Quinazoline compounds and methods of use

Abstract

Disclosed herein are substituted quinazoline compounds, conjugates, and pharmaceutical compositions for use in the treatment of cancer. The disclosed compounds are useful, inter alia, in the inhibition of CDK. In certain embodiments, the present 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

Technical Field

[0001] Cross - reference to related applications 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 foregoing patent applications are hereby incorporated by reference into this specification.

Background Art

[0002] The division and proliferation of mammalian cells mediated by the cell cycle is an important and fundamental biological process that controls the production and generation of cells with extremely important biological functions. The cell cycle is a highly regulated process that responds to a complex set of intracellular and extracellular cell signals. A complex network of cell signaling, including components that promote and suppress cancer, plays an important role in controlling the cell cycle. A gain - of - function of tumor - promoting components or a loss - of - function of tumor - suppressing products can lead to a disordered cell cycle and subsequent tumor formation.

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

[0004] Dysregulation of the cell cycle machinery is a hallmark of cancer, leading to hyperactivation of CDKs and uncontrolled cell division and proliferation. Genetic alterations of genes encoding cyclin D, CDK4 / 6, and CDK4 / 6 inhibitor proteins (such as p21, p27) all contribute to tumorigenesis. Cyclin E, a regulatory cyclin of CDK2, is frequently overexpressed in cancer. Since tumorigenesis is closely associated with gene mutations and deregulation of CDKs and their regulators, CDK inhibitors are useful for cancer treatment. CDK inhibitors have been developed as cancer therapies using multiple FDA-approved drugs (palbociclib, ribociclib, and abemaciclib) since the early 1990s. However, these early-generation CDK inhibitors on the market have low selectivity and high toxicity (such as myelosuppression), resulting in adverse effects that limit clinical dosing levels for further patient benefit. There remains an unmet medical need to develop novel CDK inhibitors with better selectivity and fewer side effects against normal cells.

Summary of the Invention

[0005] 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 in a subject in need thereof for the treatment of abnormal cell proliferation such as cancer.

[0006] In some embodiments, a method of treating cancer can include administering to an individual in need thereof a compound or a pharmaceutically acceptable salt of any one of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA).

[0007] In certain embodiments, the present disclosure provides formula (I)

[0008]

Chem.

[0009] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0010] In certain aspects, the present disclosure provides a method of treating cancer, the method comprising administering to a subject in need thereof a compound or pharmaceutical composition described herein. In certain aspects, the present disclosure provides a method of inhibiting cyclin-dependent kinase (CDK) in a cell using a compound or pharmaceutically acceptable salt or pharmaceutical composition described herein.

[0011] Incorporation by reference All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety 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 OF THE INVENTION

[0012] Preferred embodiments of the invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0013] The basic functions of cell regulation, cell division, and cell proliferation are controlled by cyclin-dependent kinases (CDKs) that are activated by regulatory subunits such as cyclins. CDK inhibitors are useful for treating cancer due to the role of CDKs in cell regulation. Increased or transient abnormal activation of CDK activity has been shown to lead to tumorigenesis, which is often associated with changes in CDKs or CDK regulators.

[0014] CDKs bind to cyclins, which are regulatory proteins, and without cyclins, they have little kinase activity. Cyclin-CDK complexes are active kinases typically regulated by phosphorylation and other binding proteins. Currently, there are 21 known CDKs and 5 CDK-like genes in the human genome. Many of the CDKs are associated with transcription, while CDK2, CDK4, and CDK6 are associated with the cell cycle. CDK2 is associated with DNA replication in higher eukaryotes, while CDK4 and CDK6 are associated with various growth regulatory signals.

[0015] CDK2 overexpression is associated with abnormal regulation of the cell cycle. Cyclin E, a cyclin partner of CDK2, binds to CDK2 to form an active kinase complex. The CDK2-Cyclin E complex is important in the regulation of G1 / S transition, centrosome duplication, and histone biosynthesis. Progressive phosphorylation can release the G1 transcription factor E2F and promote the transition to the S phase. Cyclin A, another cyclin partner of CDK2, binds to and activates CDK2 during the early stages of the S phase and can promote phosphorylation of endogenous substrates, which enables DNA replication and E2F inactivation to complete the S phase.

[0016] CDK4 and CDK6 are also associated with the cell cycle. CDK4 and CDK6 inhibitors can block phosphorylation of the Rb protein and arrest the cell cycle from the G1 phase to the S phase by inhibiting the proliferation of Rb-positive tumor cells. In addition to cell cycle activity, CDK4 and CDK6 inhibitors can also suppress tumor growth through other mechanisms, including, but not limited to, inducing senescence, promoting the anti-tumor immune response, regulating cell metabolism, and enhancing cell division arrest caused by signal transduction pathway inhibitors.

[0017] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0018] As used in this specification and the claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0019] As used in this specification and the appended claims, the following terms have the meanings set forth below unless otherwise specified.

[0020] "Amino" refers to the -NH2 radical.

[0021] "Cyano" refers to the -CN radical.

[0022] "Nitro" refers to the -NO2 radical.

[0023] "Oxo" refers to the -O- radical.

[0024] "Oxo" refers to the =O radical.

[0025] "Thioxo" refers to the =S radical.

[0026] "Imino" refers to the =N-H radical.

[0027] "Oximo" refers to the =N-OH radical.

[0028] "Hydrazino" refers to the =N-NH2 radical.

[0029] "Alkyl" consists of only carbon and hydrogen atoms, contains no unsaturation, and has from 1 to 15 carbon atoms (e.g., C1-C 15 alkyl), and refers to a straight-chain or branched-chain hydrocarbon chain radical. In certain embodiments, alkyl contains from 1 to 13 carbon atoms (e.g., C1-C 13(alkyl). In certain embodiments, alkyl contains from 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains from 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains from 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains from 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains from 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains from 5 to 15 carbon atoms (e.g., C5-C 15 (alkyl). In other embodiments, alkyl contains from 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, alkyl contains from 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, alkyl contains from 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). Alkyl is bonded to the remainder of the molecule by a single bond.

[0030] "Heteroalkyl" refers to an alkyl group as defined above having one or more carbon atoms substituted with heteroatoms, e.g., the heteroatom is individually selected from N, O, and S at each substitution position. Without limitation, additional heteroatoms including B, Al, Si, and P may also be useful. The heteroatom may be further oxidized, e.g., without limitation, -S(O)- and -S(O)2-. For example, heteroalkyl can include ethers, thioethers, and alkylamines. Heteroalkyl consisting of the recited number of carbon atoms may include one or more heteroatoms selected from the group consisting of O, N, Si, and S, and nitrogen heteroatoms may optionally be quaternized. The heteroatoms O, N, and S can be disposed at any internal position of the heteroalkyl group. The heteroatom Si can be disposed at any position of the heteroalkyl group including the position where the alkyl group is attached to the rest of the molecule. Two heteroatoms may be consecutive, e.g., -CH2NHOCH3 and -CH2OSi(CH3)3. Heteroalkyl can include any recited number of carbon atoms as defined herein and in the definition of alkyl.

[0031] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0032] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain radical group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. Alkenyl is bonded to the rest of the molecule by a single bond, e.g., ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.

[0033] "Alkynyl" refers to a straight-chain or branched hydrocarbon chain radical group consisting of only carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In certain embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl contains 2 to 6 carbon atoms. In other embodiments, alkynyl contains 2 to 4 carbon atoms. Alkynyl is bonded to the rest of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0034] "Alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting of only carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms, which binds the rest of the molecule to the radical group, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is bonded to the rest of the molecule via a single bond and to the radical group via a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are via one carbon in the alkylene chain or any two carbons within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene).

[0035] "Alkenylene" or "alkenylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon chain that consists of only carbon and hydrogen, contains at least one carbon-carbon double bond, has 2 to 12 carbon atoms, and attaches the remainder of the molecule to a radical group. The alkenylene chain is attached to the remainder of the molecule by a single bond and to the radical group by a single bond. In certain embodiments, alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene).

[0036] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, having at least one carbon-carbon triple bond, having 2 to 12 carbon atoms, and bonding the rest of the molecule to a radical group. The alkynylene chain is bonded to the rest of the molecule by a single bond and to the radical group by a single bond. In certain embodiments, alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene).

[0037] "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain consisting of heteroatoms such as N, O, and S, and bonding the rest of the molecule to a radical group. Additional heteroatoms, including but not limited to B, Al, Si, and P, may also be useful. The heteroalkylene chain is bonded to the rest of the molecule by a single bond and to the radical group by a single bond. In certain embodiments, heteroalkylene contains 1 heteroatom. In certain embodiments, heteroalkylene contains 2 heteroatoms. In certain embodiments, heteroalkylene contains 3 heteroatoms. In certain embodiments, heteroalkylene contains 4 heteroatoms. In certain embodiments, heteroalkylene contains 5 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.

[0038] 「C x-y 」 or "C x -C y 」 When used with chemical moieties such as alkyl, alkenyl, or alkynyl, the term means a group 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 containing a straight-chain or branched-chain alkyl group having 1 to 6 carbons.

[0039] 「C x-y alkenyl」 and 「C x-y alkynyl」 The terms refer to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitution to the above alkyl, but each contains at least one double bond or triple bond.

[0040] As used herein, the term "carbocyclic ring" refers to a saturated ring, an unsaturated ring, or an aromatic ring in which each atom of the ring is carbon. Carbocyclic rings include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocyclic ring can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In a typical embodiment, an aromatic ring, for example, phenyl, can be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings as permitted by valency. Bicyclic carbocyclic rings further include spirobicyclic rings, for example, spiropentane. Bicyclic carbocyclic rings include any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl.

[0041] The term "aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, that is, it contains a cyclic delocalized (4n + 2)π - electron system according to Hückel's theory. The ring system from which the aryl group is derived includes groups such as, but not limited to, benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0042] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl can include monocyclic and polycyclic rings such as 3 - to 10 - membered monocyclic rings, 5 - to 12 - membered bicyclic rings, 5 - to 12 - membered spirobicyclic rings, and 5 - to 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 attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 - dimethylbicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like.

[0043] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl 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, cycloalkenyl contains 5 to 7 carbon atoms. Cycloalkenyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0044] The term "halo", or alternatively "halogen" or "halide", means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0045] The term "haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the haloalkyl radical is optionally further substituted as described herein.

[0046] The term "heterocyclic ring" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Typical heteroatoms include atoms of N, O, Si, P, B, and S. Heterocyclic rings include monocyclic rings of 3 to 10 members, bicyclic rings of 6 to 12 members, spirobicycles of 5 to 12 members, and bridged rings of 5 to 12 members. Monocyclic heterocyclic rings include any saturated, unsaturated, and aromatic rings as allowed by valency. Monocyclic heterocyclic rings include, but are not limited to, oxetane, azetidine, furan, tetrahydrofuran, pyrrole, pyrrolidine, pyran, piperidine, piperazine, imidazole, thiazole, morpholine, pyridine, and pyrimidine. Bicyclic heterocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings as allowed by valency. In a typical embodiment, an aromatic ring, e.g., pyridyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocyclic rings include any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Examples of fused ring systems include, but are not limited to, isoindoline, isoquinoline, tetrahydroisoquinoline, 3-azabicyclo[3.1.0]hexane, and 6-oxa-3-azabicyclo[3.1.1]heptane.The bicyclic heterocyclic ring further includes spirobicyclic rings having 5 to 12 members, 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 2,2-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.

[0047] The term "heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, at least one of the rings in the ring system being aromatic, i.e., containing a cyclic delocalized (4n+2)π-electron system in accordance with Huckel's theory. Heteroaryl includes fused ring systems or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, benzimidazolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridopyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and thiophenyl (i.e., thienyl).

[0048] The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include atoms of N, O, Si, P, B, and S. Heterocycloalkyl can include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. Heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl for which valence permits, such as any carbon atom or nitrogen atom of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, azetidinyl, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 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 2,2-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.

[0049] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom, with at least one double bond existing between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Typical heteroatoms include atoms of N, O, Si, P, B, and S. 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, heterocycloalkenyl includes 5 to 7 ring atoms. Heterocycloalkenyl can be bonded to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), -10-idrazine 10-one (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0050] The term "replaced" refers to a moiety having a substituent that replaces hydrogen on one or more carbons or replaceable heteroatoms, for example, NH or NH2 of a compound. "Substituted" or "substituted with" means that such substitution follows the allowed valences of the substituted atom and the substituents, and includes the implicit condition that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation such as rearrangement, cyclization, elimination, etc. In certain embodiments, being substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom (e.g., replacing two hydrogen atoms on one carbon with an oxo group, an imino group, or a thioxo group). As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, spirocyclic and non-spirocyclic, aromatic and non-aromatic substituents of an organic compound. Acceptable substituents are one or more for a suitable organic compound and can be the same or different.

[0051] In some embodiments, each substituent individually is any substituent described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), -11-idrazine (=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 -O-R 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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2), and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), 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 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R 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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2) may be optionally substituted, where R a is each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where R a is each, to the extent permitted by valence, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), 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 -O-R c -C(O)N(Ra ) 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 (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) may be optionally substituted, where R b is each independently selected from a direct bond, or a straight or branched alkylene chain, alkenylene chain, or alkynylene chain, and R c is each a straight or branched alkylene chain, alkenylene chain, or alkynylene chain.

[0052] Double bonds to oxygen atoms such as oxo groups are represented herein by both "=O" and "(O)". Double bonds to nitrogen atoms are represented by both "=NR" and "(NR)". Double bonds to sulfur atoms are represented by both "=S" and "(S)".

[0053] As used herein, the terms "parenteral administration" and "administered parenterally" generally mean administration by injection, a route of administration other than enteral administration and topical administration, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subdural, intraspinal, and substeral injections and infusions.

[0054] As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment and that are commensurate with a reasonable benefit / risk ratio.

[0055] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" mean pharmaceutically acceptable substances, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. 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 substances that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0056] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well-known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which the salts can be derived include, for example, primary amines, secondary amines, and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from the salts of ammonium, potassium, sodium, calcium, and magnesium.

[0057] As used herein, "treatment" or "treating" refers to an approach for obtaining a beneficial or desired result, including but not limited to therapeutic and / or prophylactic benefits, with respect to a disease, disorder, or medical condition. Therapeutic benefits can include, for example, eradication or remission of the underlying disease being treated. Similarly, therapeutic benefits can include, for example, eradication or remission of one or more of the physiological symptoms associated with the underlying disease such that an improvement is observed in the subject, even though the subject may still potentially suffer from the underlying disease. In certain embodiments, with respect to prophylactic benefits, the composition is administered to a subject at risk of developing a particular disease or to a subject reporting one or more of the physiological symptoms of a disease, even in the absence of a diagnosis of this disease. Treatment by administration of the compounds described herein does not require the involvement of a medical professional.

[0058]

Table 1-1

[0059]

Table 1-2

[0060] Compound The following is a discussion of compounds and salts thereof that can be used in the methods of the present disclosure. In certain embodiments, the compounds and salts are those described by formula (I0), (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA).

[0061] In one aspect, formula (I)

[0062]

Chemical formula

[0063]

Chem.

[0064] In one embodiment, formula (I)

[0065] [Chem.] The compounds represented by are disclosed herein, wherein, R 1 is selected from 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 ring, and optionally substituted 3- to 4-membered heterocycloalkyl, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl.

[0066] In one embodiment, the compound of formula (I)

[0067] [Chem.] The compounds represented by are disclosed herein, wherein, R 1 is selected from optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine, R 2is selected from optionally substituted cycloalkyl and optionally substituted heterocycle, R 3 , R 4 , R 5 , R 6 each of which is independently hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, and, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl.

[0068] R 1 can be any suitable functional group known to those skilled in the art. In some embodiments, R 1 is selected from optionally substituted piperidine, optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R 1 is selected from optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R 1 is selected from optionally substituted piperidine, optionally substituted pyridine, optionally substituted azetidine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole. In some embodiments, R 1 is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole. In some embodiments, R 1is selected from azabicyclo[3.1.0]hexane optionally substituted and isoindole optionally substituted. In some embodiments, R 1 is -SO2R 1a or C 1-3 substituted with alkyl, and R 1a is selected from C 1-6 alkyl.

[0069] In some embodiments, R 1 is selected from 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 optionally substituted, and azetidine optionally substituted. In some embodiments, R 1 is selected from 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 optionally substituted, and azetidine optionally substituted.

[0070] In some embodiments, R 1 is

[0071]

Chemical formula

[0072] In some embodiments, R 1 is selected from 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 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 optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine. In some embodiments, R 1 is optionally substituted piperidine. In some embodiments, R 1 is optionally substituted azabicyclo[3.1.0]hexane. In some embodiments, R 1 is optionally substituted indole. In some embodiments, R 1 is optionally substituted isoindole. In some embodiments, R 1 is optionally substituted azetidine. In some embodiments, R 1 is optionally substituted indazole. In some embodiments, R 1 is optionally substituted tetrahydroisoquinoline.

[0073] R 2 can be any suitable functional group known to those skilled in the art. In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. In some embodiments, R 2 is 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.

[0074] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. In some embodiments, R 2 is selected from optionally substituted cycloalkyl. In some embodiments, R 2is selected from cycloalkyl. In some embodiments, R 2 is optionally substituted C 3-6 selected from cycloalkyl. In some embodiments, R 2 is optionally substituted C 5-6 selected from cycloalkyl. In some embodiments, R 2 is selected from optionally substituted heterocycloalkyl. In some embodiments, R 2 is selected from heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2is selected from 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-thia-6-azaspiro[3.4]octane 2,2-dioxide, 4-oxa-7-azaspiro[2.5]octane optionally substituted, 2-azaspiro[4.4]nonane optionally substituted, 2,7-diazaspiro[4.4]nonane optionally substituted, 2-oxa-6-azaspiro[3.5]nonane optionally substituted, 7-oxa-2-azaspiro[3.5]nonane optionally substituted, 2-azaspiro[4.5]decane optionally substituted, 2,8-diazaspiro[4.5]decane optionally substituted, 8-oxa-2-azaspiro[4.5]decane optionally substituted, and 2-oxa-7-azaspiro[4.5]decane optionally substituted. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0075] In some embodiments, R 2 is 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 substituted with an optionally substituted 3- to 6-membered heterocycloalkyl, and R 2a is hydrogen and C 1-6is selected from alkyl. In some embodiments, R 2 is -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 cycloalkyl, oxetane, piperidine, piperazine, or azetidine, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, oxo, and C 1-4 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, and -NR 2a -, oxo, and C 1-3 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is fluoro, -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 fluoro, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R 2 is fluoro, -SO2Me, oxo, and methyl. In some embodiments, R 2 is -CN, -SO2R 2a -, -NR 2a -, oxo, C 1-3 alkyl, C 1-3Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 Substituted with cycloalkyl, oxetane, methylpiperidine, or azetidine, R 2a is C 1-6 Selected from alkyl.

[0076] In some embodiments, R 2 is

[0077]

Chemical formula

[0078] R 11are each independently hydrogen and optionally substituted C 1-4 alkyl selected from.

[0079] In some embodiments, R 2 is

[0080]

Chemical formula

[0081] In some embodiments, R 2 is selected from optionally substituted cycloalkyl. In some embodiments, R 2 is selected from optionally substituted cyclopentane. In some embodiments, R 2 is

[0082]

Chemical formula

[0083] R 3 can be any suitable functional group known to those skilled in the art. In some embodiments, hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl selected from. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0084] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. 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 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0085] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0086] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, an optionally substituted C 1-4 alkyl, an optionally substituted C 3-4 carbon ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, an optionally substituted C 3-4 carbon ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0087] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0088] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IA)

[0089]

Chemical formula

[0090] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocyclic ring. In some embodiments, R 2 is selected from optionally substituted cycloalkyl. In some embodiments, R 2 is selected from cycloalkyl. In some embodiments, R 2 is selected from optionally substituted C 3-6 cycloalkyl. In some embodiments, R 2 is selected from optionally substituted C 5-6is selected from cycloalkyl. In some embodiments, R 2 is selected from optionally substituted heterocycloalkyl. In some embodiments, R 2 is selected from heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2is selected from 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-thia-6-azaspiro[3.4]octane 2,2-dioxide, 4-oxa-7-azaspiro[2.5]octane optionally substituted, 2-azaspiro[4.4]nonane optionally substituted, 2,7-diazaspiro[4.4]nonane optionally substituted, 2-oxa-6-azaspiro[3.5]nonane optionally substituted, 7-oxa-2-azaspiro[3.5]nonane optionally substituted, 2-azaspiro[4.5]decane optionally substituted, 2,8-diazaspiro[4.5]decane optionally substituted, 8-oxa-2-azaspiro[4.5]decane optionally substituted, and 2-oxa-7-azaspiro[4.5]decane optionally substituted. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0091] In some embodiments, R 2 is 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 substituted with an optionally substituted 3- to 6-membered heterocycloalkyl, and R 2a is hydrogen and C 1-6is selected from alkyl. In some embodiments, R 2 is -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 cycloalkyl, oxetane, piperidine, piperazine, or azetidine, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, oxo, and C 1-4 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, and -NR 2a -, oxo, as well as C 1-3 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is fluoro, -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 fluoro, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R 2 is fluoro, -SO2Me, oxo, and methyl. In some embodiments, R 2 is -CN, -SO2R 2a -, -NR 2a -, oxo, C 1-3 alkyl, C 1-3Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 Substituted with cycloalkyl, oxetane, methylpiperidine, or azetidine, R 2a is C 1-6 selected from alkyl.

[0092] In some embodiments, R 2 is 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. In some embodiments, R 2 is -CN, -SO2R 2a , -NR 2a , oxo, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 1-3 alkylen-C 3-6 cycloalkyl, substituted with oxetane, or azetidine, R 2a is C 1-6 selected from alkyl. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0093] In some embodiments, R 2 is

[0094]

Chemical formula

[0095] In some embodiments, R 2 is selected from optionally substituted cycloalkyl. In some embodiments, R 2 is selected from optionally substituted cyclopentane. In some embodiments, R 2is selected from

[0096] [Chemical formula] selected from

[0097] R 3 can be any suitable functional group known to those skilled in the art. In some embodiments, hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0098] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4is 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 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0099] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0100] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0101] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0102] 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.

[0103] R 8 can be any suitable functional group known to those skilled in the art. In some embodiments, R 8 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 8 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 8 is fluoro, chloro, bromo, methyl, ethyl, or propyl.

[0104] R 9 can be any suitable functional group known to those skilled in the art. In some embodiments, R 9 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 9 is selected from methyl, ethyl, and propyl.

[0105] In some embodiments, the compound is

[0106]

Chemical formula

[0107] In some embodiments, the compound is

[0108]

Chemical formula

[0109] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is of formula (IAA)

[0110] [Chemical formula] has the structure of In the formula, R 8 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, R 9 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocyclic ring, and 3- to 6-membered heterocycloalkyl, n is selected from 0 to 9, Y 1 is selected from -N- and -CR 10 -, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each 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-, and Z 5 is further selected from a bond, each of a, b, c, and d is independently selected from 1, 2, 3, and 4, R 10 each is independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 10 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 substituents together form an optionally substituted heterocyclic ring, and R 11 each is independently hydrogen and optionally substituted C1-4 is selected from alkyl.

[0111] R 3 can be any suitable functional group known to those skilled in the art. In some embodiments, hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0112] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4is 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 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0113] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0114] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0115] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0116] 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.

[0117] R 8 can be any suitable functional group known to those skilled in the art. In some embodiments, R 8 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 8 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 8 is fluoro, chloro, bromo, methyl, ethyl, or propyl.

[0118] R 9 can be any suitable functional group known to those skilled in the art. In some embodiments, R 9 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 9 is selected from methyl, ethyl, and propyl.

[0119] Y 1 can be any suitable atom known to those skilled in the art. In some embodiments, Y 1 is selected from -N- and -CR 10 -. In some embodiments, Y 1 is -N-. In some embodiments, Y 1 is -CR 10 -.

[0120] Z 1 Z 2 Z 3 Z 4 and Z 5 can each independently be any suitable atom known to those skilled in the art. In some embodiments, Z 1 Z 2 Z 3 Z4 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-, and Z 5 is further selected from a bond. 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-, and Z 5 is further selected from a bond.

[0121] The variables a, b, c, and d can be any suitable numbers 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.

[0122] R 10 can be any suitable functional group known to those skilled in the art. In some embodiments, each R 10 is independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 10 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle, or R 10 and R 11The substituents combine to form an optionally substituted heterocyclic ring. In some embodiments, R 10 is each independently hydrogen, halogen, -OH, optionally substituted C 1-3 alkyl, and optionally substituted C 3-6 cycloalkyl. In some embodiments, R 10 is each independently hydrogen, fluoro, chloro, bromo, -OH, methyl, ethyl, propyl, cyclopropyl, and cyclobutyl. In some embodiments, R 10 is each independently hydrogen, fluoro, -OH, methyl, and cyclopropyl.

[0123] R 11 can be any suitable functional group known to those skilled in the art. In some embodiments, R 11 is each independently hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 11 is each independently hydrogen and optionally substituted C 1-2 alkyl. In some embodiments, R 11 is each independently hydrogen, methyl, and ethyl, and methyl and ethyl are optionally substituted with -OMe, -OEt, and -OPr. In some embodiments, R 11 is each independently hydrogen, methyl, and ethyl, and ethyl is optionally substituted with -OMe.

[0124] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IAAA)

[0125]

Chemical formula

[0126]

Chemical formula

[0127] In some embodiments, the compound is

[0128]

Chemical formula

[0129]

Chemical formula

[0130] In some embodiments, the compound is

[0131]

Chemical formula

[0132]

Chemical formula

[0133] In some embodiments, the compound is

[0134]

Chemical formula

[0135] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IB)

[0136]

Chemical formula

[0137] In some embodiments, R 2 is an optionally substituted heterocycle.

[0138] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. In some embodiments, R 2 is selected from optionally substituted cycloalkyl. In some embodiments, R 2 is selected from cycloalkyl. In some embodiments, R 2 is selected from optionally substituted C 3-6 cycloalkyl. In some embodiments, R 2 is selected from optionally substituted C 5-6 cycloalkyl. In some embodiments, R2 is selected from optionally substituted heterocycloalkyl. In some embodiments, R 2 is selected from heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2is selected from 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-thia-6-azaspiro[3.4]octane 2,2-dioxide, 4-oxa-7-azaspiro[2.5]octane optionally substituted, 2-azaspiro[4.4]nonane optionally substituted, 2,7-diazaspiro[4.4]nonane optionally substituted, 2-oxa-6-azaspiro[3.5]nonane optionally substituted, 7-oxa-2-azaspiro[3.5]nonane optionally substituted, 2-azaspiro[4.5]decane optionally substituted, 2,8-diazaspiro[4.5]decane optionally substituted, 8-oxa-2-azaspiro[4.5]decane optionally substituted, and 2-oxa-7-azaspiro[4.5]decane optionally substituted. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0139] In some embodiments, R 2 is 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 substituted with an optionally substituted 3- to 6-membered heterocycloalkyl, where R 2a is hydrogen and C 1-6is selected from alkyl. In some embodiments, R 2 is -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 cycloalkyl, oxetane, piperidine, piperazine, or azetidine, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, oxo, and C 1-4 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, and -NR 2a -, oxo, and C 1-3 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is 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 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 fluorine, -SO2Me, oxo, and methyl. In some embodiments, R 2 is -CN, -SO2R 2a -, -NR 2a -, oxo, C 1-3 alkyl, C 1-3Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 Substituted with cycloalkyl, oxetane, methylpiperidine, or azetidine, R 2a is C 1-6 Selected from alkyl.

[0140] In some embodiments, R 2 is 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. In some embodiments, R 2 is -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, R 2a is C 1-6 Selected from alkyl. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0141] In some embodiments, R 2 is

[0142]

Chemical formula

[0143] In some embodiments, R 2 is

[0144]

Chemical formula

[0145] R 3 may be any suitable functional group known to those skilled in the art. In some embodiments, hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0146] R 4 may be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4is 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 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0147] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0148] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0149] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0150] X 1 X 2 and X 3 each can be any suitable atom known to those skilled in the art. In some embodiments, X 1 X 2 and X 3 each are independently selected from N and CR 13 In some embodiments, X 1, X 2 , and X 3 Each of which 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 Are each CH.

[0151] R 12 Can be any suitable functional group known to those skilled in the art. In some embodiments, 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 Is R 13 Together with to form an optionally substituted ring. In some embodiments, R 12 Is an optionally substituted heterocycle. In some embodiments, R 12 Is an optionally substituted 3- to 8-membered heterocycle. In some embodiments, R 12 Is an optionally substituted 5- to 8-membered heterocycle. In some embodiments, R 12 Is an optionally substituted 6- to 7-membered heterocycle.

[0152] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IBB)

[0153]

Chemical formula

[0154] R 3 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 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0155] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. 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 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0156] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is hydrogen, halogen, -CN, an optionally substituted C 3-4 It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0157] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6 is hydrogen, halogen, -CN, an optionally substituted C 1-4 alkyl, an optionally substituted C 3-4 It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 6 is hydrogen, halogen, -CN, an optionally substituted C 3-4 It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0158] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0159] X 1 、X 2 、and X 3 each can be any suitable atom known to those skilled in the art. In some embodiments, X 1 、X 2 、and X 3 each is independently selected from N and CR 13 . In some embodiments, X 1 、X 2 、and X 3 each is independently N. In some embodiments, X 1 、X 2 、and X 3 each is independently selected from CR 13 . In some embodiments, X 1 、X 2 、and X 3 are each CH.

[0160] R 12 can be any suitable functional group known to those skilled in the art. In some embodiments, R 12is 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 is R 13 together with R forms an optionally substituted ring. In some embodiments, R 12 is an optionally substituted heterocycle. In some embodiments, R 12 is an optionally substituted 3- to 8-membered heterocycle. In some embodiments, R 12 is an optionally substituted 5- to 8-membered heterocycle. In some embodiments, R 12 is an optionally substituted 6- to 7-membered heterocycle.

[0161] R 13 can each be any suitable functional group known to those skilled in the art. In some embodiments, R 13 are each independently selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, or R 12 is R 13 together with R forms an optionally substituted ring. In some embodiments, R 13 are each independently selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, and propyl. In some embodiments, R 13 are each independently selected from hydrogen, fluoro, -CN, methyl, and ethyl. In some embodiments, R 13 are each independently hydrogen.

[0162] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can each independently be any suitable atom known to those skilled in the art. In some embodiments, Z 1 , Z 2 , Z 3 , Z4 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-, and Z 5 is further selected from a bond. 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-, and Z 5 is further selected from a bond.

[0163] The variables a, b, c, and d can be any suitable numbers 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.

[0164] R 10 can be any suitable functional group known to those skilled in the art. In some embodiments, each R 10 is independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 10 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle, or R 10 and R 11The substituents together form an optionally substituted heterocyclic ring. In some embodiments, R 10 is each independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, and optionally substituted C 1-3 alkyl. In some embodiments, R 10 is each independently selected from hydrogen, halogen, -CN, -OH, -OMe, -OEt, methyl, ethyl, propyl, and -CH2CH2OCH3. In some embodiments, R 10 is each independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3. In some embodiments, R 10 is each independently selected from hydrogen, fluoro, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3.

[0165] R 11 can be any suitable functional group known to those skilled in the art. In some embodiments, R 11 is each independently selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 11 is each independently selected from hydrogen and optionally substituted C 1-2 alkyl. In some embodiments, R 11 is each independently selected from hydrogen, methyl, and ethyl, and methyl and ethyl are optionally substituted with -OMe, -OEt, and -OPr. In some embodiments, R 11 is each independently selected from hydrogen, methyl, and ethyl, and ethyl is optionally substituted with -OMe.

[0166] In some embodiments, the compound is

[0167]

Chemical Structure

[0168] In some embodiments, the compound is

[0169] [Chemical formula] selected from

[0170] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IC)

[0171] [Chemical formula] and wherein R 14 is selected from halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R 15 together form an optionally substituted heterocycle, and R 15 is selected from -S(O)2R 16 -, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0172] In some embodiments, R 2 is an optionally substituted heterocycle.

[0173] In some embodiments, R 2 is selected from optionally substituted cycloalkyl and optionally substituted heterocycle. In some embodiments, R 2 is selected from optionally substituted cycloalkyl. In some embodiments, R 2 is selected from cycloalkyl. In some embodiments,2 is optionally substituted C 3-6 selected from cycloalkyl. In some embodiments, R 2 is optionally substituted C 5-6 selected from cycloalkyl. In some embodiments, R 2 is selected from optionally substituted heterocycloalkyl. In some embodiments, R 2 is selected from heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments, R 2 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2is selected from 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-thia-6-azaspiro[3.4]octane 2,2-dioxide, 4-oxa-7-azaspiro[2.5]octane optionally substituted, 2-azaspiro[4.4]nonane optionally substituted, 2,7-diazaspiro[4.4]nonane optionally substituted, 2-oxa-6-azaspiro[3.5]nonane optionally substituted, 7-oxa-2-azaspiro[3.5]nonane optionally substituted, 2-azaspiro[4.5]decane optionally substituted, 2,8-diazaspiro[4.5]decane optionally substituted, 8-oxa-2-azaspiro[4.5]decane optionally substituted, and 2-oxa-7-azaspiro[4.5]decane optionally substituted. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0174] In some embodiments, R 2 is 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 substituted with an optionally substituted 3- to 6-membered heterocycloalkyl, and R 2a is hydrogen and C 1-6is selected from alkyl. In some embodiments, R 2 is -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 cycloalkyl, oxetane, piperidine, piperazine, or azetidine, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, oxo, and C 1-4 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is halogen, -SO2R 2a -, and -NR 2a -, oxo, and C 1-3 alkyl, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is fluoro, -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 fluoro, -SO2Me, oxo, acetyl, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -CH2OH, -(CH2)2OMe, -OH, -OMe, -CN, -C-CN, and oxetane. In some embodiments, R 2 is fluoro, -SO2Me, oxo, and methyl. In some embodiments, R 2 is -CN, -SO2R 2a -, -NR 2a -, oxo, C 1-3 alkyl, C 1-3Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-3 Alkylene-C 3-6 Substituted with cycloalkyl, oxetane, methylpiperidine, or azetidine, and R 2a is selected from C 1-6 alkyl.

[0175] In some embodiments, R 2 is 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. In some embodiments, R 2 is -CN, -SO2R 2a , -NR 2a , oxo, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 1-3 alkylen-C 3-6 substituted with cycloalkyl, oxetane, or azetidine, and R 2a is selected from C 1-6 alkyl. In some embodiments, R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane.

[0176] In some embodiments, R 2 is

[0177]

Chemical formula

[0178] In some embodiments, R 2 is

[0179]

Chemical formula

[0180] R 3 may be any suitable functional group known to those skilled in the art. In some embodiments, hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0181] R 4 may be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4is 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 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0182] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0183] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0184] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0185] R 14 can be any suitable functional group known to those skilled in the art. In some embodiments, R 14 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14 and R15 combine together to form an optionally substituted complex ring. In some embodiments, R 14 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 14 is selected from fluoro, chloro, bromo, methyl, ethyl, and propyl.

[0186] R 15 can be any suitable functional group known to those skilled in the art. In some embodiments, R 15 is -S(O)2R 16 -, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocyclic ring, and optionally substituted 3- to 6-membered heterocycloalkyl, or R 15 and R 14 combine together to form an optionally substituted complex ring. In some embodiments, R 15 is -S(O)2R 16 -, and optionally substituted C 1-4 alkyl. In some embodiments, R 15 is optionally substituted C 3-6 carbocyclic ring. In some embodiments, R 15 is optionally substituted 3- to 6-membered heterocycloalkyl.

[0187] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (ICC)

[0188]

Chemical formula

[0189] R 3 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 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN. In some embodiments, R 3 is selected from hydrogen and -CN.

[0190] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, an optionally substituted C 1-4 alkyl, an optionally substituted C 3-4 carbon ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4 is selected from hydrogen, -CN, an optionally substituted methyl, an optionally substituted ethyl, an optionally substituted propyl, an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 4 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. R 4 is selected from hydrogen, -CN, and -CHF2.

[0191] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, an optionally substituted C1-4 alkyl, optionally substituted C 3-4 is selected from a carbocycle, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is hydrogen, halogen, -CN, an optionally substituted C 3-4 is selected from a carbocycle, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 5 is hydrogen.

[0192] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6 is hydrogen, halogen, -CN, an optionally substituted C 1-4 alkyl, an optionally substituted C 3-4 is selected from a carbocycle, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 6 is hydrogen, halogen, -CN, an optionally substituted C 3-4 is selected from a carbocycle, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 6 is hydrogen.

[0193] R 7 can be any suitable functional group known to those skilled in the art. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0194] X 1 、X 2 、and X 3 each can be any suitable atom known to those skilled in the art. In some embodiments, X 1 、X 2 、and X 3 each is independently selected from N and CR 13 . In some embodiments, X 1 、X 2 、and X 3 each is independently N. In some embodiments, X 1 、X 2 、and X 3 each is independently selected from CR 13 . In some embodiments, X 1 、X 2 、and X 3 are each CH.

[0195] Z 1 、Z 2 、Z 3 、Z 4 、and Z 5can each independently be any suitable atom known to those skilled in the art. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is 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-, and Z 5 is further selected from a bond. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 10 )2-, -NR 11 -, -N(C(O)R 10 ), -NS(O2)R 11 , -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0196] The variables a, b, c, and d can each 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.

[0197] R 14 can be any suitable functional group known to those skilled in the art. In some embodiments, R 14 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 14is selected from fluoro, chloro, bromo, methyl, ethyl, and propyl.

[0198] R 16 can be any suitable functional group known to those skilled in the art. In some embodiments, R 16 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 16 is optionally substituted C 1-4 alkyl. In some embodiments, R 16 is methyl, ethyl, or propyl. In some embodiments, R 16 is methyl.

[0199] In some embodiments, the compound is

[0200]

Chemical Structure

[0201] In some embodiments, the compound is

[0202]

Chemical Structure

[0203]

Chemical Structure

[0204]

Chemical Structure

[0205]

Chemical Structure

[0206] In some embodiments, the compound is

[0207]

Chem.

[0208] In one aspect, a compound represented by formula (II)

[0209]

Chem.

[0210] The A ring can be any suitable carbocyclic and heterocyclic ring known to those skilled in the art. In some embodiments, A is a ring selected from an optionally substituted C 3-6 carbocycle and an optionally substituted 3- to 12-membered heterocycle. In some embodiments, A is an optionally substituted C 5-6It is selected from a carbon ring and an optionally substituted 5- to 10-membered heterocyclic ring. In some embodiments, A is selected from an optionally substituted C6 carbon ring and an optionally substituted 5- to 10-membered heterocyclic ring. 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, pyrazole, and tetrahydroisoquinoline.

[0211] 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.

[0212] R 1 can be any suitable functional group known to those skilled in the art. R 1 can be any functional group as described earlier herein. In some embodiments, R 1 is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbon ring, and optionally substituted heterocyclic ring. In some embodiments, R 1 is optionally substituted C 1-3 alkyl, and an optionally substituted 5- to 8-membered heterocyclic ring. In some embodiments, R 1 is C 1-3It is selected from alkyl and a substituted 5- to 8-membered heterocyclic ring. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl,

[0213]

Chemical formula

[0214]

Chemical formula

[0215] R 3 can be any suitable functional group known to those skilled in the art. R 3 can be any functional group as described earlier herein. In some embodiments, R 3 is hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN.

[0216] R4 can be any suitable functional group known to those skilled in the art. R 4 can be any functional group as described previously herein. In some embodiments, R 4 is hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4 is hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4 is hydrogen, fluoro, chloro, bromo, -CN, optionally substituted methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 4 is hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 4 is selected from hydrogen, -CN, and -CHF2.

[0217] R 5 can be any suitable functional group known to those skilled in the art. R 5 can be any functional group as described previously herein. In some embodiments, R 5 is hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is hydrogen, halogen, -CN, optionally substituted C 3-4It is selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 5 is hydrogen, fluoro, or -CN. In some embodiments, R 5 is hydrogen.

[0218] R 6 can be any suitable functional group known to those skilled in the art. R 6 can be any functional group as described earlier herein. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, and an optionally substituted C 1-4 alkyl, an optionally substituted C 3-4 carbon ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, halogen, -CN, an optionally substituted C 3-4 carbon ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine. In some embodiments, R 6 is hydrogen, fluoro, or -CN. In some embodiments, R6 is hydrogen.

[0219] R 7 can be any suitable functional group known to those skilled in the art. R 7 can be any functional group as previously described herein. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0220] Y 1 can be any suitable atom known to those skilled in the art. In some embodiments, Y 1 is selected from -N- and -CR 10 -. In some embodiments, Y 1 is -N-. In some embodiments, Y 1 is -CR 10 -. Z 1 Z 2 Z 3 Z 4 and Z 5 can each independently be any suitable atom known to those skilled in the art. Z 1 Z 2 Z 3 Z 4 and Z 5 can be any atom as previously described herein. In some embodiments, Z 1 Z 2 Z 3 Z 4 and Z 5 each independently is 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-, and Z 5is further selected from a bond. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 10 )2-, -NR 11 -, -N(C(O)R 10 ), -NS(O2)R 11 , -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0221] The variables a, b, c, and d can be any suitable numbers known to those skilled in the art. The variables a, b, c, and d can be any numbers as described previously herein. The variables a, b, c, and d can be any suitable numbers 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.

[0222] R 10 can be any suitable functional group known to those skilled in the art. R 10 can be any functional group as described previously herein. In some embodiments, each of R 10 is independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, and optionally substituted C 1-3 alkyl. In some embodiments, each of R 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, -OEt, methyl, ethyl, propyl, and -CH2CH2OCH3. In some embodiments, each of R 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3. In some embodiments, each of R 10are each independently selected from hydrogen, fluoro, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3.

[0223] R 11 can be any suitable functional group known to those skilled in the art. R 11 can be any functional group as described previously herein. In some embodiments, R 11 are each independently selected from hydrogen and optionally substituted C 1-2 alkyl. In some embodiments, R 11 are each independently selected from hydrogen, methyl, and ethyl, where methyl and ethyl are optionally substituted with -OMe, -OEt, and -OPr. In some embodiments, R 11 are each independently selected from hydrogen, methyl, and ethyl, where ethyl is optionally substituted with -OMe.

[0224] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IIA)

[0225]

Chemical formula

[0226] R3 can be any suitable functional group known to those skilled in the art. R 3 can be any functional group as described previously herein. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, fluoro, and -CN.

[0227] R 4 can be any suitable functional group known to those skilled in the art. R 4 can be any functional group as described previously herein. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R4 is selected from hydrogen, fluoro, chloro, bromo, -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. In some embodiments, R 4 is selected from hydrogen, -CN, and -CHF2.

[0228] R 5 can be any suitable functional group known to those skilled in the art. R 5 can be any functional group as described previously herein. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 5 is hydrogen, fluoro, or -CN. In some embodiments, R 5 is hydrogen.

[0229] R 6can be any suitable functional group known to those skilled in the art. R 6 can be any functional group as previously described herein. In some embodiments, R 6 is hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, bromo, -CN, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 6 is hydrogen, fluoro, or -CN. In some embodiments, R 6 is hydrogen.

[0230] R 7 can be any suitable functional group known to those skilled in the art. R 7 can be any functional group as previously described herein. In some embodiments, R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0231] Y 1 can be any suitable atom known to those skilled in the art. In some embodiments, Y 1is selected from -N- and -CR 10 -. In some embodiments, Y 1 is -N-. In some embodiments, Y 1 is -CR 10 -. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 can each independently be any suitable atom known to those skilled in the art. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 can be any atom as described earlier herein. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is 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-, and Z 5 is further selected from a bond. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 10 )2-, -NR 11 (-), -N(C(O)R 10 )-, -NS(O2)R 11 , -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0232] The variables a, b, c, and d can be any suitable numbers known to those skilled in the art. The variables a, b, c, and d can be any numbers as described earlier in this specification. The variables a, b, c, and d can be any suitable numbers 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.

[0233] R 10 can be any suitable functional group known to those skilled in the art. R 10 can be any functional group as described earlier in this specification. In some embodiments, R 10 are each independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, and optionally substituted C 1-3 alkyl. In some embodiments, R 10 are each independently selected from hydrogen, halogen, -CN, -OH, -OMe, -OEt, methyl, ethyl, propyl, and -CH2CH2OCH3. In some embodiments, R 10 are each independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3. In some embodiments, R 10 are each independently selected from hydrogen, fluoro, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3.

[0234] R 11 can be any suitable functional group known to those skilled in the art. R 11 can be any functional group as described earlier in this specification. In some embodiments, R 11 are each independently selected from hydrogen and optionally substituted C 1-2 alkyl. In some embodiments, R 11is independently selected from hydrogen, methyl, and ethyl, and methyl and ethyl are optionally substituted with -OMe, -OEt, and -OPr. In some embodiments, R 11 is independently selected from hydrogen, methyl, and ethyl, and ethyl is optionally substituted with -OMe.

[0235] R 13 can be any suitable functional group known to those skilled in the art. In some embodiments, R 13 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 together form an optionally substituted heterocycle. In some embodiments, R 13 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 13 is selected from optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 is selected from optionally substituted C 3-6 carbocycle. In some embodiments, R 13 is selected from optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 and R 14 together form an optionally substituted heterocycle.

[0236] R 14 can be any suitable functional group known to those skilled in the art. In some embodiments, R 14 is halogen, -CN, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, or R 14and R 13 combines to form an optionally substituted heterocyclic ring. In some embodiments, R 14 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 14 is selected from optionally substituted C 3-6 carbocyclic ring, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 14 and R 13 combine to form an optionally substituted heterocyclic ring.

[0237] In some embodiments, the compound is

[0238]

Chemical formula

[0239] In some embodiments, the compound is

[0240]

Chemical formula

[0241] Embodiment 1 of the present disclosure relates to a compound having the structure of formula (I)

[0242]

Chemical formula

[0243]

Chemical formula

[0244] Embodiment 2 of the present disclosure relates to the compound described in Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, R 1is 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.

[0245] Embodiment 3 of the present disclosure relates to the compound described in Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, where R 1 is

[0246]

Chemical formula

[0247] Embodiment 4 of the present disclosure relates to the compound described in Embodiment 3 or a pharmaceutically acceptable salt or solvate thereof, where A is an optionally substituted C 5-6 carbocyclic ring, and an optionally substituted 5- to 10-membered heterocyclic ring.

[0248] Embodiment 5 of the present disclosure relates to the compound described in Embodiment 4 or a pharmaceutically acceptable salt or solvate thereof, where A is selected from phenyl, pyrazole, and tetrahydroisoquinoline.

[0249] Embodiment 6 of the present disclosure relates to the compound described in any one of Embodiments 3 to 5 or a pharmaceutically acceptable salt or solvate thereof, where m is selected from 0 to 4.

[0250] Embodiment 7 of the present disclosure relates to the compound described in Embodiment 6 or a pharmaceutically acceptable salt or solvate thereof, where m is selected from 0 to 2.

[0251] Embodiment 8 of the present disclosure relates to the compound described in any one of Embodiments 3 to 7 or a pharmaceutically acceptable salt or solvate thereof, and R z is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle.

[0252] Embodiment 9 of the present disclosure relates to the compound described in Embodiment 8 or a pharmaceutically acceptable salt or solvate thereof, and R z is selected from optionally substituted C 1-3 alkyl, and optionally substituted 5- to 8-membered heterocycle.

[0253] Embodiment 10 of the present disclosure relates to the compound described in Embodiment 9 or a pharmaceutically acceptable salt or solvate thereof, and R z is C 1-3 alkyl, and substituted 5- to 8-membered heterocycle.

[0254] Embodiment 11 of the present disclosure relates to the compound described in any one of Embodiments 1 to 10 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is

[0255]

Chemical formula

[0256] Embodiment 12 of the present disclosure relates to a compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt or solvate thereof having one or more structures of the following formula

[0257]

Chemical Formula

[0258] Embodiment 12(a) of the present disclosure relates to a compound described in Embodiment 12 having the structure of formula (IA) or a pharmaceutically acceptable salt or solvate thereof.

[0259] Embodiment 12(b) of the present disclosure relates to a compound described in Embodiment 12 having the structure of formula (IB) or a pharmaceutically acceptable salt or solvate thereof.

[0260] Embodiment 12(c) of the present disclosure relates to a compound described in Embodiment 12 having the structure of formula (IC) or a pharmaceutically acceptable salt or solvate thereof.

[0261] Embodiment 13 of the present disclosure relates to the compound described in any one of Embodiments 12, 12(a), 12(b), or 12(c), or a pharmaceutically acceptable salt or solvate thereof, where R 2 is an optionally substituted heterocyclic ring.

[0262] Embodiment 14 of the present disclosure relates to the compound described in any one of Embodiments 12, 12(a), 12(b), or 12(c), or a pharmaceutically acceptable salt or solvate thereof, where R 2 is 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.

[0263] Embodiment 15 of the present disclosure relates to the compound described in Embodiment 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, where R 2 is -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 cycloalkyl, oxetane, or azetidine, and R 2a is selected from C 1-6 alkyl.

[0264] Embodiment 16 of the present disclosure relates to the compound described in Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having one or more structures of the following formula

[0265] [Chemical formula] wherein in the formula, Y 1 is selected from -N- and -CR 10 -. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 Each of the groups independently represents -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-; Z 5 is further selected from a bond, each of a, b, c, and d is independently selected from 1, 2, 3, and 4; R 8 is halogen, -CN, and optionally substituted C 1-4 alkyl, R 9 is optionally replaced by C 1-4 Alkyl, optionally substituted C 3-6 carbocycle, and 3- to 6-membered heterocycloalkyl; n is selected from 0 to 9, X 1 , X 2 , and X 3 are CH, respectively, R 10 are each independently hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; or two R 10 The substituents taken 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; R 11 each independently represents hydrogen and optionally substituted C 1-4 alkyl, R 16 is optionally replaced by C 1-4Alkyl, optionally substituted C 3-6 Selected from a carbon ring, and an optionally substituted 3- to 6-membered heterocycloalkyl, R 17 is optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Selected from a carbon ring, and an optionally substituted 3- to 6-membered heterocycloalkyl, or R 13 and R 14 together form an optionally substituted heterocyclic ring, and, R 18 is halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Selected from a carbon ring, and an optionally substituted 3- to 6-membered heterocycloalkyl.

[0266] Embodiment 16(a) of the present disclosure relates to a compound described in Embodiment 16 having the structure of formula (IAA) or a pharmaceutically acceptable salt or solvate thereof.

[0267] Embodiment 16(b) of the present disclosure relates to a compound described in Embodiment 16 having the structure of formula (IBB) or a pharmaceutically acceptable salt or solvate thereof.

[0268] Embodiment 16(c) of the present disclosure relates to a compound described in Embodiment 16 having the structure of formula (ICC) or a pharmaceutically acceptable salt or solvate thereof.

[0269] Embodiment 16(d) of the present disclosure relates to a compound described in Embodiment 16 having the structure of formula (IDD) or a pharmaceutically acceptable salt or solvate thereof.

[0270] Embodiment 17 of the present disclosure relates to a compound described in any one of Embodiments 11, 16, 16(a), 16(b), 16(c), or 16(d) or a pharmaceutically acceptable salt or solvate thereof, where Y 1 is -N-.

[0271] Embodiment 18 of the present disclosure relates to a compound described in any one of Embodiments 11, 16, 16(a), 16(b), 16(c), or 16(d), or a pharmaceutically acceptable salt or solvate thereof, where Y 1 is -CR 10 -.

[0272] Embodiment 19 of the present disclosure relates to a compound described in any one of Embodiments 11, 16, 16(a), 16(b), 16(c), or 16(d), or a pharmaceutically acceptable salt or solvate thereof, where Z 1 Z 2 Z 3 Z 4 and Z 5 each independently is selected from -C(R 10 )2-, -NR 11 -, -N(C(O)R 10 )-, -NS(O2)R 11 , -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0273] Embodiment 20 of the present disclosure relates to a compound described in 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, where each of a, b, c, and d independently is selected from 1, 2, and 3.

[0274] Embodiment 21 of the present disclosure relates to a compound described in Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, where each of a, c, and d independently is selected from 1 and 2.

[0275] Embodiment 22 of the present disclosure relates to a compound described in 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, where R 10 each independently is hydrogen, halogen, -CN, -OH, -O-C1-4 Alkyl, optionally substituted C 1-3 Alkyl, and optionally substituted C 3-6 Selected from cycloalkyl.

[0276] Embodiment 23 of the present disclosure relates to the compound described in Embodiment 22 or a pharmaceutically acceptable salt or solvate thereof, where R 10 Are each independently selected from hydrogen, halogen, -CN, -OH, methyl, -OMe, -CH2CH2OCH3, and cyclopropyl.

[0277] Embodiment 24 of the present disclosure relates to the compound described in 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 solvate thereof, where R 11 Are each independently selected from hydrogen and optionally substituted C 1-2 Alkyl.

[0278] Embodiment 25 of the present disclosure relates to the compound described in Embodiment 24 or a pharmaceutically acceptable salt or solvate thereof, where R 11 Are each independently selected from hydrogen, methyl, and ethyl, and ethyl is optionally substituted with -OMe.

[0279] Embodiment 26 of the present disclosure relates to the compound described in Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, where R 1 Is selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole.

[0280] Embodiment 27 of the present disclosure relates to the compound described in Embodiment 26 or a pharmaceutically acceptable salt or solvate thereof, where R 1 Is selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole.

[0281] Embodiment 28 of the present disclosure relates to the compound or a pharmaceutically acceptable salt or solvate thereof described in Embodiment 26 or 27, where R 1 is -SO2R 1a or C 1-3 substituted with alkyl, and R 1a is selected from C 1-6 alkyl.

[0282] Embodiment 29 of the present disclosure relates to the compound or a pharmaceutically acceptable salt or solvate thereof described in any one of Embodiments 1, 2, 26, 27, or 28, where R 2 is selected from an optionally substituted heterocyclic ring and an optionally substituted cycloalkyl.

[0283] Embodiment 30 of the present disclosure relates to the compound or a pharmaceutically acceptable salt or solvate thereof described in Embodiment 29, where R 2 is an optionally substituted heterocycloalkyl.

[0284] Embodiment 31 of the present disclosure relates to the compound or a pharmaceutically acceptable salt or solvate thereof described in Embodiment 30, where R 2 is selected from an optionally substituted 3- to 6-membered heterocycloalkyl.

[0285] Embodiment 32 of the present disclosure relates to the compound or a pharmaceutically acceptable salt or solvate thereof described in Embodiment 31, where R 2 is selected from an optionally substituted azetidine, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazine, and an optionally substituted morpholine.

[0286] Embodiment 33 of the present disclosure relates to the compound or a pharmaceutically acceptable salt or solvate thereof described in any one of Embodiments 29 to 32, where R 2 is halogen, -SO2R 2a , -NR 2a, -C(O)CH3, -CN, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C 3-5 carbocyclic ring, oxo, and optionally substituted C 1-3 substituted with alkyl, R 2a is C 1-6 selected from alkyl.

[0287] Embodiment 34 of the present disclosure relates to the compound described in Embodiment 32 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is substituted with fluoro, -SO2Me, oxo, and methyl.

[0288] Embodiment 35 of the present disclosure relates to the compound described in any one of Embodiments 1 to 10, 12, 12(a), 12(b), 12(c), or 29 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is

[0289]

Chemical formula

[0290]

Chemical formula

[0291] Embodiment 36 of the present disclosure relates to the compound described in Embodiment 35 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is

[0292]

Chemical formula

[0293]

Chemical formula

[0294] Embodiment 37 of the present disclosure relates to the compound described in any one of Embodiments 1 to 10, 12, 12(a), 12(b), or 12(c) or a pharmaceutically acceptable salt solvate thereof, where R 2 is optionally substituted heterocycloalkyl.

[0295] Embodiment 38 of the present disclosure relates to the compound described in any one of Embodiments 1 to 37 or a pharmaceutically acceptable salt or solvate thereof, where R 3 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0296] Embodiment 39 of the present disclosure relates to the compound described in Embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, where R 3 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0297] Embodiment 40 of the present disclosure relates to the compound described in Embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, where R 3 is selected from hydrogen, fluoro, and -CN.

[0298] Embodiment 41 of the present disclosure relates to the compound described in Embodiment 40 or a pharmaceutically acceptable salt or solvate thereof, where R 3 is selected from hydrogen and -CN.

[0299] Embodiment 42 of the present disclosure relates to the compound described in any one of Embodiments 1 to 41 or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0300] Embodiment 43 of the present disclosure relates to the compound described in Embodiment 42, or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen, -CN, -CHF2, -CF3, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0301] Embodiment 44 of the present disclosure relates to the compound described in Embodiment 43, or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen, -CN, and -CHF2.

[0302] Embodiment 45 of the present disclosure relates to the compound described in Embodiments 1 to 44, or a pharmaceutically acceptable salt or solvate thereof, where R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0303] Embodiment 46 of the present disclosure relates to the compound described in Embodiment 45, or a pharmaceutically acceptable salt or solvate thereof, where R 5 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0304] Embodiment 47 of the present disclosure relates to the compound described in Embodiment 46, or a pharmaceutically acceptable salt or solvate thereof, where R 5 is hydrogen.

[0305] Embodiment 48 of the present disclosure relates to the compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt or solvate thereof, where R 6 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0306] Embodiment 49 of the present disclosure relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, where R 6 is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0307] Embodiment 50 of the present disclosure relates to the compound described in Embodiment 49 or a pharmaceutically acceptable salt or solvate thereof, where R 6 is hydrogen.

[0308] Embodiment 51 of the present disclosure relates to the compound described in any one of Embodiments 1 to 50 or a pharmaceutically acceptable salt or solvate thereof, where R 7 is hydrogen.

[0309] Embodiment 52 of the present disclosure relates to the compound described in Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, which is selected from one or more of the compounds in Table 1.

[0310] Embodiment 52(a) of the present disclosure relates to the compound described in Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0311] Embodiment 53 of the present disclosure relates to the compound described in Embodiment 12 or a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0312] Embodiment 53(a) of the present disclosure relates to the compound (IA) described in Embodiment 53 or a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0313] Embodiment 53(b) of the present disclosure relates to the compound (IB) described in Embodiment 53 or a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0314] Embodiment 53(c) of the present disclosure relates to a compound (IC) described in Embodiment 53, a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0315] Embodiment 54 of the present disclosure relates to a compound described in Embodiment 16, a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0316] Embodiment 54(a) of the present disclosure relates to a compound (IAA) described in Embodiment 54, a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0317] Embodiment 54(b) of the present disclosure relates to a compound (IBB) described in Embodiment 54, a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0318] Embodiment 54(c) of the present disclosure relates to a compound (ICC) described in Embodiment 54, a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0319] Embodiment 54(d) of the present disclosure relates to a compound (IDD) described in Embodiment 54, a pharmaceutically acceptable salt or solvate thereof, which is selected from the compounds in Table 1.

[0320] In some embodiments, the compounds disclosed herein are used in various enriched isotope forms, for example, 2 H, 3 H, 11 C, 13 C, and / or 14It is enriched in the contents of C. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures 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 or efficacy, and thus increase the duration of action of the pharmaceutical.

[0321] Unless otherwise specified, the compounds described herein are intended to include only those compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of hydrogen with deuterium or tritium, or substitution of carbon with carbon enriched in 13 C or 14 C, compounds having this structure are within the scope of this disclosure.

[0322] The compounds of the present disclosure optionally contain unnatural ratios of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compound may be labeled with isotopes such as 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 125Isotopic substitution by I is contemplated for all. All variations of isotopes of the compounds of the present invention are included within the scope of the present invention, whether radioactive or not.

[0323] In certain embodiments, the compounds disclosed herein 2 are exchanged with 1 some or all of the H atoms. Methods for the synthesis of compounds containing deuterium are known in the art and include, as a non-limiting example only, the following synthetic methods.

[0324] Deuterium-substituted compounds are synthesized using a variety of methods such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0325] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein for the synthesis of compounds containing deuterium. Many deuterium-containing reagents and building blocks are commercially available from chemical supply companies such as Aldrich Chemical Co.

[0326] The compounds of the present invention include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrides), stereopolymorphs, and amorphous forms of the above compounds, as well as mixtures thereof.

[0327] Salts of the compounds described herein, particularly pharmaceutically acceptable salts, are included in the present disclosure. Compounds of the present disclosure having sufficient acidic, sufficient basic, or both functional groups can react with many inorganic bases, as well as either inorganic or organic acids, to form salts. Alternatively, essentially charged compounds, such as those having a quaternary nitrogen, can form salts with suitable counterions, such as bromide, chloride, or fluoride, particularly halides such as bromide.

[0328] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric forms, enantiomeric forms, and epimeric forms, as well as suitable mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by diastereomer formation and separation 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). Stereoisomers can also be obtained by stereoselective synthesis.

[0329] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of such compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein can exist not only in the unsolvated form but also in solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are likewise considered to be those disclosed herein.

[0330] In certain embodiments, the compound or a salt of the compound can be a prodrug, for example, where a hydroxyl group in the parent compound is presented as an ester or carbonate, or where a carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted to the pharmaceutical agents of the present disclosure under physiological conditions. One way to make a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0331] Prodrug forms of the compounds described herein that produce the compounds as specified herein when metabolized in vivo are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0332] Prodrugs are often useful because, depending on the situation, they may be easier to administer than the parent drug. For example, a prodrug may be bioavailable by oral administration while the parent drug is not. A prodrug may help enhance the cellular permeability of a compound compared to the parent drug. Additionally, a prodrug has improved solubility in a pharmaceutical composition compared to the parent drug. A prodrug may be designed as a reversible drug derivative for use as a modifying factor that enhances the transport of the drug to a site-specific tissue or increases the retention of the drug within cells.

[0333] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical. In some embodiments, the prodrug design increases 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, Vol. 14 of the A.C.S. Symposium Series, and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference for all of the above disclosures). According to another embodiment, the present disclosure provides a method for manufacturing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are successfully synthesized from readily available starting materials.

[0334] Synthetic chemical transformations and methods useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0335] Therapeutic use The methods of administration of the compounds of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or pharmaceutically acceptable salts described herein can be used for the treatment of cancer. In some embodiments, methods for treating solid tumors are disclosed herein. Examples of cancers include, but are not limited to, ovarian cancer, breast cancer, colon cancer, and brain tumors.

[0336] In some embodiments, methods for treating cancer by administration of a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt are disclosed herein. In some embodiments, methods for treating cancer are disclosed herein that include the step of administering to a subject in need thereof a pharmaceutical composition described herein.

[0337] In some embodiments, methods of inhibiting cyclin-dependent kinases (CDKs) in cells by administration of a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt thereof are disclosed herein. In some embodiments, methods of inhibiting cyclin-dependent kinases (CDKs) in cells using any one of the compounds or pharmaceutically acceptable salts of the compounds described herein, or a pharmaceutical composition described herein, are disclosed herein.

[0338] The CDK can be any suitable CDK known to those of skill in the art. In some embodiments, the CDK is selected from CDK2, CDK4, CD6, or any combination thereof. In some embodiments, the CDK is selected from CDK2, CDK4, CDK6, CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6. In some embodiments, the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6. Further embodiments of the therapeutic uses of the present disclosure include the following. Embodiment 56 of the present disclosure relates to a method of treating cancer, comprising administering the pharmaceutical composition described in Embodiment 54 to a subject in need of treatment. Embodiment 57 of the present disclosure relates to the method described in Embodiment 56, wherein the cancer is a solid tumor. Embodiment 58 of the present disclosure relates to the method described in Embodiment 56 or 57, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumor. Embodiment 59 of the present disclosure relates to the method described in Embodiment 58, wherein the cancer is ovarian cancer or breast cancer. Embodiment 60 of the present disclosure relates to a method of inhibiting cyclin-dependent kinases (CDKs) in cells using a compound or pharmaceutically acceptable salt according to any one of Embodiments 1 to

[0399] , or a pharmaceutical composition described in Embodiment 54. Embodiment 61 of the present disclosure relates to the method described in Embodiment 59, wherein the CDK is selected from CDK2, CDK4, CD6, or any combination thereof. Embodiment 62 of the present disclosure relates to the method described in Embodiment 60, and the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6. Embodiment 63 of the present disclosure relates to the method described in Embodiment 62, and the CDK is CDK2 / 4 / 6.

[0339] Pharmaceutical preparation The compositions and methods described herein can be considered useful as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical composition can include at least a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) described herein or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and / or thickening agents. In some embodiments, a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and a pharmaceutically acceptable excipient is disclosed herein. In some embodiments, a pharmaceutical composition comprising a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) described herein or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient is disclosed herein.

[0340] A pharmaceutical composition comprising a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt can be formulated using one or more physiologically acceptable carriers including excipients and adjuvants. The formulation can be modified according to the selected route of administration. A pharmaceutical composition comprising a compound, salt, or conjugate can be produced, for example, by lyophilizing the compound, salt, or conjugate and mixing, dissolving, emulsifying, encapsulating, or enclosing the conjugate. The pharmaceutical composition can also include the compound, salt, or conjugate in free base form or pharmaceutically acceptable salt form.

[0341] A method for formulating a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt may include formulating any of the compound, salt, or conjugate with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. The solid composition may include, for example, powders, tablets, dispersible granules, and capsules, and in some embodiments, the solid composition further contains non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compound, salt, or conjugate may be in lyophilized form or powder form for reconstitution prior to use with a suitable vehicle such as pyrogen-free sterile water.

[0342] A pharmaceutical composition comprising a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt may contain at least one active ingredient (e.g., a compound, salt, or conjugate, and other agents). The active ingredient can be encapsulated, for example, in microcapsules prepared by coacervation techniques or interfacial polymerization (e.g., hydroxy methylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions.

[0343] The composition and formulation can be sterilized. Sterilization can be achieved by filtration through sterile filtration.

[0344] A composition comprising a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt thereof can be formulated for administration as an injection. Non-limiting examples of injectable formulations include sterile suspensions, solutions, or emulsions in an oily or aqueous vehicle. 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 injectable suspensions can contain substances that increase the viscosity of the suspension. The suspension can further contain suitable stabilizers. The injection can be formulated for bolus injection or continuous infusion. Alternatively, the composition can be lyophilized or in powder form for reconstitution with a suitable vehicle, such as pyrogen-free sterile water, before use.

[0345] For parenteral administration, a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt thereof can be formulated in 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, glucose 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 a carrier. The vehicle can contain trace amounts of additives (e.g., buffers and preservatives) such as substances that enhance isotonicity and chemical stability.

[0346] In one embodiment, the present invention relates to methods and compositions of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) formulated 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 the subject through the mucosal layer of the mouth or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to the subject through the mucosal layer of the stomach and / or intestine.

[0347] In one embodiment, the compositions of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) are provided in a modified release dosage form. Suitable vehicles for modified release administration include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiple microparticle devices, and combinations thereof. The composition may further comprise non-release controlling excipients.

[0348] In another embodiment, the compositions of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) are provided in an enteric-coated dosage form. These enteric-coated dosage forms can further comprise 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 can further comprise 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 can further comprise glycerol monostearate 40 - 50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[0349] 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 further contain carnauba wax, crospovidone, diacetyl monoglyceride, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow iron oxide.

[0350] Sustained-release preparations containing a compound or pharmaceutically acceptable salt of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) can also be prepared. Examples of sustained-release preparations can include a semipermeable matrix of a solid hydrophobic polymer that can contain the compound, salt, or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, e.g., LUPRON DEPO™ (i.e., injectable microspheres composed of a lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0351] A pharmaceutical preparation comprising a compound of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) or a pharmaceutically acceptable salt can be prepared for storage by mixing the compound, salt, or conjugate with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. This preparation can be a lyophilized preparation or an aqueous solution. The acceptable carrier, excipient, and / or stabilizer can be non-toxic to the recipient at the dosage and concentration used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphoric acid, citric acid, 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 dextrin, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose, or sorbitol, salt-forming counterions such as sodium, metal complexes, and / or non-ionic surfactants or polyethylene glycol.

[0352] In another embodiment, a composition of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) can further include calcium stearate, crospovidone, hydroxypropylmethylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0353] In another embodiment, a composition of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) is provided in a foaming agent form. These foaming agent forms can also include non-release control excipients.

[0354] In another embodiment, the compositions 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 result in discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 hour to a maximum of 24 hours. The composition can include one or more release control excipients and non-release control excipients, for example, excipients suitable for a breakable semipermeable membrane and suitable as a swelling substance.

[0355] In another embodiment, the compositions of formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) are provided in a dosage form for oral administration to a subject, which comprises one or more pharmaceutically acceptable excipients or carriers encapsulated in an intermediate reactive layer comprising a gastric juice resistant polymeric layered material that is partially neutralized with an alkali and has cation exchange capacity, and a gastric juice resistant outer layer.

[0356] In some embodiments, the compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) provided herein can be in unit dosage forms or multiple dosage forms. As used herein, a 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 the active ingredient sufficient to produce the desired therapeutic effect, together with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include, but are not limited to, ampules, syringes, and individually packaged tablets and capsules. In some embodiments, the unit dosage form can be administered in its fraction or multiple. A multiple dosage form is a plurality of 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, bottles of tablets or capsules, or pints or gallons of bottles. In another embodiment, the multiple dosage form contains different pharmaceutically active agents.

[0357] In some embodiments, the compositions of Formula (I), (IA), (IAA), (IB), (IBB), (IC), (ICC), (II), or (IIA) can further be formulated as modified release dosage forms, including immediate release, delayed release, sustained release, extended release, slow release, pulsed release, controlled release, sustained release, accelerated release, and rapid release, targeted release, programmed release, and as intragastric retention dosage forms. These dosage forms can be prepared according to known methods and techniques (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126. The relevant technical literature is hereby incorporated by reference in its entirety).

[0358] Further embodiments of the pharmaceutical formulations of the present disclosure include the following. Embodiment 55 of the present disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt described in any one of Embodiments 1 to 54 or any lower-level embodiment and a pharmaceutically acceptable excipient.

[0359] Combination therapy Also contemplated herein is combination therapy, e.g., co-administering a disclosed compound and an additional active agent as part of a particular treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. Beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination is typically carried out over a defined period (usually several hours, days, weeks, months, or years, depending on the selected combination). Combination therapy is intended to include administration of multiple therapeutic agents in a sequential manner, i.e., administration of each therapeutic agent at different times, as well as administration of these therapeutic agents or at least two of the therapeutic agents in a substantially simultaneous manner.

[0360] Substantially simultaneous administration is achieved, for example, by administering to the subject a single formulation or composition (e.g., a tablet or capsule having each therapeutic agent in a fixed ratio) or multiple single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is affected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents are administered by the same route or different routes. For example, the first therapeutic agent of a selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all of the therapeutic agents are administered orally or all of the therapeutic agents are administered by intravenous injection.

[0361] The components of the combination are administered to the patient either simultaneously or sequentially. The components are present in the same pharmaceutically acceptable carrier and will thus be understood to be administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers such as conventional oral dosage forms that are administered simultaneously or sequentially.

[0362] Additional embodiments Embodiment 101. Formula (I)

[0363]

Chemical formula

[0364] Embodiment 102. Formula (IA)

[0365]

Chemical formula

[0366] Embodiment 103. R 2 is 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, the compound according to Embodiment 2 or a pharmaceutically acceptable salt or solvate thereof.

[0367] Embodiment 104. R 2 is -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 cycloalkyl, oxetane, or azetidine-substituted, and R 2a is selected from C 1-6 alkyl, the compound according to Embodiment 13 or a pharmaceutically acceptable salt or solvate thereof.

[0368]

[0310] Embodiment 105. R 2 is 6-oxa-3-azabicyclo[3.1.1]heptane, the compound according to Embodiment 13 or a pharmaceutically acceptable salt or solvate thereof.

[0369] Embodiment 106. The compound is

[0370] [Chemical Formula] a compound selected from those described in any one of Embodiments 1 to

[0310] or a pharmaceutically acceptable salt or solvate thereof.

[0371]

[0312] Embodiment 107. The compound is

[0372] [Chemical Formula] a compound selected from those described in any one of Embodiments 1 to

[0310] or a pharmaceutically acceptable salt or solvate thereof.

[0373] Embodiment 108. Formula (IAA)

[0374] [Chemical Formula] has the structure of wherein R 8 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, R 9 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and 3- to 6-membered heterocycloalkyl, n is selected from 0 to 9, Y 1 is selected from -N- and -CR 10 -, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently -C(R 10 )2-, -C(O)-, -NR 11 -, -N(C(O)R 10 )-, -NS(O2)R11 is selected from -O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond, each of a, b, c, and d is independently selected from 1, 2, 3, and 4, R 10 are each independently hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 10 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 10 and R 11 substituents together form an optionally substituted heterocyclic ring, and, R 11 are each independently hydrogen and optionally substituted C 1-4 alkyl, the compound according to embodiment 1 or 2 or a pharmaceutically acceptable salt or solvate thereof.

[0375] Embodiment 109. Y 1 is -N-, the compound according to embodiment

[0312] or a pharmaceutically acceptable salt or solvate thereof.

[0376] Embodiment 110. Y 1 is -CR 10 -, the compound according to embodiment 16 or a pharmaceutically acceptable salt or solvate thereof.

[0377]

[0316] Embodiment 111. 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-, Z5 Also a compound according to embodiment 16 or a pharmaceutically acceptable salt or solvate thereof, which is further selected from the linkages.

[0378]

[0317] Each of embodiments 112.a, b, c, and d is independently a compound according to any one of embodiments 16 to

[0316] or a pharmaceutically acceptable salt or solvate thereof, which is selected from 1, 2, and 3.

[0379]

[0318] Each of embodiments 113.a, c, and d is independently a compound according to embodiment

[0317] or a pharmaceutically acceptable salt or solvate thereof, which is selected from 1 and 2.

[0380]

[0319] Embodiment 114.R 10 Each is independently hydrogen, halogen, -OH, optionally substituted C 1-3 alkyl, and optionally substituted C 3-6 cycloalkyl, which is a compound according to any one of embodiments 16 to

[0318] or a pharmaceutically acceptable salt or solvate thereof.

[0381]

[0320] Embodiment 115.R 10 Each is independently hydrogen, fluoro, -OH, methyl, and cyclopropyl, which is a compound according to embodiment

[0319] or a pharmaceutically acceptable salt or solvate thereof.

[0382]

[0321] Embodiment 116.R 11 Each is independently hydrogen and optionally substituted C 1-2 alkyl, which is a compound according to any one of embodiments 16 to

[0320] or a pharmaceutically acceptable salt or solvate thereof.

[0383] Embodiment 117.R 11Each independently, a compound according to Embodiment

[0321] , or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, methyl, and ethyl, wherein ethyl is optionally substituted with -OMe.

[0384]

[0323] Embodiment 118. The compound is

[0385]

Chemical formula

[0386]

Chemical formula

[0387] Embodiment 119. The compound is

[0388]

Chemical formula

[0389]

Chemical formula

[0323] , or a pharmaceutically acceptable salt or solvate thereof, selected from

[0390]

[0325] Embodiment 120. The compound is

[0391]

Chemical formula

[0323] , or a pharmaceutically acceptable salt or solvate thereof, selected from

[0392]

[0326] Embodiment 121. Formula (IB)

[0393]

Chemical formula

[0394]

[0327] Embodiment 122. R 2 is an optionally substituted heterocycle. The compound according to Embodiment

[0325] or a pharmaceutically acceptable salt or solvate thereof.

[0395]

[0328] Embodiment 123. Formula (IBB)

[0396]

Chemical formula

[0325] or a pharmaceutically acceptable salt or solvate thereof.

[0397]

[0329] Embodiment 124.X 1 , X 2 , and X 3 are each CH, a compound according to Embodiment

[0328] or a pharmaceutically acceptable salt or solvate thereof.

[0398]

[0330] Embodiment 125.Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 10 )2-, -NR 11 -, -N(C(O)R 10 )-, -NS(O2)R 11 , -O-, and -S(O)2-, and Z 5Also a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment

[0328] or

[0329] , further selected from the linkages.

[0399]

[0331] Each of Embodiments 126.a, b, c, and d is independently a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of Embodiments

[0329] to

[0330] , selected from 1 and 2.

[0400]

[0332] Embodiment 127.R 10 Each is independently hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, and optionally substituted C 1-3 alkyl, a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of Embodiments

[0328] to

[0331] .

[0401]

[0333] Embodiment 128.R 10 Each is independently hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3, a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment

[0332] .

[0402]

[0334] Embodiment 129.R 11 Each is independently hydrogen and optionally substituted C 1-2 alkyl, a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of Embodiments

[0328] to

[0333] .

[0403]

[0335] Embodiment 130.R 11 Each is independently selected from hydrogen, methyl, and ethyl, and ethyl is optionally substituted with -OMe, a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment

[0334] .

[0404]

[0336] Embodiment 131. The compound is

[0405]

Chem.

[0328] to

[0335] , selected from

[0406]

[0337] Embodiment 132. The compound is

[0407]

Chem.

[0336] , selected from

[0408]

[0338] Embodiment 133. Formula (IC)

[0409]

Chem.

[0410]

[0339] Embodiment 134. Formula (ICC)

[0411] [Chemical] has the structure of wherein Y 1 is selected from -N- and -CR 10 -, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is 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-, and Z 5 is further selected from a bond, each of a, b, c, and d independently is selected from 1, 2, 3, and 4, R 10 each independently is hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 10 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or the substituents of R 10 and R 11 together form an optionally substituted heterocyclic ring, R 11 each independently is selected from hydrogen and optionally substituted C 1-4 alkyl, and R 16 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocyclic ring, and optionally substituted 3- to 6-membered heterocycloalkyl, a compound according to Embodiment

[0336] or a pharmaceutically acceptable salt or solvate thereof.

[0412]

[0340] Embodiment 135. R1 is the compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole.

[0413]

[0341] Embodiment 136.R 1 is the compound according to Embodiment 26, or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole.

[0414]

[0342] Embodiment 137.R 1 is -SO2R 1a or C 1-3 substituted with alkyl, where R 1a is selected from C 1-6 alkyl, being the compound according to Embodiment 26 or 27, or a pharmaceutically acceptable salt or solvate thereof.

[0415]

[0343] Embodiment 138. The compound is

[0416]

Chemical formula

[0417]

[0344] Embodiment 139.R 2 is selected from optionally substituted heterocyclic ring and optionally substituted cycloalkyl, being the compound according to any one of Embodiments 1, 2,

[0326] , or 26 to 27, or a pharmaceutically acceptable salt or solvate thereof.

[0418]

[0345] Embodiment 140.R 2 is selected from optionally substituted heterocycloalkyl, being the compound according to Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof.

[0419]

[0346] Embodiment 141.R 2 is a compound according to Embodiment 29 or a pharmaceutically acceptable salt or solvate thereof, which is selected from optionally substituted 3- to 6-membered heterocycloalkyls.

[0420]

[0347] Embodiment 142.R 2 is a compound according to Embodiment 30 or a pharmaceutically acceptable salt or solvate thereof, which is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, and optionally substituted morpholine.

[0421]

[0348] Embodiment 143.R 2 is halogen, -SO2R 2a -, -NR 2a -, -C(O)CH3, -CN, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C 3-5 carbocycle, oxo, and optionally substituted C 1-3 alkyl-substituted, where R 2a is selected from C 1-6 alkyl, and is a compound according to any one of Embodiments 29 to 42 or a pharmaceutically acceptable salt or solvate thereof.

[0422]

[0349] Embodiment 144.R 2 is a compound according to Embodiment 32 or a pharmaceutically acceptable salt or solvate thereof, which is substituted with fluoro, -SO2Me, oxo, and methyl.

[0423]

[0350] Embodiment 145.R 2 is

[0424]

Chemical formula

[0425]

[0351] Embodiment 146.R 2 is a compound according to Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, selected from cycloalkyl optionally substituted.

[0426]

[0352] Embodiment 147.R 2 is a compound according to Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, selected from cyclopentane optionally substituted.

[0427]

[0353] Embodiment 148.R 2 is

[0428]

Chemical Structure

[0429]

[0354] Embodiment 149.R 3 is hydrogen, halogen, -CN, C optionally substituted 3-4 carbocyclic ring, and a compound according to any one of Embodiments 1 to

[0310] , 16 to 25,

[0325] to

[0335] , or

[0338] to 33, or a pharmaceutically acceptable salt or solvate thereof, selected from 3- to 4-membered heterocycloalkyl optionally substituted.

[0430]

[0355] Embodiment 150.R 3 is hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, oxetane optionally substituted, and a compound according to Embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, selected from azetidine optionally substituted.

[0431]

[0356] Embodiment 151.R 3 is hydrogen, fluoro, and -CN, a compound according to Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, selected from.

[0432]

[0357] Embodiment 152.R 3 is a compound according to Embodiment 39 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen and -CN.

[0433]

[0358] Embodiment 153.R 4 is selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, and is a compound according to any one of Embodiments 1 to

[0310] , 16 to 25,

[0325] to

[0335] ,

[0338] to 33, or 38 to 40, or a pharmaceutically acceptable salt or solvate thereof.

[0434]

[0359] Embodiment 154.R 4 is selected from hydrogen, -CN, -CHF2, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, and is a compound according to Embodiment 42 or a pharmaceutically acceptable salt or solvate thereof.

[0435]

[0360] Embodiment 155.R 4 is selected from hydrogen, -CN, and -CHF2, and is a compound according to Embodiment 43 or a pharmaceutically acceptable salt or solvate thereof.

[0436]

[0361] Embodiment 156.R 5 is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, and is a compound according to any one of Embodiments 1 to

[0310] , 16 to 25,

[0325] to

[0335] ,

[0338] to 33, or 38 to 43, or a pharmaceutically acceptable salt or solvate thereof.

[0437]

[0362] Embodiment 157.R 5is the compound according to embodiment 44 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0438]

[0363] Embodiment 158.R 5 is hydrogen, the compound according to embodiment 46 or a pharmaceutically acceptable salt or solvate thereof.

[0439]

[0364] Embodiment 159.R 6 is hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, the compound according to any one of embodiments 1 to

[0310] , 16 to 25,

[0325] to

[0335] ,

[0338] to 33, or 38 to 46 or a pharmaceutically acceptable salt or solvate thereof.

[0440]

[0365] Embodiment 160.R 6 is hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, the compound according to embodiment 47 or a pharmaceutically acceptable salt or solvate thereof.

[0441]

[0366] Embodiment 161.R 6 is hydrogen, the compound according to embodiment 48 or a pharmaceutically acceptable salt or solvate thereof.

[0442]

[0367] Embodiment 162.R 7 is hydrogen, the compound according to any one of embodiments 1 to

[0310] , 16 to 25,

[0325] to

[0335] ,

[0338] to 33, or 38 to 49 or a pharmaceutically acceptable salt or solvate thereof.

[0443]

[0368] Embodiment 163. The compound is

[0444]

Chem.

[0445]

Chem.

[0446]

Chem.

[0447]

Chem.

[0448]

[0369] Embodiment 164. The compound is

[0449]

Chem.

[0450]

[0370] Embodiment 165. A compound having the structure of formula (II)

[0451]

Chem.

[0452]

[0371] Embodiment 166.A is a compound according to Embodiment 51 or a pharmaceutically acceptable salt or solvate thereof, which is selected from an optionally substituted C 5-6 carbocyclic ring and an optionally substituted 5- to 10-membered heterocyclic ring.

[0453]

[0372] Embodiment 167.A is a compound according to Embodiment

[0371] or a pharmaceutically acceptable salt or solvate thereof, which is selected from phenyl, pyrazole, and tetrahydroisoquinoline.

[0454]

[0373] Embodiment 168.m is selected from 0 to 4, a compound according to any one of Embodiments 51 to 5 or a pharmaceutically acceptable salt or solvate thereof.

[0455]

[0374] Embodiment 169.m is selected from 0 to 2, a compound according to Embodiment 6 or a pharmaceutically acceptable salt or solvate thereof.

[0456]

[0375] Embodiment 170.R 1 is selected from halogen, -CN, optionally substituted alkyl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring, a compound according to any one of Embodiments 51 to 7 or a pharmaceutically acceptable salt or solvate thereof.

[0457]

[0376] Embodiment 171.R 1 is selected from optionally substituted C 1-3 alkyl and an optionally substituted 5- to 8-membered heterocyclic ring, a compound according to Embodiment 8 or a pharmaceutically acceptable salt or solvate thereof.

[0458]

[0377] Embodiment 172.R 1 is C 1-3 alkyl, and a compound according to Embodiment 9 selected from a substituted 5- to 8-membered heterocyclic ring, or a pharmaceutically acceptable salt or solvate thereof.

[0459]

[0378] Embodiment 173. Formula (IIA)

[0460]

Chemical formula

[0461]

[0379] Embodiment 174.R 3 is hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, a compound according to any one of Embodiments 51 to

[0378] or a pharmaceutically acceptable salt or solvate thereof.

[0462]

[0380] Embodiment 175.R 3is a compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0379] , selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0463]

[0381] Embodiment 176.R 3 is a compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0380] , selected from hydrogen, fluoro, and -CN.

[0464]

[0382] Embodiment 177.R 4 is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 51 to

[0381] , selected from hydrogen, halogen, -CN, optionally substituted C1 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0465]

[0383] Embodiment 178.R 4 is a compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

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

[0466]

[0384] Embodiment 179.R 4 is a compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0383] , selected from hydrogen, -CN, and -CHF2.

[0467]

[0385] Embodiment 180.R 5 is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 51 to

[0384] , selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0468]

[0386] Embodiment 181.R 5 is a compound according to Embodiment

[0385] or a pharmaceutically acceptable salt or solvate thereof, which is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0469]

[0387] Embodiment 182.R 5 is a compound according to Embodiment

[0386] or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

[0470]

[0388] Embodiment 183.R 6 is a compound according to any one of Embodiments 51 to

[0387] or a pharmaceutically acceptable salt or solvate thereof, which is selected from hydrogen, halogen, -CN, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0471]

[0389] Embodiment 184.R 6 is a compound according to Embodiment

[0388] or a pharmaceutically acceptable salt or solvate thereof, which is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0472]

[0390] Embodiment 185.R 6 is a compound according to Embodiment

[0389] or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

[0473]

[0391] Embodiment 186.R 7 is a compound according to any one of Embodiments 51 to

[0390] or a pharmaceutically acceptable salt or solvate thereof, wherein is hydrogen.

[0474]

[0392] Embodiment 187.Z 1 , Z 2 , Z 3 , Z 4, and Z 5 Each of which is independently, -C(R 10 )2-, -NR 11 -, -N(C(O)R 10 )-, -NS(O2)R 11 , -O-, and -S(O)2-; Z 5 is further selected from a bond; a compound according to any one of embodiments 51 to

[0391] or a pharmaceutically acceptable salt or solvate thereof.

[0475]

[0393] Each of embodiments 188.a, b, c, and d is independently selected from 1 and 2; a compound according to any one of embodiments 51 to

[0392] or a pharmaceutically acceptable salt or solvate thereof.

[0476]

[0394] In embodiment 189, R 10 is independently selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, and optionally substituted C 1-3 alkyl; a compound according to any one of embodiments 51 to

[0393] or a pharmaceutically acceptable salt or solvate thereof.

[0477]

[0395] In embodiment 190, R 10 is independently selected from hydrogen, halogen, -CN, -OH, -OMe, methyl, and -CH2CH2OCH3; a compound according to

[0394] or a pharmaceutically acceptable salt or solvate thereof.

[0478]

[0396] In embodiment 191, R 11 is independently selected from hydrogen and optionally substituted C 1-2 alkyl; a compound according to any one of embodiments 51 to

[0395] or a pharmaceutically acceptable salt or solvate thereof.

[0479]

[0397] In embodiment 192, R 11Each independently selected from hydrogen, methyl, and ethyl, wherein ethyl is optionally substituted with -OMe, a compound according to embodiment

[0396] or a pharmaceutically acceptable salt or solvate thereof.

[0480]

[0398] Embodiment 193. The compound is

[0481]

Chemical formula

[0397] or a pharmaceutically acceptable salt or solvate thereof.

[0482]

[0399] Embodiment 194. The compound is

[0483]

Chemical formula

[0398] or a pharmaceutically acceptable salt or solvate thereof.

[0484]

[0400] Embodiment 195. A pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to

[0399] and a pharmaceutically acceptable excipient.

[0485]

[0401] Embodiment 196. A method for treating cancer, comprising the step of administering the pharmaceutical composition according to embodiment 54 to a subject in need of treatment.

[0486]

[0402] Embodiment 197. The method according to embodiment 196, wherein the cancer is a solid tumor.

[0487]

[0403] Embodiment 198. The method according to embodiment 196 or 197, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumor.

[0488]

[0404] Embodiment 199. The method according to embodiment 198, wherein the cancer is ovarian cancer or breast cancer.

[0489]

[0405] Method for inhibiting cyclin-dependent kinase (CDK) in cells using the compound or salt according to any one of Embodiments 1 to

[0399] , or the pharmaceutical composition according to Embodiment 54.

[0490]

[0406] Embodiment 201. The method according to Embodiment 59, wherein the CDK is selected from CDK2, CDK4, CD6, or any combination thereof.

[0491]

[0407] Embodiment 202. The method according to Embodiment 60, wherein the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6.

[0492]

[0408] Embodiment 203. The method according to Embodiment 202, wherein the CDK is CDK2 / 4 / 6.

Examples

[0493] Although the present invention has been outlined above, it will be more readily understood by reference to the following examples. These examples are included for the sole purpose of exemplifying specific aspects and embodiments of the present invention and are in no way intended to limit the present invention.

[0494] The following synthetic schemes are provided for illustrative purposes only and are not limiting. The following examples illustrate various methods for preparing the compounds described herein. It is understood that those skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art will be able to prepare them in a manner similar to that described below by using appropriate starting materials and modifying the synthetic routes as necessary. Generally, the starting materials and reagents can be obtained from commercial vendors, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0495] General synthetic schemes 1 - 4

[0496]

Chem.

[0497] Intermediate Intermediate 1: 8 - Bromo - N-(1-(methylsulfonyl)piperidin - 4 - yl)quinazolin - 2 - amine

[0498] Reaction scheme

[0499]

Chem.

[0500] Detailed procedure Step 1: 8 - Bromo - N-(1-(methylsulfonyl)piperidin - 4 - yl)quinazolin - 2 - amine

[0501]

Chem.

[0502] 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 h, diluted with water (1000 mL), and extracted with ethyl acetate (3 × 1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate) to give 8 - bromo - N-(1-(methylsulfonyl)piperidin - 4 - yl)quinazolin - 2 - amine (5.04 g, 13.09 mmol, yield 15.9%). LCMS(ESI) m / z = 385 [M + H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.04 (d, J = 7.6 Hz, 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).

[0503] 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

[0504] Reaction Scheme

[0505]

Chem.

[0506] Detailed Procedure Step 1: Tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0507]

Chem.

[0508] 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 layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by trituration with 100 mL of 1:5 EA / PE to give the desired product tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield). LCMS (ESI) m / z = 321.1 [M+H] + .

[0509] Step 2: Tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0510]

Chemical Structure

[0511] Pd / C (10% on carbon, 200 mg) was added to a mixture of tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1 g, 3.12 mmol) in EtOH (25 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (800 mg, 83.8% yield). LCMS (ESI-MS) m / z = 291.2 [M+H] + .

[0512] Step 3: Tert-butyl 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0513]

Chemical formula

[0514] A mixture of tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4.7 g, 16.2 mmol) and 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 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (EA / PE, 7:3) to afford the desired product tert-butyl 6-(6-formamidopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (5.2 g, yield 95.8%). LCMS (ESI-MS) m / z = 319.2 [M+H] + .

[0515] Step 4: Tert-butyl 6-(6-((8-bromoquinazolin-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0516]

Chemical formula

[0517] 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 h, and 8-bromo-2-(methylsulfonyl)quinazoline (0.99 g, 3.45 mmol) was added. The resulting mixture was warmed to room temperature and stirred for an additional 1 h. The reaction mixture was quenched by the addition of water (100 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by trituration with DCM (40 mL) to give 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, yield 46.1%). LCMS (ESI-MS) m / z = 497.2 [M+H] + .

[0518] Step 5: N-(5-(2,6-Diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-8-bromoquinazolin-2-amine

[0519]

Chemical Structure

[0520] TFA (3 mL) was added to a stirred mixture of tert-butyl 6-(6-((8-bromoquinazolin-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (800 mg, 1.60 mmol) in DCM (9 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give crude N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-8-bromoquinazolin-2-amine (1 g). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 397.1 [M+H] + .

[0521] 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

[0522]

Chem.

[0523] To a solution of N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-8-bromokynazoline-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 then 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 1:10) to give the desired product 8-bromo-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)kynazoline-2-amine (200 mg, yield 15.3%). LCMS (ESI) m / z = 425.1 [M+H] + .

[0524] Intermediate 3: N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)formamide

[0525] Reaction Scheme

[0526] [Chemical]

[0527] Detailed procedure Step 1: tert-Butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0528] [Chemical]

[0529] 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 h. 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 give the 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, yield 83.7%).

[0530] LCMS(ESI) m / z = 321 [M+H] + .

[0531] Step 2: 2-(6-Nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0532] [Chemical]

[0533] To a stirred mixture of tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 21.16 mmol) in dichloromethane (80 mL) was added trifluoroacetic acid (16 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL) and concentrated again under vacuum to afford crude 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g). The crude product was used in the next step without further purification.

[0534] LCMS(ESI) m / z = 221 [M+H] + .

[0535] Step 3: 2-Ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0536]

Chemical formula

[0537] 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 min, then acetaldehyde (4.16 g, 94.5 mmol), acetic acid (0.23 mL, 4.08 mmol), and sodium cyanoborohydride (2.51 g, 39.8 mmol) were added. The resulting mixture was stirred at room temperature for 3 h 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 afford the crude product. The residue was purified by trituration with dichloromethane (100 mL) to give 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, yield 58.9%).

[0538] LCMS(ESI) m / z = 249 [M+H] + .

[0539] Step 4: 5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine

[0540]

Chem.

[0541] A solution of 2-Ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 16.11 mmol), ammonium chloride (4.31 g, 80.55 mmol), and iron powder (9.00 g, 161.100 mmol) in ethanol (60 mL) and water (20 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 obtain the crude product. The residue was purified by reverse-phase flash chromatography (C18 silica gel, gradient of acetonitrile / water (containing 10 mmol / L NH4HCO3)) to obtain 5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine (2 g, yield 56.6%).

[0542] LCMS(ESI) m / z = 219 [M+H] + .

[0543] Step 5: N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)formamide

[0544]

Chem.

[0545] A solution of acetic anhydride (2 mL) in formic acid (4 mL) was stirred at room temperature for 1 hour, and then 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine (400 mg, 1.83 mmol) was added portionwise 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 (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative reverse-phase HPLC (gradient of acetonitrile / water (containing 10 mM NH4HCO3 and 0.1% NH3·H2O)) to give the title compound (70 mg, yield 15.3%).

[0546] LCMS(ESI) m / z = 247 [M+H] + .

[0547] Intermediate 4: 8-Bromo-7-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0548] Reaction Scheme

[0549]

Chemical Structure

[0550] Detailed Procedure Step 1: 8-Bromo-7-fluoroquinazolin-2-amine

[0551]

Chemical Structure

[0552] 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 layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (EA / PE, 2:1) to obtain the desired product 8-bromo-7-fluoroquinazolin-2-amine (800 mg, yield 14.6%). LCMS (ESI-MS) m / z = 242.0 [M+H] + .

[0553] Step 2: 8-Bromo-2-chloro-7-fluoroquinazoline

[0554]

Chem.

[0555] A mixture of tert-butyl nitrite (511 mg, 4.95 mmol) and copper(I) chloride (490 mg, 4.95 mmol) in acetonitrile (10 mL) was stirred at 60 °C for 1 hour. 8-Bromo-7-fluoroquinazolin-2-amine (800 mg, 3.30 mmol) was added portionwise at room temperature over 1 minute. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA, 1:1) to obtain 8-bromo-2-chloro-7-fluoroquinazoline (300 mg, yield 34.7%). LCMS (ESI-MS) m / z = 261.0 [M+H] + .

[0556] Step 3: 8-Bromo-7-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0557]

Chem.

[0558] 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 at 65 °C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate) to give the desired product 8-bromo-7-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (120 mg, yield 25.8%). LCMS (ESI-MS) m / z = 403.1 [M+H] + .

[0559] Intermediate 5: 8-Bromo-2-chloro-6-(difluoromethyl)quinazoline

[0560] Reaction Scheme

[0561]

Chem.

[0562] Detailed Procedure Step 1: 2-Bromo-4-(difluoromethyl)-1-fluorobenzene

[0563]

Chem.

[0564] 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) at 0 °C. The resulting mixture was stirred at 40 °C overnight and quenched by adding saturated aqueous NaHCO3 solution (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 obtain crude 2-bromo-4-(difluoromethyl)-1-fluorobenzene (32.2 g, yield 96.8%). LCMS (ESI-MS) m / z = 225.0 [M+H] + .

[0565] Step 2: 3-Bromo-5-(difluoromethyl)-2-fluorobenzaldehyde

[0566]

Chem.

[0567] To a cooled mixture of 2-bromo-4-(difluoromethyl)-1-fluorobenzene (10 g, 44.4 mmol) in 100 mL of THF at -78 °C, LDA (2 M in THF, 24.4 mL, 48.8 mmol) was added dropwise under a nitrogen atmosphere. The mixture was stirred at -78 °C for 0.5 h. DMF (3.89 g, 53.3 mmol) was added dropwise, and the resulting mixture was stirred at -78 °C for an additional 1 h. The reaction mixture was slowly poured into 200 mL of saturated aqueous NH4Cl solution at 0 °C and stirred for 1 h. 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 obtain crude 3-bromo-5-(difluoromethyl)-2-fluorobenzaldehyde (15 g). The crude product was used in the next step without further purification.

[0568] Step 3: 8-Bromo-6-(difluoromethyl)quinazolin-2-amine

[0569]

Chem.

[0570] 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 give 8-bromo-6-(difluoromethyl)quinazolin-2-amine (0.9 g, yield 5.54%). LCMS (ESI-MS) m / z = 274.0 [M+H] + .

[0571] Step 4: 8-Bromo-2-chloro-6-(difluoromethyl)quinazoline

[0572]

Chemical formula

[0573] Tert-butyl nitrite (3.9 mL) was added to a mixture of 8-bromo-6-(difluoromethyl)quinazolin-2-amine (3 g, 10.94 mmol), TBA-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 give 8-bromo-2-chloro-6-(difluoromethyl)quinazoline (1.03 g, yield 31.9%). 11H NMR (400 MHz, DMSO-d6) δ 9.79 - 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] + .

[0574] Intermediate 6: 8-Bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine

[0575] Reaction Scheme

[0576]

Chem.

[0577] Detailed Procedure Step 1: 2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde

[0578]

Chem.

[0579] A solution of n-BuLi (2.5 M in hexane, 52.6 mL, 131.5 mmol) was added to a stirred mixture of 2,6-dibromo-4-(trifluoromethyl)aniline (20 g, 62.7 mmol) in THF (250 mL) at -78 °C under a nitrogen atmosphere. A solution of DMF (6.42 g, 87.8 mmol) in THF (10 mL) was added slowly, and the resulting mixture was stirred at -78 °C for 3 h, quenched by the addition of 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 give crude 2-amino-3-bromo-5-(trifluoromethyl)benzaldehyde (10.2 g, yield 60.7%). LCMS (ESI-MS) m / z = 268.1 [M+H] + .

[0580] Step 2: 8-Bromo-6-(trifluoromethyl)quinazolin-2(1H)-one

[0581]

Chem.

[0582] 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 h. 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 recovered solid was dried under high vacuum to give crude 8-bromo-6-(trifluoromethyl)quinazolin-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] + .

[0583] Step 3: 8-Bromo-2-chloro-6-(trifluoromethyl)quinazoline

[0584]

Chem.

[0585] POCl3 (60 mL, 643 mmol) was added to a mixture of 8-bromo-6-(trifluoromethyl)quinazolin-2(1H)-one (7.3 g, 24.9 mmol) in toluene (60 mL). The resulting mixture was stirred at 110 °C for 2 h and concentrated under reduced pressure. The residue was quenched slowly by adding saturated aqueous NaHCO3 at 0 °C until no more gas evolution was observed. The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 1:20) to give 8-bromo-2-chloro-6-(trifluoromethyl)quinazoline (1.06 g, yield 13.6%). 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H). LCMS (ESI-MS) m / z = 312.7 [M + H] + .

[0586] Intermediate 7: 2-Methylisoindolin-5-amine

[0587]

Chemical Structure

[0588] A solution of LiAlH4 (2 M in THF, 4.25 mL, 8.50 mmol) was added to 5-amino-2-methylisoindoline-1,3-dione (500 mg, 2.83 mmol) in THF (10 mL) at 0 °C. The reaction mixture was heated to 70 °C and stirred for 1 h. After cooling to 0 °C, the reaction was quenched by the addition of ethanol and water. The resulting slurry was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give crude 2-methylisoindolin-5-amine (300 mg). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 149.1 [M + H] + .

[0589] Intermediate 8: 8-Bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine

[0590]

Chem.

[0591] 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 give 8-bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine (180 mg, yield 26.3%). LCMS (ESI-MS) m / z = 405.0 [M+H] + .

[0592] Intermediate 9: 1-(1-Methylazetidin-3-yl)-1H-pyrazol-4-amine

[0593] Reaction Scheme

[0594]

Chem.

[0595] Detailed Procedure Step 1: 1-(1-Methylazetidin-3-yl)-4-nitro-1H-pyrazole - (1-Methylazetidin-3-yl)-1H-pyrazol-4-amine

[0596]

Chem.

[0597] A solution of 1-(azetidin-3-yl)-4-nitro-1H-pyrazole (2 g, 7.08 mmol) and HCHO (319 mg, 10.6 mmol) in MeOH (30 mL) was stirred at room temperature for 2 h. NaBH3CN (891 mg, 14.2 mmol) was added. The resulting mixture was stirred at room temperature overnight, filtered, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 10:90) to obtain 1-(1-methylazetidin-3-yl)-4-nitro-1H-pyrazole (500 mg, yield 33.3%). LCMS (ESI-MS) m / z = 183.1 [M+H] + .

[0598] Step 2: 1-(1-Methylazetidin-3-yl)-1H-pyrazol-4-amine

[0599]

Chemical formula

[0600] Pd / C (10% on carbon, 99.3 mg) was added to a solution of 1-(1-methylazetidin-3-yl)-4-nitro-1H-pyrazole (680 mg, 3.73 mmol) in MeOH (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h under a hydrogen atmosphere, filtered, and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to obtain the crude title product (700 mg). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 153.1 [M+H] + .

[0601] Intermediate 10: 1-(5-Cyclopropylpyrimidin-2-yl)piperidin-4-amine

[0602] Reaction scheme

[0603] [Chemistry]

[0604] Detailed procedure Step 1: Tert-butyl (1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl)carbamate

[0605] [Chemistry]

[0606] 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 at 70 °C overnight, diluted with water (30 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (EA / PE, 0:100~20:80) to give the desired product tert-butyl N-[1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl]carbamate (1.5 g, yield 70.3%). LCMS (ESI-MS) m / z = 319.2 [M+H] + .

[0607] Step 2: 1-(5-Cyclopropylpyrimidin-2-yl)piperidin-4-amine

[0608] [Chemistry]

[0609] TFA (3 mL) was added to a stirred mixture of tert-butyl N-[1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl]carbamate (1.5 g, 4.71 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under high vacuum to give crude 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-amine (1.5 g crude). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 219.1 [M+H] + .

[0610] Intermediate 11: 1-(7-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine

[0611] Reaction Scheme

[0612]

Chem.

[0613] Detailed Procedure Step 1: 2-Chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine

[0614]

Chem.

[0615] 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, 0:100~20:80) to give the desired product 2-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, yield 59.4%). LCMS (ESI-MS) m / z = 194.0 [M+H] + .

[0616] Step 2: Tert-butyl (1-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate

[0617]

Chemical Structure

[0618] 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 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, 0:100~20:80) to give the desired product tert-butyl (1-(7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-yl)carbamate (1.5 g, yield 58.0%). LCMS (ESI-MS) m / z = 358.2 [M+H] + .

[0619] Step 3: 1-(7-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperidin-4-amine

[0620]

Chem.

[0621] 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 give 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. LCMS (ESI-MS) m / z = 258.2 [M+H] + .

[0622] Intermediate 12: 2-(2-Methoxyethyl)-2,6-diazaspiro[3.3]heptane

[0623] Reaction Scheme

[0624]

Chem.

[0625] Detailed Procedure Step 1: Tert-butyl 6-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0626]

Chem.

[0627] 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 the addition of 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 afford 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] + .

[0628] Step 2: 2-(2-Methoxyethyl)-2,6-diazaspiro[3.3]heptane

[0629]

Chemical Structure

[0630] 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 h and concentrated under high vacuum to afford 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] + .

[0631] Intermediate 13: 1-((1-Methylcyclopropyl)sulfonyl)piperidin-4-amine

[0632] Reaction Scheme

[0633]

Chemical Structure

[0634] Detailed procedure Step 1: Tert-butyl (1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)carbamate

[0635]

Chem.

[0636] 1-Methylcyclopropane-1-sulfonyl chloride (463 mg, 2.99 mmol) was added dropwise to a solution of tert-butyl piperidin-4-ylcarbamate (400 mg, 1.99 mmol) and DIEA (774 mg, 5.99 mmol) in DCM (10 mL) cooled to 0 °C. The resulting mixture was stirred at room temperature for 1 hour, diluted with water (10 mL), and extracted with DCM (3 × 250 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, 1:5) to give tert-butyl (1-((1-methylcyclopropyl)sulfonyl)piperidin-4-yl)carbamate (580 mg, yield 82.1%). LCMS (ESI-MS) m / z = 263.2 [M+H-56] + .

[0637] Step 2: 1-((1-Methylcyclopropyl)sulfonyl)piperidin-4-amine

[0638]

Chem.

[0639] 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 h and concentrated under reduced pressure to afford the TFA salt of 1-((1-methylcyclopropyl)sulfonyl)piperidin-4-amine (255 mg, 74.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 3H), 3.69 (d, J = 12.5 Hz, 2H), 3.20 (s, 1H), 3.07 - 2.94 (m, 2H), 1.95 (d, J = 12.4 Hz, 2H), 1.55 - 1.43 (m, 2H), 1.39 (s, 3H), 1.18 - 1.11 (m, 1H), 0.86 - 0.73 (m, 3H). LCMS (ESI-MS) m / z = 219.1 [M+H] + .

[0640] Intermediate 14: 1-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate

[0641] Reaction Scheme

[0642]

Chemical Structure

[0643] Detailed Procedure Step 1: Tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate

[0644]

Chemical Structure

[0645] 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 the addition of water (20 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM, 0:100~5:95) to obtain tert-butyl (1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidin-4-yl)carbamate (2.2 g, yield 64.1%). LCMS (ESI-MS) m / z = 367.1 [M+Na+H] + .

[0646] Step 2: 1-((1-Methyl-1H-pyrazole-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate

[0647]

Chemical Structure

[0648] TFA (5 mL) was added to a stirred mixture of tert-butyl (1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidin-4-yl)carbamate (2 g, 5.80 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 0:100~18:82) to obtain 1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidin-4-amine 2,2,2-trifluoroacetate (250.7 mg, yield 11.6%). 11H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.21 (s, 3H), 3.89 (s, 3H), 3.61 - 3.48 (m, 2H), 3.13 - 3.00 (m, 1H), 2.42 - 2.25 (m, 2H), 2.07 - 1.89 (m, 2H), 1.67 - 1.50 (m, 2H). LCMS (ESI-MS) m / z = 245.0 [M+H] + .

[0649] Intermediate 15: 1-(Cyclopropylsulfonyl)piperidin-4-amine

[0650] Reaction Scheme

[0651]

Chemical Structure

[0652] Detailed Procedure Step 1: Tert-butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate

[0653]

Chemical Structure

[0654] 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 tert-butyl N-(piperidin-4-yl)carbamate (10 g, 49.93 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (500 mL). The aqueous solution was extracted with CH2Cl2 (3 × 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EA (100 mL) to give tert-butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, yield 59.2%). LCMS (ESI-MS) m / z = 249.1 [M+H - 56]+ .

[0655] Step 2: 1-(Cyclopropylsulfonyl)piperidin-4-amine

[0656]

Chem.

[0657] 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 h. The resulting mixture was concentrated under reduced pressure to give 1-(cyclopropylsulfonyl)piperidin-4-amine (8 g). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 205.1 [M+H] + .

[0658] Intermediate 16: Tert-butyl 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate

[0659] Reaction Scheme

[0660]

Chem.

[0661] Detailed Procedure Step 1: 2-((3-(Benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0662]

Chem.

[0663] A solution of 2,2,6,6-tetramethylpiperidine (9.62 g, 68.09 mmol) in dry THF (100 mL) cooled to -30 °C was added dropwise with n-BuLi (2.5 M, 27.2 mL) under a N2 atmosphere. The mixture was stirred at -30 °C for 0.5 h. Then, the reaction was cooled to -78 °C, and a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (15.21 g, 56.74 mmol) in 50 mL of dry THF was added dropwise. The reaction mixture was stirred at -78 °C for 0.5 h, and a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.74 mmol) in 50 mL of dry THF was added dropwise. Thereafter, the reaction mixture was warmed to 20 °C and stirred for an additional 12 h. The reaction mixture was slowly poured into 20 mL of saturated aqueous NH4Cl at 0 °C, stirred for 1 h, then 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 obtain crude 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.7 g), which was used without further purification. LCMS (ESI-MS) m / z = 301.1 [M+H] + .

[0664] Step 2: 6-Benzyl-2-(benzyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-azaspiro[3.4]octane

[0665]

Chemical Structure

[0666] A solution of 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.7 g crude) in DMSO (200 mL), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (13.00 g, 54.76 mmol), and LiF (3.55 g, 136.90 mmol) was stirred at 110 °C for 1 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (1000 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 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. LCMS (ESI-MS) m / z = 434.2 [M+H] + .

[0667] Step 3: 6-Benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol

[0668]

Chemical Structure

[0669] 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 h. 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 give 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol (10 g, 67.0%) as a colorless oil. LCMS (ESI-MS) m / z = 324.1 [M+H] + .

[0670] Step 4: 6-Benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one

[0671]

Chemical Structure

[0672] A solution of oxalyl chloride (7.85 g, 61.8 mmol) in DCM (100 mL) cooled to -78 °C was added dropwise with a solution of DMSO (4.83 g, 61.8 mmol) in DCM (20 mL) under a nitrogen atmosphere. The mixture was stirred at -78 °C for 20 minutes. Then, a solution of 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-ol (10 g, 30.9 mmol) in DCM (20 mL) was 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 layers were 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 - 10%). Fractions with the desired mass signal were combined and concentrated under reduced pressure to obtain 6-benzyl-2-(benzyloxy)-6-azaspiro[3.4]octan-8-one (5.8 g, yield 58.4%). LCMS (ESI-MS) m / z = 322.2 [M+H] + .

[0673] Step 5: 6-Benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane

[0674]

Chemical formula

[0675] 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% - 10%). Fractions with the desired mass signal were combined and concentrated under reduced pressure to obtain 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane (1.2 g, yield 19.4%). LCMS (ESI-MS) m / z = 344.2 [M+H] + .

[0676] Step 6: Tert-butyl 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate

[0677]

Chem.

[0678] Pd(OH)2 / C (0.49 g, 3.49 mmol) was added to a solution of 6-benzyl-2-(benzyloxy)-8,8-difluoro-6-azaspiro[3.4]octane (1.2 g, 3.49 mmol), Boc2O (0.92 g, 4.19 mmol), and Et3N (1.06 g, 10.48 mmol) in MeOH (120 mL). The resulting mixture was stirred at room temperature for 5 days under a H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH in DCM, 0% - 5%). The fractions having the desired mass signal were combined, concentrated under reduced pressure, and lyophilized to give tert-butyl 8,8-difluoro-2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (500 mg, yield 54.4%). 1 1H NMR (400 MHz, DMSO-d6) δ 5.3 - 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).

[0679] Intermediate 17: 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-1-ol

[0680] Reaction Scheme

[0681] [Chemical formula]

[0682] Detailed procedure Step 1: (3-(Benzyloxy)cyclobutane-1,1-diyl)dimethanol

[0683] [Chemical formula]

[0684] A solution of LiAlH4 in THF (2 M, 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) at 0 °C. The resulting mixture was stirred at room temperature for 3 h, carefully 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 give 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. LCMS (ESI-MS) m / z = 223.3 [M+H] + .

[0685] Step 2: (3-(Benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol

[0686] [Chemical formula]

[0687] 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) cooled to 0 °C in THF (40 mL). The resulting suspension was stirred at 0 °C for 1 h, and TBDPSCl (3.96 g, 14.3 mmol) was added slowly. 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 give 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. LCMS (ESI-MS) m / z = 461.4 [M+H] + .

[0688] Step 3: 3-(Benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarbaldehyde

[0689]

Chem.

[0690] Des-Martin periodinane (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 under a nitrogen atmosphere. After stirring at 0 °C for 2 h, the reaction was warmed to room temperature and stirred for 4 h. 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 give 3-(benzyloxy)-1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbaldehyde (1.8 g, yield 60.2%). LCMS(ESI-MS) m / z = 459.2 [M+H] + .

[0691] Step 4: ((3-(Benzyloxy)-1-(difluoromethyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane

[0692]

Chemical formula

[0693] 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 h, 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 give ((3-(benzyloxy)-1-(difluoromethyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane (1 g, yield 53.0%). LCMS(ESI-MS) m / z = 481.4 [M+H] + .

[0694] Step 5: 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-1-ol

[0695]

Chem.

[0696] Pd / C (10% on carbon, 1.11 g) was added to a mixture of (3-(benzyloxy)-1-(difluoromethyl)cyclobutyl)methoxy)(tert-butyl)diphenylsilane (1 g, 2.08 mmol) in MeOH (15 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-1-ol (100 mg, yield 12.3%). LCMS (ESI-MS) m / z = 391.2 [M+H] + .

[0697] Intermediate 18: racemic (3R,4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol

[0698] Reaction Scheme

[0699]

Chem.

[0700] Step 1: racemic tert-butyl (3R,4R)-4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1-carboxylate

[0701]

Chem.

[0702] A solution of CbzCl (50% in toluene, 946 mg, 2.77 mmol) was added dropwise to a mixture of racemic tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (500 mg, 2.31 mmol) in DCM (3.8 mL) and saturated aqueous Na2CO3 solution (3.8 mL) 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 preparative TLC (EA / PE, 2:1) to give racemic tert-butyl (3R,4R)-4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1-carboxylate (800 mg, yield 98.7%). LCMS (ESI-MS) m / z = 351.2 [M+H] + .

[0703] Step 2: Racemic benzyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate

[0704]

Chemical Structure

[0705] A solution of racemic tert-butyl (3R,4R)-4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-1-carboxylate (750 mg, 2.14 mmol) was added to a solution of 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. LCMS (ESI-MS) m / z = 251.2 [M+H] + .

[0706] Step 3: Racemic benzyl ((3R,4R)-3-hydroxy-1-(methylsulfonyl)piperidin-4-yl)carbamate

[0707] [Chemistry]

[0708] Methanesulfonyl chloride (549 mg, 4.79 mmol) was added to a stirred mixture of crude racemic benzyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (750 mg, 2.99 mmol) and NaHCO3 (420 mg, 5 mmol) in EA (4.5 mL) at 0 °C. The resulting mixture was stirred for 1 h, quenched by the addition of 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 preparative TLC (EA) to give racemic benzyl ((3R,4R)-3-hydroxy-1-(methylsulfonyl)piperidin-4-yl)carbamate (500 mg, 50.8% yield). LCMS (ESI-MS) m / z = 329.1 [M+H] + .

[0709] Step 4: Racemic (3R,4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol

[0710] [Chemistry]

[0711] Pd / C (10% on carbon, 25 mg) was added to a mixture of racemic benzyl ((3R,4R)-3-hydroxy-1-(methylsulfonyl)piperidin-4-yl)carbamate (100 mg, 0.30 mmol) in MeOH (5 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a hydrogen atmosphere and then filtered. The filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give crude racemic (3R,4R)-4-amino-1-(methylsulfonyl)piperidin-3-ol (75.6 mg). The crude product was used in the next step without further purification. LCMS (ESI-MS) m / z = 195.1 [M+H] + .

[0712] Example 31: N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0713]

Chemical Structure

[0714] Step 1: tert-Butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[0715]

Chemical Structure

[0716] 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 Cl (10.18 mg, 0.01 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. H2O (0.1 mL) was added to the mixture, and the residue was purified by preparative reverse-phase HPLC to give the title compound (50 mg, 38% yield) as a yellow solid. LCMS (ESI) [M+H] + =517.1

[0717] Step 2: N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0718]

Chemical Structure

[0719] To a mixture of tert-butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-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 afford the title compound (12.9 mg, 32% yield) as a yellow solid. LCMS(ESI)[M+H] + =417.1.

[0720] Exemplary compound Example 24: 8-(2-Methyl-2,6-diazaspiro[3.4]octan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0721]

Chemical formula

[0722] A mixture of 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (200 mg, 0.52 mmol), 2-methyl-2,6-diazaspiro[3.4]octane (72.06 mg, 0.57 mmol), and cesium carbonate (507.40 mg, 1.55 mmol) in toluene (2 mL) was added with Pd2(dba)3 (47.6 mg, 0.052 mmol) and BINAP (32.3 mg, 0.052 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered. The recovered solid was washed with dichloromethane (5 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methanol, 10:1). The product was further purified by preparative reverse-phase HPLC (gradient of acetonitrile / water (containing 10 mM NH4HCO3 and 0.1% NH3.H2O)) to give the title compound (59.6 mg, yield 25.4%). LCMS(ESI) m / z = 431 [M + H] + . 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.15 - 7.09 (m, 2H), 6.83 - 6.79 (m, 1H), 5.31 (s, 1H), 4.11 - 4.05 (m, 3H), 3.80 - 3.75 (m, 2H), 3.67 - 3.43 (m, 6H), 3.05 - 2.98 (m, 2H), 2.84 (s, 3H), 2.48 (s, 3H), 2.26 - 2.19 (m, 4H), 1.81 - 1.69 (m, 2H).

[0723] Example 32: N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0724]

Chemical Structure

[0725] Project 1: Tert-butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

[0726]

Chem.

[0727] 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 Cl (10.18 mg, 0.01 mmol) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. H2O (0.1 mL) was added to the mixture, and the residue was purified by preparative reverse-phase HPLC to give the title compound (50 mg, 38% yield). LCMS(ESI)[M+H] + =517.1

[0728] Project 2: N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine (Example 31)

[0729]

Chem.

[0730] To a mixture of tert-butyl 2-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-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 h. 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 afford the title compound (12.9 mg, 32% yield). LCMS(ESI)[M+H] + =417.1.

[0731] Example 35: 1-(7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonan-2-yl)ethan-1-one

[0732] Reaction Scheme

[0733]

Chemical Structure

[0734] Detailed Procedure Step 1: Tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate

[0735]

Chemical Structure

[0736] A solution of LiHMDS (1 M, 4.10 mL, 4.10 mmol) in THF was added to a stirred mixture of tert-butyl 7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (500 mg, 2.04 mmol) in THF (6 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere, and a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.10 g, 3.07 mmol) in THF (6 mL) was added. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere, quenched by the addition of saturated aqueous NH4Cl solution (50 mL), and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 0:100~10:90) to give tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate (700 mg, yield 73.6%). LCMS (ESI-MS) m / z = 372.1 [M+H] + .

[0737] 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

[0738]

Chemical Structure

[0739] 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 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated directly under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 0:100~50:50) to give 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, yield 84.3%). LCMS(ESI-MS) m / z = 350.2 [M+H] + .

[0740] Step 3: Tert-butyl 7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate

[0741]

Chemical Structure

[0742] 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 at 100 °C overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 0:100~70:30) to obtain 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, yield 69.6%). LCMS(ESI-MS) m / z = 528.3 [M+H] + .

[0743] Step 3: Tert-butyl 7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonane-2-carboxylate

[0744]

Chemical Structure

[0745] Pd / C (10% on carbon, 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 for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 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). LCMS (ESI-MS) m / z = 530.3 [M+H] + .

[0746] Step 4: N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2-amine

[0747]

Chemical formula

[0748] 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 obtain the crude N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[4.4]nonan-7-yl)quinazolin-2-amine (180 mg crude). LCMS (ESI-MS) m / z = 430.2 [M+H] + .

[0749] Step 5: 1-(7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonan-2-yl)ethan-1-one

[0750]

Chem.

[0751] 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]nonan-7-yl)quinazolin-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 h and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give the desired product 1-(7-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[4.4]nonan-2-yl)ethan-1-one (29.0 mg, 99.4% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 9.09 (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). LCMS (ESI-MS) m / z = 472.2 [M + H] + , 98.9% purity.

[0752] Example 33: 1-(7-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one

[0753] Reaction Scheme

[0754]

Chem.

[0755] Detailed procedure Step 1: 8-Bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine

[0756]

Chem.

[0757] Droplets of concentrated HCl were added to a mixture of 4-(4-methylpiperazin-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 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 0:100 to 10:90) to give the desired product 8-bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (180 mg, yield 42.1%). LCMS (ESI-MS) m / z = 398.1 [M+H] + .

[0758] 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

[0759]

Chem.

[0760] Pd2(dba)3 (18.4 mg, 0.02 mmol) was added to a mixture of 8-bromo-N-[4-(4-methylpiperazin-1-yl)phenyl]quinazolin-2-amine (80 mg, 0.21 mmol), 1-(2,7-diazaspiro[4.4]nonan-2-yl)ethan-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) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to obtain 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 1H NMR (400 MHz, DMSO-d6) δ 9.32 (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). LCMS (ESI-MS) m / z = 486.2 [M + H] + , 3% purity.

[0761] Example 46: 1-(7-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one

[0762]

Chemical formula

[0763] A mixture of 8-bromo-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)quinazolin-2-amine (80 mg, 0.18 mmol), 1-(2,7-diazaspiro[4.4]nonan-2-yl)ethan-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 preparative TLC (MeOH / DCM, 1:10). The residue was further purified by preparative RP-HPLC to give the desired product 1-(7-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)quinazolin-8-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one (19.6 mg, yield 22.3%). 1 H NMR (300 MHz, chloroform-d) δ 9.07 (d, J = 4.2 Hz, 1H), 8.15 (dd, J = 8.8, 4.1 Hz, 1H), 7.81 (s, 1H), 7.63 (t, J = 2.7 Hz, 1H), 7.26 - 7.15 (m, 2H), 6.95 - 6.82 (m, 2H), 4.07 - 3.97 (m, 4H), 3.79 - 3.53 (m, 7H), 3.51 - 3.39 (m, 5H), 2.51 (dd, J = 7.2, 4.7 Hz, 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.

[0764] Example 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

[0765]

Chemical formula

[0766] A mixture of 8-bromo-7-fluoro-N-(1-methanesulfonylpiperidin-4-yl)quinazolin-2-amine (80 mg, 0.19 mmol), 1-(2,7-diazaspiro[4.4]nonan-2-yl)ethan-1-one (33.4 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium (18.2 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (24.7 mg, 0.04 mmol), and sodium t-butoxide (38.1 mg, 0.39 mmol) in 1,4-dioxane (3 mL) was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EA (3 × 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 give 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, yield 29.2%). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (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). LCMS (ESI-MS) m / z = 491.1 [M+H] + .

[0767] Example 58: 6-(Difluoromethyl)-N-(2-methylisoindolin-5-yl)-8-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)quinazolin-2-amine

[0768]

Chemical Structure

[0769] Pd-PEPPSI-IHeptCl3-chloropyridine (20.4 mg, 0.02 mmol) was added to a mixture of 8-bromo-6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)quinazolin-2-amine (85 mg, 0.21 mmol), 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane (36.9 mg, 0.21 mmol), and Cs2CO3 (205 mg, 0.63 mmol) in 1,4-dioxane (2 mL) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM, 1:10). The product was further purified by preparative RP-HPLC to give the desired product 6-(difluoromethyl)-N-(2-methylisoindolin-5-yl)-8-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)quinazolin-2-amine (23.2 mg, yield 21.7%) (Example 58). 1 H NMR (300 MHz, chloroform-d) δ 9.06 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.29 (s, 2H), 7.24 (d, J = 8.1 Hz, 1H), 6.69 (t, J = 54.3 Hz, 2H), 4.35 (s, 4H), 4.15 (s, 4H), 4.04 (d, J = 10.9 Hz, 4H), 2.92 (s, 3H), 2.69 (s, 3H). LCMS (ESI-MS) m / z = 501.0 [M+H] + .

[0770] Example 67: 6-(Difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0771] Reaction Scheme

[0772] [Chemistry]

[0773] Detailed procedure Step 1: tert-Butyl 6-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0774] [Chemistry]

[0775] Into an oven-dried 20 mL vial were placed 4,4'-di-tert-butyl-2,2'-bipyridine (30.8 mg, 0.11 mmol) and NiCl2.dme (25.2 mg, 0.11 mmol). DCE (3 mL) was added under a nitrogen atmosphere, and the reaction mixture was stirred at 60 °C for 10 minutes (mixture A). Into another oven-dried 40 mL vial were placed 8-bromo-6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (500 mg, 1.15 mmol), tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (744 mg, 2.30 mmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (314 mg, 1.26 mmol), Na2CO3 (243 mg, 2.30 mmol), and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (16.6 mg, 0.11 mmol). DCE (5 mL) was added under a nitrogen atmosphere (mixture B). 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 6 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 TLC (EA / PE, 2:1) to obtain tert-butyl 6-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg). LCMS(ESI-MS) m / z = 552.2 [M+H] + .

[0776] Step 2: 6-(Difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]heptan-6-yl)quinazolin-2-amine

[0777]

Chemical Structure

[0778] TFA (1 mL) was added to a stirred mixture of tert-butyl 6-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.41 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM, 10:90) to give 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]heptan-6-yl)quinazolin-2-amine (100 mg, yield 47.8%). LCMS (ESI-MS) m / z = 452.1 [M+H] + .

[0779] Step 3: 6-(Difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0780]

Chemical Structure

[0781] A solution of 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(2-azaspiro[3.3]heptan-6-yl)quinazolin-2-amine (70 mg, 0.15 mmol) and HCHO (23.3 mg, 0.77 mmol) in MeOH (1 mL) was stirred at room temperature for 1 hour. NaBH3CN (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 preparative TLC (MeOH / DCM, 1:7). The product was further purified by preparative RP-HPLC to give 6-(difluoromethyl)-8-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (7.9 mg, yield 10.7%). 1 1H NMR (400 MHz, chloroform-d) δ 8.97 (s, 1H), 7.70 - 7.54 (m, 2H), 6.71 (t, J = 56.4 Hz, 1H), 5.30 (d, J = 7.3 Hz, 1H), 4.14 - 3.95 (m, 2H), 3.80 (d, J = 12.4 Hz, 2H), 3.47 (s, 2H), 3.20 (s, 2H), 3.08 - 2.97 (m, 2H), 2.86 (s, 3H), 2.72 - 2.63 (m, 2H), 2.39 - 2.27 (m, 7H), 1.75 (s, 1H), 1.25 (s, 1H). LCMS (ESI-MS) m / z = 466.1 [M + H] + .

[0782] Example 74: N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0783] Reaction Scheme

[0784]

Chem.

[0785] Detailed Procedure Step 1: 8-Bromo-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)quinazolin-2-amine

[0786]

Chem.

[0787] K2CO3 (1.84 g, 13.3 mmol) was added to a mixture of 1-(cyclopropylsulfonyl)piperidin-4-amine (0.90 g, 4.42 mmol) and 8-bromo-2-chloro-6-(difluoromethyl)quinazoline (1.3 g, 4.42 mmol) in DMSO (10 mL). The resulting mixture was stirred at 100 °C for 1 h, diluted with water (100 mL), and extracted with DCM (3 × 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 give 8-bromo-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)quinazolin-2-amine (1.2 g, yield 55.8%). LCMS (ESI-MS) m / z = 461.2 [M+H] + .

[0788] 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

[0789]

Chemical Structure

[0790] 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-methylpropane-2-olate (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 at 100 °C 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. The residue was purified by preparative TLC (MeOH / DCM, 1:10) to give 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, yield 42.0%). LCMS (ESI-MS) m / z = 593.4 [M+H] + .

[0791] Step 3: N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0792]

Chemical Structure

[0793] TFA (0.3 mL) was added to a stirred mixture of tert-butyl 2-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-6-(difluoromethyl)quinazolin-8-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (80 mg, 0.13 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM, 1:10). The product was further purified by preparative RP-HPLC to give N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-(difluoromethyl)-8-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-2-amine (18.3 mg, 27.2% yield) (Example 74). 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.64 - 7.49 (m, 1H), 7.31 (s, 1H), 6.99 (t, J = 56.1 Hz, 1H), 6.56 (d, J = 7.0 Hz, 1H), 4.14 (d, J = 9.8 Hz, 3H), 3.87 (s, 1H), 3.65 (d, J = 12.8 Hz, 2H), 3.06 - 2.93 (m, 4H), 2.91 - 2.81 (m, 2H), 2.67 - 2.57 (m, 2H), 2.09 - 1.92 (m, 4H), 1.66 - 1.51 (m, 2H), 1.24 (s, 1H), 1.05 - 0.91 (m, 4H). LCMS (ESI-MS) m / z = 493.1 [M+H] + , 98.6% purity.

[0794] Example 89:

[0795]

Chemical Structure

[0796] 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]heptan-6-yl)quinazolin-2-amine (100 mg, 0.22 mmol) and 2-bromoethyl methyl ether (30.8 mg, 0.22 mmol) in MeCN (4 mL). The resulting mixture was stirred 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 preparative TLC (MeOH / DCM, 1:10) to give 6-(difluoromethyl)-8-(2-(2-methoxyethyl)-2-azaspiro[3.3]heptan-6-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (7.3 mg, yield 6.33%) (Example 89). 1 H NMR (400 MHz, chloroform-d) δ 8.98 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 6.72 (t, J = 56.4 Hz, 1H), 5.39 (d, J = 7.3 Hz, 1H), 4.16 - 3.94 (m, 2H), 3.87 - 3.76 (m, 2H), 3.66 - 3.60 (m, 2H), 3.46 (t, J = 5.4 Hz, 2H), 3.36 (s, 5H), 3.13 - 3.01 (m, 2H), 2.89 (s, 3H), 2.79 - 2.64 (m, 4H), 2.42 - 2.24 (m, 4H), 1.83 - 1.67 (m, 2H). LCMS (ESI-MS) m / z = 510.3 [M+H] + .

[0797] Example 101:

[0798] Reaction Scheme

[0799]

Chemical Structure

[0800] Detailed Procedure Project 1: tert-Butyl 2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate

[0801]

Chem.

[0802] Into an oven-dried 20 mL vial were placed tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (548 mg, 2.41 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (871 mg, 2.21 mmol). Under nitrogen, tert-butyl methyl ether (24 mL) was added and the reaction was stirred at room temperature for 5 minutes. A mixture of pyridine (401 mg, 5.10 mmol) in tert-butyl methyl ether (6 mL) was added and the mixture was stirred at room temperature for 10 minutes (Mixture A). Into another oven-dried 40 mL vial were placed 8-bromo-6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (600 mg, 1.37 mmol), NiBr2(dtbbpy) (33.56 mg, 0.06 mmol), Ir(ppy)2(dtbbpy)PF6 (18.9 mg, 0.021 mmol), and 1-azabicyclo[2.2.2]octane (Q, 268.2 mg, 2.41 mmol). DMA (30 mL) was added under nitrogen (Mixture B). 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 layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE, 2:1) to obtain 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). LCMS (ESI-MS) m / z = 566.2 [M+H] + .

[0803] Step 2: 6-(Difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0804]

Chem.

[0805] TFA (2 mL) was added to a stirred mixture of tert-butyl 2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octane-6-carboxylate (700 mg, 1.23 mmol) in DCM (6 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM, 1:10) to give 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine (500 mg, yield 86.8%). LCMS (ESI-MS) m / z = 466.2 [M+H] + .

[0806] 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

[0807]

Chem.

[0808] 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]octan-2-yl)quinazolin-2-amine (100 mg, 0.21 mmol) in MeCN (1 mL). The resulting mixture was stirred at 50 °C overnight, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC to give 6-(difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-(3,3,3-trifluoropropyl)-6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine (9.8 mg, yield 8.1%). 1 1H NMR (400 MHz, chloroform-d) δ 8.98 (s, 1H), 7.72 - 7.53 (m, 2H), 6.72 (t, J = 56.4 Hz, 1H), 5.30 (d, J = 7.1 Hz, 1H), 4.2 - 4.02 (m, 2H), 3.78 (dd, J = 10.9, 6.0 Hz, 2H), 3.09 - 2.94 (m, 2H), 2.85 (s, 3H), 2.76 - 2.65 (m, 4H), 2.62 (s, 2H), 2.57 - 2.47 (m, 2H), 2.40 - 2.23 (m, 6H), 2.22 - 2.15 (m, 2H), 1.81 - 1.69 (m, 2H). LCMS (ESI-MS) m / z = 562.3 [M+H] + .

[0809] Example 102: 6-(Difluoromethyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(6-(oxetan-3-yl)-6-azaspiro[3.4]octan-2-yl)quinazolin-2-amine

[0810]

Chemical Structure

[0811] STAB (91.1 mg, 0.43 mmol) was added to a mixture of oxetan-3-one (15.5 mg, 0.21 mmol) and 6-(difluoromethyl)-N-(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 give 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, yield 5.5%) (Example 102). 1 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). LCMS (ESI-MS) m / z = 522.4 [M+H] + .

[0812] Example 106: 3-(2-(6-(Difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octan-6-yl)-2,2-difluoropropan-1-ol

[0813]

Chemical Structure

[0814] 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-dioxathiane 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). To the combined filtrate were added 4-methylbenzene-1-sulfonic acid hydrate (53.9 mg, 0.28 mmol) and H2O (51.1 mg, 2.83 mmol). The resulting biphasic mixture was heated to 80 °C and stirred for 3 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 preparative TLC (MeOH / DCM, 1:10) to give 3-(2-(6-(difluoromethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)-6-azaspiro[3.4]octan-6-yl)-2,2-difluoropropan-1-ol (2.7 mg, yield 1.8%) (Example 106). 1 H NMR (400 MHz, Methanol-d4) δ 9.05 (d, J = 2.1 Hz, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 6.85 (t, J = 56.3 Hz, 1H), 5.36 (t, J = 4.8 Hz, 1H), 4.18 - 4.04 (m, 2H), 3.83 - 3.70 (m, 4H), 3.08 - 2.97 (m, 4H), 2.91 (s, 3H), 2.85 (t, J = 6.8 Hz, 1H), 2.75 (d, J = 3.6 Hz, 2H), 2.64 - 2.50 (m, 2H), 2.28 - 2.18 (m, 5H), 2.04 (d, J = 6.1 Hz, 1H), 1.90 (d, J = 2.6 Hz, 1H), 1.80 - 1.72 (m, 2H), 1.62 (s, 1H). LCMS (ESI-MS) m / z = 560.4 [M+H] + , 95.1% purity.

[0815] Example 120

[0816] Reaction scheme

[0817]

Chem.

[0818] Detailed procedure Step 1: 1-(Difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl benzoate

[0819]

Chem.

[0820] Into an oven-dried 20 mL vial were placed 1-(difluoromethyl)-3-hydroxycyclobutyl benzoate (110 mg, 0.45 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (NHC) (164 mg, 0.42 mmol). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction mixture 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). Into another oven-dried 40 mL vial were placed 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-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). DMA (5 mL) was added under nitrogen (mixture B). 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 layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE, 2:1) to afford 1-(difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl benzoate (150 mg). LCMS(ESI-MS) m / z = 531.2 [M+H] + .

[0821] Step 2: 1-(Difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutan-1-ol

[0822]

Chemical Structure

[0823] 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)cyclobutyl benzoate (150 mg, 0.28 mmol) in THF (3 mL) and H2O (1 mL). The resulting mixture was stirred overnight at room temperature, neutralized by the addition of aqueous HCl solution (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 obtain 1-(difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutan-1-ol (14.5 mg, yield 11.6%) (Example 120). 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (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] + .

[0824] Example 121: [1-(Difluoromethyl)-3-(2-((1-methanesulfonylpiperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl]methanol

[0825] Reaction Scheme

[0826]

Chemical Structure

[0827] Project 1: 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine

[0828]

Chem.

[0829] Into an oven-dried 20 mL vial were placed methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutan-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). Under nitrogen, tert-butyl methyl ether (4 mL) was added and the reaction mixture 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). Into another oven-dried 40 mL vial were placed 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)quinazolin-2-amine (43.1 mg, 0.11 mmol), NiBr2(dtbbpy) (4 mg, 0.01 mmol), Ir(ppy)2(dtbbpy)PF6 (5.43 mg, 0.006 mmol), phthalic amide (9.65 mg, 0.02 mmol), and 1-azabicyclo[2.2.2]octane (77.1 mg, 0.69 mmol). DMA (5 mL) was added under nitrogen (mixture B). 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 layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE, 2:1) to give 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] + .

[0830] Step 2: (1-(Difluoromethyl)-3-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl)methanol

[0831] [Chemical]

[0832] A solution of TBAF in THF (1 M, 0.06 mL, 0.06 mmol) was added to a stirred mixture of 8-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(difluoromethyl)cyclobutyl)-N-(1-methanesulfonylpiperidin-4-yl)quinazolin-2-amine (40 mg, 0.059 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 hour, quenched by the addition of water (5 mL), and extracted with EA (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give [1-(difluoromethyl)-3-(2-((1-methanesulfonylpiperidin-4-yl)amino)quinazolin-8-yl)cyclobutyl]methanol (1.0 mg, yield 3.9%) (Example 121). 1 H NMR (400 MHz, chloroform-d) δ 8.99 (s, 1H), 7.65 (s, 1H), 7.60 (s, 2H), 5.43 - 5.15 (m, 2H), 4.35 (s, 1H), 4.19 - 3.94 (m, 2H), 3.82 (s, 2H), 3.61 - 3.45 (s, 1H), 3.00 (t, J = 11.1 Hz, 1H), 2.85 (s, 3H), 2.68 - 2.44 (m, 1H), 2.27 (d, J = 11.0 Hz, 2H), 2.06 - 1.90 (m, 1H), 1.75 (s, 2H), 1.56 (s, 2H), 1.39 - 1.23 (m, 2H). LCMS (ESI-MS) m / z = 441.2 [M + H] + .

[0833] Example 116: Reaction Scheme

[0834] [Chemical]

[0835] Detailed Procedure Step 1: 8-Bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine

[0836]

Chem.

[0837] 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-methanesulfonylpiperidin-4-amine (171 mg, 0.96 mmol) in DMSO (8 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was quenched by the addition of water (30 mL) and extracted with EA (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE, 1:1) to give 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine (400 mg, yield 91.6%). LCMS (ESI-MS) m / z = 453.0 [M+H] + .

[0838] 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

[0839]

Chem.

[0840] Pd-PEPPSI-IHeptCl3-chloropyridine (23.6 mg, 0.02 mmol) was added to a mixture of 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(trifluoromethyl)quinazolin-2-amine (110 mg, 0.24 mmol), benzyl 8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (68.5 mg, 0.24 mmol), and Cs2CO3 (158 mg, 0.48 mmol) in 1,4-dioxane (1 mL) under a nitrogen atmosphere. The resulting mixture was heated to 100 °C and stirred overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filter cake was wash...

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof, 【Chemical 1】 wherein, In the formula, R １ is selected from 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 optionally substituted, and azetidine optionally substituted, 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 ring, and optionally substituted 3- to 4-membered heterocycloalkyl, R ７ is selected from hydrogen and optionally substituted C １－４ alkyl, R １ When R is a pyrazole optionally substituted, ２ a compound or a pharmaceutically acceptable salt or solvate thereof, wherein R is not piperidine.

2. R １ is the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, 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. R １ is the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted piperidine, optionally substituted 2-pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted indole, optionally substituted isoindole, and optionally substituted azetidine.

4. R １ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is piperidine optionally substituted.

5. R １ is the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is an optionally substituted azabicyclo[3.1.0]hexane.

6. R １ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted indole.

7. R １ The compound or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R is an optionally substituted isoindole.

8. R １ is an azetidine optionally substituted, the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

9. R １ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted indazole.

10. R １ The compound or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R is a tetrahydroisoquinoline optionally substituted.

11. R ２ is 【Chemical Formula 2】 and Y １ is selected from -N- and -CR １０ - and Z １ 、Z ２ 、Z ３ 、Z ４ 、and Z ５ each of which is independently, -C(R １０ ), -C(O)-, -NR ２ -, -N(C(O)R １１ ), -NS(O １０ ), -NS(O ２ ), -O-, -S-, -S(O)-, and -S(O １１ ), and Z ２ is further selected from bonds, ５ ​ each of a, b, c, and d is independently selected from 1, 2, 3, and 4, R １０ Each is independently selected from hydrogen, halogen, -CN, -OH, -O-C １－４ alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R １０ substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R １０ and R １１ substituents together form an optionally substituted heterocyclic ring, and, R １１ is each independently selected from hydrogen and optionally substituted C １－４ alkyl, a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or solvate thereof.

12. having one or more structures of the following formula: 【Chemical 3】 wherein, In the formula, R ８ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R ９ is optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and 3- to 6-membered heterocycloalkyl, and is selected from 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 and R １２ is selected from hydrogen, halogen, -CN, -NO ２ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle, or R １２ is R １３ combines with R to form an optionally substituted ring, and R １３ are each 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 ring, and optionally substituted 3- to 6-membered heterocycloalkyl, or R １４ and R １５ together form an optionally substituted heterocyclic ring, and R １５ is -S(O) ２ R １６ -, optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

13. R ２ The compound according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted heterocyclic ring.

14. R ２ is 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, the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

15. R ２ is selected from -CN, -SO ２ R ２ａ , -NR ２ａ , oxo, C １－３ alkyl, C １－３ hydroxyalkyl, C ３－６ cycloalkyl, C １－３ alkylene-C ３－６ cycloalkyl, oxetane, or azetidine, and R ２ａ is selected from C １－６ alkyl, or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 or 14.

16. having one or more structures of the following formula: [Chemical Formula 4] wherein, In the formula, Y １ is selected from -N- and -CR １０ -, and Z １ 、Z ２ 、Z ３ 、Z ４ 、and Z ５ each of which is independently, -C(R １０ )( ２ -, -C(O)-, -NR １１ -, -N(C(O)R １０ ), -NS(O ２ )R １１ -, -O-, -S-, -S(O)-, and -S(O ２ -) selected from, Z ５ is further selected from bonds, 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 is optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and 3- to 6-membered heterocycloalkyl, and is selected from n is selected from 0 to 9, X １ , X ２ , and X ３ are each CH, R １０ is each independently selected from hydrogen, halogen, -CN, -OH, -O-C １－４ alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R １０ substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or the R １０ and R １１ substituents together form an optionally substituted heterocyclic ring, R １１ are each independently selected from hydrogen and optionally substituted C １－４ alkyl, R １６ is optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, selected from R １７ is optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, or R １３ and R １４ together form an optionally substituted heterocycle, and R １８ is halogen, -CN, optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

17. Y １ The compound according to claim 11 or 16, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N-.

18. Y １ is -CR １０ - and is the compound according to claim 11 or 16, or a pharmaceutically acceptable salt or solvate thereof.

19. Z １ , Z ２ , Z ３ , Z ４ , and Z ５ Each of the groups independently represents -C(R １０ ) ２ --, --NR １１ -, -N(C(O)R １０ ) -, -NS(O ２ ) R １１ , —O—, and —S(O) ２ -, Z ５ 17. The compound of claim 11 or 16, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is further selected from a bond.

20. The compound according to any one of Claims 11 or 16 - 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.

21. The compound according to Claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein each of a, c, and d is independently selected from 1 and 2.

22. R １０ Each independently is hydrogen, halogen, -CN, -OH, -O-C １－４ alkyl, optionally substituted C １－３ alkyl, and optionally substituted C ３－６ cycloalkyl, the compound according to any one of claims 11 or 16 to 21, or a pharmaceutically acceptable salt or solvate thereof.

23. R １０ Each is independently hydrogen, halogen, -CN, -OH, methyl, -OMe, -CH ２ CH ２ OCH ３ The compound according to claim 22, or a pharmaceutically acceptable salt or solvate thereof, which is selected from and cyclopropyl.

24. R １１ each independently is selected from hydrogen and optionally substituted C １－２ alkyl, a compound according to any one of claims 11 or 16 to 23, or a pharmaceutically acceptable salt or solvate thereof.

25. R １１ is each independently selected from hydrogen, methyl, and ethyl, and ethyl is optionally substituted with -OMe, a compound according to claim 24 or a pharmaceutically acceptable salt or solvate thereof.

26. R １ is the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted azabicyclo[3.1.0]hexane, optionally substituted isoindole, and optionally substituted indole.

27. R １ is the compound according to claim 26 or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted azabicyclo[3.1.0]hexane and optionally substituted isoindole.

28. R １ is -SO ２ R １ａ or C １－３ substituted with alkyl, and R １ａ is selected from C １－６ alkyl, the compound according to claim 26 or 27, or a pharmaceutically acceptable salt or solvate thereof.

29. R ２ is a compound according to any one of claims 1, 2, 26, 27 or 28, or a pharmaceutically acceptable salt or solvate thereof, selected from an optionally substituted heterocyclic ring and an optionally substituted cycloalkyl.

30. R ２ The compound according to claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted heterocycloalkyl.

31. R ２ is a compound according to claim 30, or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted 3- to 6-membered heterocycloalkyl.

32. R ２ is the compound according to claim 31, or a pharmaceutically acceptable salt or solvate thereof, selected from azetidine optionally substituted, pyrrolidine optionally substituted, piperidine optionally substituted, piperazine optionally substituted, and morpholine optionally substituted.

33. R ２ is halogen, -SO ２ R ２ａ , -NR ２ａ , -C(O)CH ３ , -CN, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C ３－５ carbocycle, oxo, and optionally substituted C １－３ substituted with alkyl, and R ２ａ is selected from C １－６ alkyl, a compound according to any one of claims 29 to 32 or a pharmaceutically acceptable salt or solvate thereof.

34. R ２ is a compound according to claim 32 or a pharmaceutically acceptable salt or solvate thereof, substituted with fluoro, -SO ２ Me, oxo, and methyl.

35. R ２ is 【Chemical Formula 5-1】 【Chemical Formula 5-2】 The compound according to any one of Claims 1 - 10, 12, or 29, or a pharmaceutically acceptable salt or solvate thereof, selected from

36. R ２ is 【Chemical Formula 6-1】 【Chemical Formula 6-2】 The compound according to Claim 35, or a pharmaceutically acceptable salt or solvate thereof, selected from

37. R ２ The compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 10 or 12, wherein R is an optionally substituted heterocycloalkyl.

38. R ３ is hydrogen, halogen, -CN, optionally substituted C ３－４ carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, the compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 37.

39. R ３ is a compound according to claim 38, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

40. R ３ is a compound according to claim 38 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, fluoro, and -CN.

41. R ３ is a compound according to claim 40 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen and -CN.

42. R ４ is hydrogen, halogen, -CN, optionally substituted C １ alkyl, optionally substituted C ３－４ carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, the compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt or solvate thereof.

43. R ４ is selected from hydrogen, -CN, -CHF ２ , -CF ３ , cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, and is the compound according to claim 42 or a pharmaceutically acceptable salt or solvate thereof.

44. R ４ is a compound according to claim 43 or a pharmaceutically acceptable salt or solvate thereof selected from hydrogen, -CN, and -CHF ２ ​

45. R ５ is hydrogen, halogen, -CN, optionally substituted C ３－４ carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, the compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 44.

46. R ５ is the compound according to claim 45, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

47. R ５ The compound according to claim 46, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

48. R ６ is hydrogen, halogen, -CN, optionally substituted C ３－４ carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt or solvate thereof.

49. R ６ is a compound according to claim 48 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

50. R ６ The compound according to claim 49, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

51. R ７ is hydrogen, a compound or a pharmaceutically acceptable salt or solvate according to any one of claims 1 to 50.

52. The compound according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the compounds in Table I.

53. The compound according to Claim 12, or a pharmaceutically acceptable salt or solvate thereof, selected from the compounds in Table I.

54. The compound according to Claim 16, or a pharmaceutically acceptable salt or solvate thereof, selected from the compounds in Table I.

55. A pharmaceutical composition comprising the compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

56. A method for treating cancer, comprising the step of administering the pharmaceutical composition according to claim 54 to a subject in need of treatment.

57. The method according to claim 56, wherein the cancer is a solid tumor.

58. The method according to claim 56 or 57, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumor.

59. The method according to claim 58, wherein the cancer is ovarian cancer or breast cancer.

60. A method for inhibiting cyclin-dependent kinase (CDK) in a cell using the compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 55.

61. The method according to claim 59, wherein the CDK is selected from CDK2, CDK4, CD6, or any combination thereof.

62. The method according to claim 60, wherein the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6.

63. The method according to claim 62, wherein the CDK is CDK2 / 4 / 6.

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