifluoro-3-iodopropane (48.1 mg, 0.21 mmol) and 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3.4]oct-2-yl)quinazoline-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 provide 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-(3,3,3-trifluoropropyl)-6-azaspiro[3.4]oct-2-yl)quinazoline-2-amine (9.8 mg, 8.1% yield).

[1089] 1H NMR (400MHz, chloroform-d) δ8.98(s,1H),7.72-7.53(m,2H),6.72(t,J=56.4Hz,1H),5.30(d,J=7.1Hz,1H),4.2-4.02(m,2H),3.78(dd,J=10.9,6.0Hz,2 H),3.09-2.94(m,2H),2.85(s,3H),2.76-2.65(m,4H),2.62(s,2H),2.5 7-2.47(m,2H),2.40-2.23(m,6H),2.22-2.15(m,2H),1.81-1.69(m,2H).

[1090] LCMS (ESI-MS) m / z = 562.3 [M+H] + .

[1091] Embodiment 102: 6-(Difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-(oxetane- 3-yl)-6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine

[1092]

[1093] STAB (91.1 mg, 0.43 mmol) was added to a mixture of oxetane-3-one (15.5 mg, 0.21 mmol) and 6-(difluoromethyl)-N-(1-(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 at room temperature overnight, diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to provide 6-(difluoromethyl)-N-(1-(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).

[1094] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.04-8.91 (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).

[1095] LCMS (ESI-MS) m / z = 522.4 [M+H] + .

[1096] Embodiment 106: 3-(2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline- 8-yl)-6-azaspiro[3.4]octan-6-yl)-2,2-difluoropropan-1-ol

[1097]

[1098] A solution of 6-(difluoromethyl)-N-(1-(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-1,3,2-dioxathiolane 2,2-dioxide (45.8 mg, 0.26 mmol) in ACN (1 mL) was stirred at 80 ° C for 4 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with MeCN (2×0.5 ml). 4-Methylbenzene-1-sulfonic acid hydrate (53.9 mg, 0.28 mmol) and H2O (51.1 mg, 2.83 mmol) were added to the combined filtrate. The resulting biphasic mixture was heated to 80 ° C and stirred for 3 hours. The resulting mixture was filtered and the filter cake was washed with DCM (2 × 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to provide 3-(2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-6-azaspiro[3.4]octan-6-yl)-2,2-difluoropropan-1-ol (2.7 mg, 1.8% yield) (Example 106).

[1099] 1H NMR (400MHz, methanol-d4) δ9.05 (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=6.8Hz,1H),2.75(d,J=3.6Hz,2H),2.64-2.50(m,2H),2.28-2.1 8(m,5H),2.04(d,J=6.1Hz,1H),1.90(d,J=2.6Hz,1H),1.80-1.72(m,2H),1.62(s,1H). LCMS(ESI-MS)m / z=560.4[M+H] + , 95.1% purity.

[1100] Embodiment 120

[1101] Reaction scheme

[1102]

[1103] Detailed steps

[1104] Step 1: 1-(Difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutylbenzoate

[1105]

[1106] 1-(Difluoromethyl)-3-hydroxycyclobutylbenzoate (110 mg, 0.45 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (164 mg, 0.42 mmol) were loaded into a dried 20 mL vial. Under nitrogen, tert-butyl methyl ether (4 mL) was added, and the reaction was 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 was stirred at room temperature for 10 minutes (Mixture A). 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (100 mg, 0.26 mmol), Ir(ppy)2(dtbbpy)PF6(3.56 mg, 0.004 mmol), NiBr2(dtbbpy)(9.48 mg, 0.02 mmol) and 1-azabicyclo[2.2.2]octane (50.5 mg, 0.46 mmol) were placed in another dried 40 mL vial. DMA (5 mL) (mixture B) was added under nitrogen. Mixture A was added to 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 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2:1) to provide 1-(difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutylbenzoate (150 mg).

[1107] LCMS (ESI-MS) m / z = 531.2 [M+H] + .

[1108] Step 2: 1-(Difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutan-1-ol

[1109]

[1110] LiOH (33.6 mg, 1.41 mmol) was added to a mixture of 1-(difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutylbenzoate (150 mg, 0.28 mmol) in THF (3 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature overnight, neutralized by adding aqueous HCl (1 N) until the pH was adjusted to 5-6, and extracted with EA (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to provide 1-(difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutan-1-ol (14.5 mg, 11.6% yield) (Example 120).

[1111] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.67-7.59(m,2H),7.44(s,1H),7.26-7.17(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). LCMS(ESI-MS)m / z=427.1[M+H] + .

[1112] Embodiment 121: (1-(difluoromethyl)-3-(2-((1-methylsulfonylpiperidin-4-yl)amino)quinazolin-8-yl) Cyclobutyl]methanol

[1113] Reaction scheme

[1114]

[1115] Step 1: 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[1116]

[1117] Methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutane-1-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) were loaded into a dried 20 mL vial. Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction was 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 was stirred at room temperature for 10 minutes (Mixture A). 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-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 1-azabicyclo[2.2.2]octane (77.1 mg, 0.69 mmol) were charged into another dried 40 mL vial. DMA (5 mL) (mixture B) was added under nitrogen. Mixture A was added to mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 2:1) to provide 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (40 mg). LCMS (ESI-MS) m / z=679.3 [M+H] + .

[1118] Step 2: (1-(difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl)methanol

[1119]

[1120] A solution of TBAF in THF (1M, 0.06mL, 0.06mmol) was added to a stirred mixture of 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)-N-(1-methylsulfonylpiperidin-4-yl)quinazoline-2-amine (40mg, 0.059mmol) in THF (1mL). The resulting mixture was stirred at room temperature for 1 hour, quenched by adding water (5mL) and extracted with EA (3×5mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to provide (1-(difluoromethyl)-3-(2-((1-methylsulfonylpiperidin-4-yl)amino)quinazoline-8-yl)cyclobutyl]methanol (1.0mg, 3.9% yield) (Example 121).

[1121] 1 H NMR (400MHz, chloroform-d) δ8.99(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=11.1Hz,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).

[1122] LCMS (ESI-MS) m / z = 441.2 [M+H] + .

[1123] Embodiment 116:

[1124] Reaction scheme

[1125]

[1126] Detailed steps

[1127] Step 1: 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine

[1128]

[1129] 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 1-methylsulfonylpiperidin-4-amine (171 mg, 0.96 mmol) in DMSO (8 mL). The resulting mixture was heated to 100 ° C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was quenched by adding water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / PE, 1: 1) to provide 8-bromo-N- (1- (methylsulfonyl) piperidin-4-yl) -6- (trifluoromethyl) quinazoline-2-amine (400 mg, 91.6% yield).

[1130] LCMS (ESI-MS) m / z = 453.0 [M+H] + .

[1131] Step 2: Benzyl 8,8-difluoro-2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[1132]

[1133] Under nitrogen atmosphere, Pd-PEPPSI-IHeptCl 3-chloropyridine (23.6 mg, 0.02 mmol) was added to 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazoline-2-amine (110 mg, 0.24 mmol), 8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (68.5 mg, 0.24 mmol) and Cs2CO3 (158 mg, 0.48 mmol) in a mixture of 1,4-dioxane (1 mL). The resulting mixture was heated to 100 ° C and stirred overnight under 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-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (110 mg, 73.0% yield).

[1134] LCMS (ESI-MS) m / z = 655.2 [M+H] + .

[1135] Step 3: 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine

[1136]

[1137] Under nitrogen atmosphere, Pd / C (10% carbon loading, 10 mg) was added to a mixture of 8,8-difluoro-2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazoline-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid benzyl ester (100 mg, 0.15 mmol) in MeOH (8 mL). The resulting mixture was stirred at room temperature for 0.5 hours 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 provide 8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine (9.8 mg, 12.2% yield) (Example 116).

[1138] 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),7.77(s,1H),7.54(d,J=1.9Hz,1H),6.63(s,1H),4.34(d,J=8.7Hz,2H),4.11(d,J=8.7Hz,2H ),3.86(s,1H),3.68-3.52(m,3H),3.26(s,2H),3.17(t,J=14.2Hz,2H),2.97-2.81(m,5H),2.12-1.95(m,2H),1.70-1.53(m,2H).

[1139] LCMS (ESI-MS) m / z = 521.2 [M+H] + .

[1140] Embodiment 114: 1-cyclopropyl-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl) Quinazolin-8-yl)cyclobutane-1-ol

[1141] Reaction scheme

[1142]

[1143] Detailed steps

[1144] Step 1: 3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)cyclobutan-1-one

[1145]

[1146] 3-Hydroxycyclobutane-1-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) were loaded into an overdried 20 mL cillin bottle. Under nitrogen, tert-butyl methyl ether (4 mL) was added, and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (81 mg, 1.03 mmol) in tert-butyl methyl ether (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes (Mixture A). 8-Chloro-6-methyl-N-(1-(methylsulfonyl)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 1-azabicyclo[2.2.2]octane (54.68 mg, 0.49 mmol) were charged into another overdried 40 mL cillin bottle. DMA (5 mL) (Mixture B) was added under nitrogen. Mixture A was added to mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with a 450 nm LED lamp under a fan for 3 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to provide 3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)cyclobutane-1-one (50 mg).

[1147] LCMS (ESI-MS) m / z = 443.1 [M+H] + .

[1148] Step 2: 1-cyclopropyl-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)cyclobutan-1-ol

[1149]

[1150] Under nitrogen atmosphere, a solution of cyclopropylmagnesium bromide in THF (1M, 0.2 mL, 0.2 mmol) was added dropwise to a solution of 1-cyclopropyl-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)cyclobutan-1-ol (50 mg, 0.1 mmol) in THF (30 mL) cooled to -20 °C. The resulting mixture was stirred at -20 °C for 30 minutes, quenched by addition of aqueous NH4Cl (30 mL) at 0 °C 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 silica gel column chromatography (EA / PE, 1:3) to provide 1-cyclopropyl-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-6-(trifluoromethyl)quinazolin-8-yl)cyclobutan-1-ol (2 mg, 3.6% yield) (Example 114).

[1151] 1 H NMR (400MHz, chloroform-d) δ9.02(s,1H),7.83(s,1H),7.71(s,1H),5.44(s,1H),4. 13(s,1H),3.83(d,J=11.9Hz,2H),3.64-3.60(m,1H),3.02(t,J=11.8Hz,1H) ,2.86(d,J=3.2Hz,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).

[1152] LCMS (ESI-MS) m / z = 485.2 [M+H] + .

[1153] Embodiment 117: (3S,4R)-4-((8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-(difluoromethoxy)- 1-(4-(4-yl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[1154] Reaction scheme

[1155]

[1156] Detailed steps

[1157] Step 1: Racemic (3S,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[1158]

[1159] 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 at 100 ° C for 1 hour. After cooling to room temperature, the reaction mixture was quenched by adding water (30 mL) and extracted with EA (2×50 mL). The combined organic layer was washed with brine (2×50 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 provide racemic (3S,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-3-ol (130 mg, 48.03% yield). LCMS (ESI-MS) m / z=374.1 [M+H] + .

[1160] Step 2: 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

[1161]

[1162] Under nitrogen atmosphere, 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), 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (66.4 mg, 0.26 mmol) and Cs2CO3 (174 mg, 0.53 mmol) in 1,4-dioxane (1 mL). The resulting mixture was heated to 100 ° C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the resulting 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 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).

[1163] LCMS (ESI-MS) m / z = 542.5 [M+H]+ .

[1164] 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

[1165]

[1166] TFA (0.3 mL) was added to a stirred mixture of racemic 6-(6-(difluoromethyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)quinazoline-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to provide racemic (3S,4R)-4-((8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-(difluoromethyl)quinazoline-2-yl)amino)tetrahydro-2H-pyran-3-ol (13.8 mg, 21.1% yield) (Example 117).

[1167] 1 H NMR(400MHz,DMSO-d6)δ8.97(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).

[1168] LCMS (ESI-MS) m / z = 442.1 [M+H] + .

[1169] Embodiment 118:

[1170] Reaction scheme

[1171]

[1172] Detailed steps

[1173] Step 1: Racemic (3R,4R)-4-((8-bromo-6-(difluoromethyl)quinazolin-2-yl)amino)-1-(methylsulfonyl)piperidin-3-ol

[1174]

[1175] K2CO3 (107 mg, 0.77 mmol) was added to a mixture of racemic (3R, 4R)-4-amino-1-(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 hour. After cooling to room temperature, the reaction mixture was quenched by adding water (15 mL) and extracted with EA (3×15 mL). The combined organic layer was 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)-1-(methylsulfonyl)piperidin-3-ol (100 mg, 86.1% yield).

[1176] LCMS (ESI-MS) m / z = 451.0 [M+H] + .

[1177] Step 2: 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

[1178]

[1179] Under nitrogen atmosphere, 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)-1-(methylsulfonyl)piperidin-3-ol (90 mg, 0.20 mmol), 8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (49.5 mg, 0.20 mmol) and Cs2CO3 (130 mg, 0.40 mmol) in 1,4-dioxane (2 mL). The resulting mixture was heated to 100 ° C and stirred overnight under 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) 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).

[1180] LCMS (ESI-MS) m / z = 619.2 [M+H] + .

[1181] Step 3: Racemic (3R,4R)-4-((8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)-6-(difluoromethyl)quinazolin-2-yl)amino)-1-(methylsulfonyl)piperidin-3-ol

[1182]

[1183] TFA (0.3 mL) was added to a stirred mixture of 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 (75 mg, 0.12 mmol) in DCM (0.9 mL). The resulting mixture was stirred at room temperature for 1 hour 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)-1-(methylsulfonyl)piperidin-3-ol (41.7 mg, 66.0% yield) (Example 118).

[1184] 1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),7.59(s,1H),7.48(s,1H),7.20-6.83(m,2H),4.37-3.91(m,7 H),3.90-3.48(m,7H),3.00-2.86(m,4H),2.80-2.68(m,1H),2.29-2.13(m,1H),1.65-1.44(m,1H).

[1185] LCMS (ESI-MS) m / z = 519.1 [M+H] + .

[1186] Embodiment 122: 8-(8,8-difluoro-6-azaspiro[3.4]octan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 1-(2-YL)quinazolin-2-amine

[1187] Reaction scheme

[1188]

[1189] Detailed steps

[1190] Step 1: tert-Butyl 8,8-difluoro-2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

[1191]

[1192] 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (240mg, 0.91mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (328mg, 0.83mmol) were loaded into a dried 20mL cillin bottle. Under nitrogen, tert-butyl methyl ether (4mL) was added, and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (65.7mg, 0.83mmol) in tert-butyl methyl ether (1mL) was added, and the mixture was stirred at room temperature for 5 minutes (Mixture A). 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (200mg, 0.52mmol), Ir(ppy)2(dtbbpy)PF6(7.3mg, 0.008mmol), NiBr2(dtbbpy)(12.7mg, 0.026mmol), phthalimide (30.9mg, 0.21mmol) and 1-azabicyclo[2.2.2]octane (101mg, 0.91mmol) were loaded into another 40mL cillin bottle dried. DMA (5mL) (mixture B) was added under nitrogen. Mixture A was added to mixture B under nitrogen atmosphere, and the resulting mixture was stirred and irradiated with 450nm LED lamp under fan for 12 hours. The reaction mixture was quenched with water (20mL) and extracted with EA (3x20mL). The combined organic layer was dried over anhydrous Na2SO4, 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-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (50 mg, 17.4% yield).

[1193] LCMS (ESI-MS) m / z = 552.2 [M+H] + .

[1194] Step 2: 8-(8,8-difluoro-6-azaspiro[3.4]octan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[1195]

[1196] TFA (0.3 mL) was added to a stirred mixture of 8,8-difluoro-2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazoline-8-yl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1:10) to provide 8-(8,8-difluoro-6-azaspiro[3.4]octan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazoline-2-amine (4.3 mg, 10.6% yield).

[1197] 1 H NMR(400MHz,DMSO-d6)δ9.10(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).

[1198] LCMS (ESI-MS) m / z = 452.2 [M+H] + .

[1199] In some embodiments, the compounds of the present disclosure are shown in Table 1 below.

[1200] Table 1

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234]

[1235]

[1236]

[1237]

[1238]

[1239]

[1240]

[1241]

[1242]

[1243]

[1244]

[1245]

[1246]

[1247]

[1248]

[1249]

[1250] In some embodiments, the compounds of the present disclosure are shown in Table 2 below.

[1251] Table 2

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258] Biochemical assays

[1259] CDK1 / Cyclin B1 ADP-Glo ​​Kinase Assay

[1260] The purpose of the CDK1 / Cyclin B1 assay is to evaluate the inhibition (% inhibition and IC) of small molecule inhibitors by using the luminescence-based ADP-Glo ​​assay. 50 CDK1 / Cyclin B1 catalyzes the production of ADP from ATP. The ADP-Glo ​​assay monitors the biochemical reaction that produces ADP. After the kinase reaction is complete, ADP-Glo ​​proceeds in 2 steps: in the first step, the kinase reaction is terminated and the remaining ATP is depleted; in the second step, the generated ADP is converted to ATP using a luciferase / luciferin reaction, and the newly generated ATP is converted to light output. The luminescent signal generated is proportional to the concentration of ADP generated and correlates with the kinase activity. CDK1 / Cyclin B1 was purchased from Carna (Cat. No. 04-102). A typical reaction solution (10 uL final reaction volume) contains 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 substrate, and 4.917 nM CDK1 / cyclin B1 enzyme complex in 50 mM HEPES buffer (pH 7.5). The enzyme and inhibitor were pre-incubated in the reaction mixture at room temperature for 30 minutes before adding the substrate solution containing ATP to start the assay. The reaction was stopped after 90 minutes at room temperature by adding 10 uL of ADP-GLO reagent. After 90 minutes of incubation, 20 uL of kinase detection reagent was added. The samples were incubated for 40 minutes before the plate wells were measured for luminescence on an Envision microplate reader. IC 50 The determination is based on a plot of fractional velocity as a function of inhibitor concentration and the 4-parameter IC 50 Equation fitting. CDK2 / Cyclin E1 Full-Length ADP-Glo ​​Kinase Assay

[1261] The purpose of the CDK2 / Cyclin E1 assay is to evaluate the inhibition (% inhibition and IC) of small molecule inhibitors by using the luminescence-based ADP-Glo ​​assay. 50value). CDK2 / Cyclin E1 full length catalyzes the generation of ADP from ATP. The ADP-Glo ​​assay monitors the biochemical reaction that generates ADP. After the kinase reaction is complete, ADP-Glo ​​proceeds in 2 steps: in the first step, the termination of the kinase reaction and the depletion of the remaining ATP are combined; in the second step, the generated ADP is converted to ATP using a luciferase / luciferin reaction, and the newly generated ATP is converted to light output. The luminescent signal generated is proportional to the concentration of ADP generated and correlates with the kinase activity. CDK2 / Cyclin E1 was purchased from Eurofins (Cat. No. 14-475M). A typical reaction solution (10 uL final reaction volume) contains 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 substrate and 0.328 nM wild-type full-length CDK2 / cyclin E1 enzyme complex in 50 mM HEPES buffer (pH 7.5). The enzyme and inhibitor were pre-incubated in the reaction mixture at room temperature for 30 minutes before adding the substrate solution containing ATP to start the assay. The reaction was stopped after 90 minutes at room temperature by adding 10 uL of ADP-GLO reagent. After 90 minutes of incubation, 20 uL of kinase detection reagent was added. The samples were incubated for 40 minutes before the plate wells were measured for luminescence on an Envision microplate reader. IC 50 The determination is based on a plot of fractional velocity as a function of inhibitor concentration and the 4-parameter IC 50 The equation was fitted.

[1262] CDK4 / Cyclin D1 CHEF assay

[1263] The purpose of the CDK4 / Cyclin D1 assay is to evaluate the inhibition (% inhibition and IC) of small molecule inhibitors by using the chelation enhanced fluorescence (CHEF) assay. 50value). In the CHEF assay, phosphorylation of the peptide substrate results in a proportional increase in fluorescence. The CHEF kinase assay uses a peptide substrate containing a synthetic α-amino acid with an 8-hydroxyquinoline derivative (sulfonamide oxide, Sox) attached to its side chain. Upon phosphorylation of nearby serine, threonine, or tyrosine and in the presence of Mg(II), the spectral properties of the Sox residue change, resulting in emission of 485 nm wavelength when excited with a 360 nm wavelength light source. CDK4 / Cyclin D1 catalyzes the transfer of a phosphoryl group to the SOX-labeled substrate peptide AQT0258 from Assayquant Technologies. A typical reaction solution contains 2% DMSO (+ / - inhibitors), 10 mM MgCl2, 1 mM DTT, 200 uM ATP (ATPKm = 195.2 uM), 0.012% Brig-35, 10 uM AQT0258 peptide, 0.02% BSA, 1% glycerol, 0.55 mM EGTA, 2.5 nM CDK4 / Cyclin D1 in 54 mM HEPES buffer (pH 7.5). The enzyme and inhibitors are pre-incubated in the reaction mixture at 22°C for 30 minutes before adding the substrate solution to start the reaction. The reaction is allowed to proceed for 3 hours at 22°C before reading the fluorescence value of the reaction. IC 50 The d...

Claims

1. A compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (I): in, R 1 is selected from the group consisting of optionally substituted pyrazole, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine; R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle; R 3 , R 4 , R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl; If R 1 is an optionally substituted pyrazole, then R 2 Not piperidine.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from optionally substituted piperidine, optionally substituted indazole, optionally substituted tetrahydroisoquinoline, optionally substituted pyrrolopyrimidine, optionally substituted tetrahydroisoquinoline, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole and optionally substituted azetidine.

3. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from the group consisting of optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole and optionally substituted azetidine.

4. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted piperidine.

5. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted azabicyclo[3.1.0]hexane.

6. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted indole.

7. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted isoindole.

8. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted azetidine.

9. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted indazole.

10. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an optionally substituted tetrahydroisoquinoline.

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 yes Y 1 Selected from -N- and -CR 10 -; Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys; Each of a, b, c and d is independently selected from 1, 2, 3 and 4; Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; and Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having a structure of one or more of the following formulae: in, R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; n is selected from 0 to 9; X 1 , X 2 and X 3 Each of which is independently selected from N and CR 13 ; R 12 is selected from hydrogen, halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle, or R 12 With R 13 together form an optionally substituted ring; and Each R 13 are independently selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl; R 14 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 15 together form an optionally substituted heterocyclic ring; and R 15 Selected from -S(O)2R 16 -, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

13. The compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an optionally substituted heterocycle.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from optionally substituted C 3-6 cycloalkyl, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted pyrazole, optionally substituted azetidine, optionally substituted oxetane, and optionally substituted morpholine.

15. The compound according to claim 1 or 14 or a pharmaceutically acceptable salt thereof, wherein R 2 -CN, -SO2R 2a 、-NR 2a , oxo, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 substituted with cycloalkyl, oxetane or azetidine, wherein R 2a Selected from C 1-6 alkyl.

16. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, having a structure of one or more of the following formulae: in, Y 1 Selected from -N- and -CR 10 -; Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-C(O)-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O-, -S-, -S(O)- and -S(O)2-, where Z 5 Also selected from keys; Each of a, b, c and d is independently selected from 1, 2, 3 and 4; R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; n is selected from 0 to 9; X 1 , X 2 and X 3 Each is CH; Each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 10 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 The substituents taken together form an optionally substituted heterocyclic ring; Each R 11 are independently selected from hydrogen and optionally substituted C 1-4 alkyl; R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl; R 17 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 together form an optionally substituted heterocyclic ring; and R 18 is selected from halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

17. The compound according to claim 11 or 16 or a pharmaceutically acceptable salt thereof, wherein Y 1 Yes-N-.

18. The compound according to claim 11 or 16 or a pharmaceutically acceptable salt thereof, wherein Y 1 Yes-CR 10 -.

19. The compound according to claim 11 or 16 or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 10 )2-、-NR 11 -、-N(C(O)R 10 )-、-NS(O2)R 11 , -O- and -S(O)2-, where Z 5 Also selected from keys. 20 . The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein each of a, b, c and d is independently selected from 1, 2 and 3. 21 . The compound according to claim 20 , or a pharmaceutically acceptable salt thereof, wherein each of a, c and d is independently selected from 1 and 2.

22. A compound according to any one of claims 11 or 16 to 21, or a pharmaceutically acceptable salt thereof, wherein each R 10 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 Alkyl, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl.

23. The compound according to any one of claims 22 or a pharmaceutically acceptable salt thereof, wherein each R 10 Independently selected from hydrogen, halogen, -CN, -OH, methyl, -OMe, -CH2CH2OCH3 and cyclopropyl.

24. A compound according to any one of claims 11 or 16 to 23, or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently selected from hydrogen and optionally substituted C 1-2 alkyl.

25. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein each R 11 independently selected from hydrogen, methyl and ethyl, wherein the ethyl is optionally substituted with -OMe.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole and optionally substituted indole.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole.

28. The compound according to claim 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R 1 SO2R 1a or C 1-3 Alkyl substituted, where R 1a Selected from C 1-6 alkyl.

29. A compound according to any one of claims 1, 2, 26, 27 or 28, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from optionally substituted heterocycle and optionally substituted cycloalkyl.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted heterocycloalkyl.

31. The compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl.

32. The compound according to claim 31 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine and optionally substituted morpholine.

33. A compound according to any one of claims 29 to 32, or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen, -SO2R 2a 、-NR 2a , -C(O)CH3, -CN, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C 3-5 Carbocyclic, oxo and optionally substituted C 1-3 Alkyl substituted, where R 2a Selected from C 1-6 alkyl.

34. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein R 2 Substituted by fluorine, -SO2Me, oxo and methyl.

35. A compound according to any one of claims 1-10, 12 or 29, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 36. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 37. A compound according to any one of claims 1-10 or 12, or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted heterocycloalkyl.

38. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

39. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

40. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, fluorine and -CN.

41. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen and -CN.

42. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

43. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, -CN, -CHF2, -CF3, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

44. The compound according to claim 43 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, -CN and -CHF2.

45. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

46. ​​The compound according to claim 45 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

47. The compound according to claim 46 or a pharmaceutically acceptable salt thereof, wherein R 5 It's hydrogen.

48. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

49. The compound according to claim 48 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

50. The compound according to claim 49 or a pharmaceutically acceptable salt thereof, wherein R 6 It's hydrogen.

51. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein R 7 It's hydrogen.

52. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the compounds in Table 1.

53. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, selected from the compounds in Table 1.

54. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, selected from the compounds in Table 1.

55. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of claims 1 to 54 and a pharmaceutically acceptable excipient.

56. A method for treating cancer, comprising administering the pharmaceutical composition of claim 54 to a subject in need thereof.

57. The method of claim 56, wherein the cancer is a solid tumor.

58. The method of claim 56 or 57, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain cancer.

59. The method of claim 58, wherein the cancer is ovarian cancer or breast cancer.

60. A method of inhibiting cyclin-dependent kinase (CDK) in a cell using a compound or pharmaceutically acceptable salt of any one of claims 1 to 54 or a pharmaceutical composition of claim 55.

61. The method of claim 59, wherein the CDK is selected from CDK 2, CDK 4, CD6, or any combination thereof.

62. The method of claim 60, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6 and CDK2 / 4 / 6.

63. The method of claim 62, wherein the CDK is CDK 2 / 4 / 6.

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