Azaindazole compounds and methods of use

Abstract

Disclosed herein are substituted aza - 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), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), and (IEE), 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 / 390,251, filed on July 18, 2022, and U.S. Provisional Patent Application No. 63 / 512,046, filed on July 5, 2023. The entire contents of the aforementioned 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 are important and fundamental biological processes that control 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. Gain - of - function of tumor - promoting components or 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 G1 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 characteristic of cancer, leading to overactivation of CDKs and uncontrolled cell division and proliferation. Genetic alterations in genes encoding cyclin D, CDK4 / 6, and CDK4 / 6 inhibitory proteins (such as p21, p27, etc.) 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 anticancer therapy. CDK inhibitors have been developed as anticancer drugs since the early 1990s, along with multiple FDA-approved drugs (palbociclib, ribociclib, and abemaciclib). However, these early-generation CDK inhibitors available 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 new CDK inhibitors with better selectivity for normal cells and fewer side effects.

Summary of the Invention

[0005] The present disclosure generally relates to substituted quinolinone amide compounds or salts of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), and (IEE), and pharmaceutical compositions thereof. The substituted quinolinone amide compounds or salts of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), and (IEE) 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), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), and (IEE).

[0007] In certain embodiments, the present disclosure provides a compound represented by formula (I0)

[0008] [Chemical formula] wherein In the formula, A is a ring selected from an optionally substituted carbocycle, an optionally substituted 4- to 8-membered heterocycle, and an optionally substituted isoindoline; Z 0 is -C(H)- or nitrogen; Z 1 , Z 2 , and Y 1 each independently is selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-; each of a and b independently is selected from 1, 2, 3, and 4; R 1 each independently is selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle; m is selected from 0 to 5; R 2 each independently is hydrogen, halogen, -CN, -OH, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted -O-cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle, or the substituents of R 2 and R 3 together form an optionally substituted heterocycle; R 3are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, R 4 is 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 5 and R 6 each are 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, and R 7 is selected from hydrogen and optionally substituted C 1-4 alkyl, and when A is optionally substituted phenyl, m is 1 to 5 and at least one R 1 is heterocycloalkyl, when A is optionally substituted pyridine, optionally substituted pyridazine, or optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen, and -CN, when A is optionally substituted piperidine sulfonamide, (i) Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen, methyl, and -CN, and A-R 1 is

[0009]

Chemical formula

[0010] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0011] In certain embodiments, the 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 embodiments, the 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.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Preferred embodiments of the invention have been 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. Those skilled in the art will envision many variations, modifications, and substitutions 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 the treatment of cancer due to the role of CDKs in cell regulation. It has been shown that increased or transient abnormal activation of CDK activity leads to tumorigenesis, which is often associated with changes in CDKs or CDK regulators.

[0014] CDKs bind to cyclins, which are regulatory proteins. Without cyclins, CDKs have little kinase activity. Cyclin-CDK complexes are active kinases typically regulated by phosphorylation and other associated 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, the cyclin partner of CDK2, binds to CDK2 to form an active kinase complex. The CDK2-cyclin E complex is important in the regulation of G1 / S transition, centrosome replication, 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, promoting 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 arrest the cell cycle from G1 to S phase by blocking phosphorylation of the Rb protein and 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 appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

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

[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 refers to a straight-chain or branched hydrocarbon chain radical having 1 to 15 carbon atoms (e.g., C1-C 15 alkyl). In certain embodiments, alkyl contains 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, for example, 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, for example, 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 the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, and S can be arranged at any internal position of the heteroalkyl group. The heteroatom Si can be arranged 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, for example, -CH2NHOCH3 and -CH2OSi(CH3)3. Heteroalkyl can include any specified number of carbon atoms as defined in this specification 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 only of carbon atoms 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 and is, for example, 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 only of 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 that binds the rest of the molecule to the radical group, consists only of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, 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 bonding points 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 one 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 that consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms, which binds the rest of the molecule to the radical group. The alkynylene chain binds 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, which binds the rest of the molecule to the 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 one heteroatom. In certain embodiments, heteroalkylene contains two heteroatoms. In certain embodiments, heteroalkylene contains three heteroatoms. In certain embodiments, heteroalkylene contains four heteroatoms. In certain embodiments, heteroalkylene contains five heteroatoms. In certain embodiments, the heteroatom can be N, O, S, Si, or P, or a combination thereof. In certain embodiments, the heteroatom can be N, O, or S, or a combination thereof. In certain embodiments, the heteroatom can be N, O, or a combination thereof.

[0038] "C x-y " or "C x -C y " When used with chemical moieties such as alkyl, alkenyl, or alkynyl, 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 alkyl group and a branched-chain alkyl group having 1 to 6 carbons.

[0039] "C x-y alkenyl" and "C x-y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups having a length and possible substitutions similar to those of the above alkyl, but each containing at least one double bond or triple bond.

[0040] As used herein, the term "carbocyclic ring" refers to a saturated ring, unsaturated ring, or 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, such as phenyl, can be fused to a saturated ring or an unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocyclic ring includes any combination of saturated, unsaturated, and aromatic bicyclic rings as long as the valency permits. A bicyclic carbocyclic ring further includes a spirobicyclic ring, such as spiropentane. A bicyclic carbocyclic ring includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary 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 systems from which aryl groups are derived include, but are not limited to, groups such as 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 bonded 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 bonded 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", 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] As used herein, the term "heterocyclic ring" refers to a saturated ring, an unsaturated ring, or an aromatic ring containing one or more heteroatoms. Typical heteroatoms include the 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, spirobicyclics of 5 to 12 members, and bridged rings of 5 to 12 members. Monocyclic heterocyclic rings include any saturated ring, unsaturated ring, and aromatic ring as long as the valence allows. 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 long as the valence allows. In a typical embodiment, an aromatic ring, for example, pyridyl, can be fused to a saturated ring or an unsaturated ring, for example, 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, such as, but not limited to, 5- to 12-membered spirobicyclic rings such as 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, 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, and at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2)π-electron system according to Huckel's theory. Heteroaryl includes fused ring systems or bridged ring systems. The heteroatoms in a 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, such as any carbon atom or nitrogen atom of the heterocycloalkyl, to which the valence permits. 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, 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 cycloalkenyls include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (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 "substituted" 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., substituting 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 organic compounds. 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 organic compounds. 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), hydrazino (=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 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、-Rb -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 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where R a are 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(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 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" mean a mode of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, 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 within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0055] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refer to 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 utilized 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 salt 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 with respect to a disease, disorder, or medical condition, including but not limited to therapeutic and / or prophylactic benefits. 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 improvement in the subject is observed, even though the subject may still be suffering 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 if the disease has not been diagnosed in the subject. Treatment by administration of a compound 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 described by Formulas (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), and (IEE).

[0061] In one aspect, Formula (I)

[0062]

Chemical formula

[0063] Ring A can be any suitable ring known to those skilled in the art. In some embodiments, A is a ring selected from an optionally substituted carbocyclic ring, an optionally substituted 4- to 10-membered heterocyclic ring, and an optionally substituted isoindoline. In some embodiments, A is a ring selected from an optionally substituted carbocyclic ring, an optionally substituted 4- to 8-membered heterocyclic ring, and an optionally substituted isoindoline. In some embodiments, A is a ring selected from an optionally substituted carbocyclic ring, an optionally substituted 4- to 6-membered heterocyclic ring, and an optionally substituted isoindoline. In some embodiments, A is a ring selected from an optionally substituted azetidine, an optionally substituted piperidine, an optionally substituted azabicyclo[3.1.0]hexane, an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted isoindoline, and an optionally substituted tetrahydroisoquinoline. In some embodiments, A is a ring selected from an optionally substituted pyridine, an optionally substituted azabicyclo[3.1.0]hexane, an optionally substituted azetidine, and an optionally substituted tetrahydroisoquinoline. In some embodiments, A is not an optionally substituted pyridine. In some embodiments, A is not an optionally substituted pyrimidine.

[0064] In some embodiments, A is substituted with methyl, -SO2Me, methylpiperidine, methylpiperazine, methylazaspiro[3.3]heptane, methyldiazaspiro[3.3]heptane, or combinations thereof. In some embodiments, A is substituted with methyl, -SO2Me, -SO2Me, methylpiperidine, methylpiperazine, or combinations thereof. In some embodiments, A is substituted with methyl, -SO2Me, or combinations thereof. In some embodiments, A is substituted with -SO2Me.

[0065] Z 1 and Z 2can be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 and Z 2 are independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-. In some embodiments, Z 1 and Z 2 are independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -NS(O2)R 2 -, -O-, and -S-. In some embodiments, Z 1 and Z 2 are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-. In some embodiments, Z 1 and Z 2 are independently -C(R 2 )2-.

[0066] The variables a and b can be any suitable numbers known to those skilled in the art. In some embodiments, each of a and b is independently selected from 1, 2, 3, and 4. In some embodiments, each of a and b is independently 1, 2, and 3. In some embodiments, each of a and b is independently selected from 1 and 2.

[0067] Y 1 can be any suitable functional group known to those skilled in the art. In some embodiments, Y 1 is selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-. In some embodiments, Y 1 is -C(R 2) 2-, -C(O)-, -NR 3 -, -NS(O2)R 2 -, -O-, and -S-. In some embodiments, Y 1 is selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-. In some embodiments, Y 1 is selected from -C(R 2 )2- and -NR 3 . In some embodiments, Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring. In some embodiments, Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring.

[0068] In some embodiments, in formula (I)

[0069]

Chemical formula

[0070]

Chemical formula

[0071]

Chemical formula

[0072] The variable m can be any suitable number known to those skilled in the art. In some embodiments, m is selected from 0 to 5. In some embodiments, m is selected from 0 to 3. In some embodiments, m is selected from 0 to 2. In some embodiments, m is selected from 0 to 1. In some embodiments, m is selected from 1 to 5. In some embodiments, m is selected from 1 to 3. In some embodiments, m is selected from 1 to 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0073] R 1 can be any suitable functional group known to those skilled in the art. In some embodiments, R 1 are each independently selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle. In some embodiments, R 1 are each independently selected from optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle. In some embodiments, R 1 are each independently selected from optionally substituted alkyl and optionally substituted heterocycle. In some embodiments, R 1 are each independently selected from methyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted azaspiro[3.3]heptane, and optionally substituted diazaspiro[3.3]heptane. In some embodiments, R 1 are each independently selected from methyl, ethyl, and optionally substituted diazaspiro[3.3]heptane.

[0074] R2 can be any suitable functional group known to those skilled in the art. In some embodiments, R 2 are 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 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or the R 2 and R 3 substituents together form an optionally substituted heterocyclic ring. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, chloro, bromo, -CN, cyclopropyl, cyclobutyl, oxetane, and azetidine. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 2 are each selected from hydrogen, fluoro, -CN, and cyclopropyl. In some embodiments, R 2 are each selected from hydrogen, -CN, and cyclopropyl.

[0075] In some embodiments, two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two R 2The substituents combine to form an optionally substituted heterocyclic ring. In some embodiments, two R 2 The substituents combine to form an optionally substituted carbocyclic ring. In some embodiments, two R 2 The substituents are this

[0076]

Chemical formula

[0077]

Chemical formula

[0078] Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each may be any suitable functional group 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 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0079] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R3 is selected from -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 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 , -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 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0080] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0081] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0082] In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are independently selected from hydrogen and fluoro.

[0083] R 3 can be any suitable functional group known to those skilled in the art. In some embodiments, R 3 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, or the substituents of R 2 and R 3 together form an optionally substituted heterocycle. In some embodiments, R 3 are each independently selected from hydrogen, optionally substituted 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 3 is each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbon ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0084] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0085] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is hydrogen, halogen, -CN, optionally substituted C 1-4Alkyl, optionally substituted C 3-4 Selected from a carbocyclic ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 4 is hydrogen, halogen, optionally substituted C 1-2 alkyl, a carbocyclic ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3-4 is hydrogen, halogen, -CN, optionally substituted C 4 alkyl, and an optionally substituted C 1-2 carbocyclic ring. In some embodiments, R 3-4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not an optionally substituted phenyl. In some embodiments, R 4 is not an optionally substituted alkyl.

[0086] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is hydrogen, halogen, -CN, optionally substituted C 1-4 alkyl, a carbocyclic ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3-4 is hydrogen, halogen, optionally substituted C 5 alkyl, a carbocyclic ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 1-2 alkyl, a carbocyclic ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3-4 is hydrogen, halogen, optionally substituted C 5is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0087] 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, 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, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0088] 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.

[0089] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IA)

[0090]

Chem.

[0091] In some embodiments, the two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, the two R 2 substituents together form an optionally substituted heterocycle. In some embodiments, the two R 2 substituents together form an optionally substituted carbocycle. In some embodiments, the two R 2 substituents are such that this

[0092]

Chem.

[0093]

Chem.

[0094] Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each may be any suitable functional group 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 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 、-O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0095] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each independently is selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 、-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 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 、-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 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0096] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0097] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen and fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0098] In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0099] In some embodiments, R 3 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0100] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0101] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R4 is not an optionally substituted alkyl.

[0102] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is 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 hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0103] R 6 can be any suitable functional group known to those skilled in the art. In some embodiments, R 6 is 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 hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is hydrogen, halogen, and optionally substituted C 1-2is selected from alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0104] 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.

[0105] 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 selected from optionally substituted C 1-4 alkyl. In some embodiments, R 8 is selected from methyl, ethyl, and propyl.

[0106] 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 carbocyclic, and 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 is selected from optionally substituted C 1-4Alkyl, and optionally substituted C 3-6 is selected from a carbon ring. 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.

[0107] The variable n can be any suitable number known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

[0108] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IAA)

[0109]

Chemical formula

[0110] Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each may be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0111] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 , -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 is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R2 )-, -NS(O2)R 3 is selected from -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 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0112] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0113] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen and fluoro, or two R2 The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0114] In some embodiments, R 2 is each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 is each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0115] In some embodiments, R 3 is each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0116] In some embodiments, R 3is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0117] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not an optionally substituted phenyl. In some embodiments, R 4 is not an optionally substituted alkyl.

[0118] 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, optionally substituted C 1-2 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, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0119] 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, 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, halogen, optionally substituted C 1-2 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 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0120] 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.

[0121] 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 selected from optionally substituted C 1-4 alkyl. In some embodiments, R 8 is selected from methyl, ethyl, and propyl.

[0122] R 9 can be any suitable functional group known to those skilled in the art. In some embodiments, R 9 is optionally substituted C 1-4 alkyl, optionally substituted C3-6 Selected from a carbon ring, a 3- to 6-membered heterocycloalkyl, and an optionally substituted C 5-6 heteroaryl. In some embodiments, R 9 is selected from an optionally substituted C 1-4 alkyl, an optionally substituted C 3-6 carbon ring, and an optionally substituted C 5-6 heteroaryl. In some embodiments, R 9 is an optionally substituted C 5-6 heteroaryl. In some embodiments, R 9 is an optionally substituted C5 heteroaryl. In some embodiments, R 9 is an optionally substituted C6 heteroaryl. In some embodiments, R 9 is an optionally substituted pyrazole. In some embodiments, R 9 is selected from an optionally substituted C 1-4 alkyl and an optionally substituted C 3-6 carbon ring. In some embodiments, R 9 is selected from an optionally substituted C 1-4 alkyl. In some embodiments, R 9 is selected from methyl, ethyl, and propyl. In some embodiments, R 9 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 9 is cyclopropyl or cyclobutyl.

[0123] The variable n can be any suitable number known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

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

[0125]

Chemical formula

[0126] Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each may be any suitable functional group 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 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0127] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 , -O-, and -S(O)2-, and Z5 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 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 , -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 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0128] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2. In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R 2are each independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0129] In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are independently selected from hydrogen and fluoro.

[0130] In some embodiments, R 3 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 are each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 are each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R3 is each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0131] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0132] In some embodiments, R 2 are each independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2Each is independently selected from hydrogen and fluoro, or two Rs 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0133] In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are independently selected from hydrogen and fluoro.

[0134] In some embodiments, R 3 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 are each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 are each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 are each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0135] In some embodiments, R3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0136] 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 3-6 carbocyclic ring, and 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 is selected from optionally substituted C 3-4 carbocyclic ring, and 5- to 6-membered heterocycloalkyl. In some embodiments, R 9 is selected from optionally substituted cyclopropyl and optionally substituted pyrazole.

[0137] In some embodiments,

[0138]

Chemical formula

[0139]

Chemical formula

[0140] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IB)

[0141]

Chemical formula

[0142] In some embodiments, two R 2 substituents combine to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, two R 2 substituents combine to form an optionally substituted heterocycle. In some embodiments, two R 2 substituents combine to form an optionally substituted carbocycle. In some embodiments, two R 2 substituents are such that this

[0143]

Chemical formula

[0144]

Chemical formula

[0145] Each of Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 can be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 、Z2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 2 )2-, -C(O)-, -NR 3 (-), -N(C(O)R 2 ), -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each can be any functional group as described above.

[0146] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 2 )2-, -NR 3 (-), -N(C(O)R 2 ), -NS(O2)R 3 , -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 2 )2-, -NR 3 (-), -N(C(O)R 2 ), -NS(O2)R 3 , -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 2 )2-, -NR 3 (-), -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0147] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2. In some embodiments, R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 2 is independently selected from hydrogen and fluoro, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0148] In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0149] In some embodiments, R 3 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each independently selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each independently selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0150] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0151] In some embodiments, R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 is independently selected from hydrogen, fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0152] In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2is independently selected from hydrogen and fluoro.

[0153] In some embodiments, R 3 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each independently selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each independently selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0154] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[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 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0157] 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, 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, halogen, optionally substituted C 1-2 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, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. 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 hydrogen and optionally substituted C 1-4It is selected from alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 7 is hydrogen.

[0159] The variable n can be any suitable number known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

[0160] R 10 can be any suitable functional group known to those skilled in the art. In some embodiments, R 10 is optionally substituted heterocycloalkyl. In some embodiments, R 10 is selected from optionally substituted piperazine, optionally substituted piperidine, and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 10 is selected from optionally substituted piperazine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 10 is selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0161] R 11 can be any suitable functional group known to those skilled in the art. In some embodiments, R 11 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 11 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 11 is optionally substituted C 1-4is selected from alkyl. In some embodiments, R 11 is selected from methyl, ethyl, and propyl.

[0162] The variable p can be any suitable number known to those skilled in the art. In some embodiments, p is selected from 0 to 4. In some embodiments, p is selected from 0 to 3. In some embodiments, p is selected from 0 to 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0.

[0163] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IBB)

[0164]

Chemical formula

[0165] Z 1 , Z 2 , Z3 , Z 4 , and Z 5 Each of which may be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 Each of which is independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 -, -O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 Each of which may be any functional group as described above.

[0166] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 Each of which is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 (-), -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 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 (-), -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(R2 ) 2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0167] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2. In some embodiments, R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 is independently selected from hydrogen and fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0168] In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2is independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0169] In some embodiments, R 3 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each independently selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each independently selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0170] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0171] In some embodiments, R 2 are each independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0172] In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0173] In some embodiments, R 3 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each independently selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each independently selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0174] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0175] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[0176] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5is 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, optionally substituted C 1-2 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, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0177] 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, 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, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0178] 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.

[0179] The variable n can be any suitable number known to those skilled in the art. In some embodiments, n is selected from 0 to 9. In some embodiments, n is selected from 0 to 5. In some embodiments, n is selected from 0 to 3. In some embodiments, n is selected from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

[0180] R 10 can be any suitable functional group known to those skilled in the art. In some embodiments, R 10 is optionally substituted heterocycloalkyl. In some embodiments, R 10 is selected from optionally substituted piperazine, optionally substituted piperidine, and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 10 is selected from optionally substituted piperazine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 10 is selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0181] R 11 can be any suitable functional group known to those skilled in the art. In some embodiments, R 11 is halogen, -CN, and optionally substituted C 1-4is selected from alkyl. In some embodiments, R 11 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 11 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 11 is selected from methyl, ethyl, and propyl.

[0182] The variable p can be any suitable number known to those skilled in the art. In some embodiments, p is selected from 0 to 4. In some embodiments, p is selected from 0 to 3. In some embodiments, p is selected from 0 to 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0.

[0183] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IC)

[0184]

Chemical formula

[0185] In some embodiments, two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two R 2The substituents combine to form an optionally substituted heterocyclic ring. In some embodiments, two R 2 The substituents combine to form an optionally substituted carbocyclic ring. In some embodiments, two R 2 The substituents are such that this

[0186]

Chemical formula

[0187]

Chemical formula

[0188] Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 Each of can be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 Each of is independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 、-O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 Each of can be any functional group as described above.

[0189] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 Each of is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R3 is selected from -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 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 , -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 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0190] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0191] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2Each is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 Each is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 Each is independently selected from hydrogen, fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0192] In some embodiments, R 2 Each is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 Each is independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 Each is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 Is independently selected from hydrogen and fluoro.

[0193] In some embodiments, R 3 Each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 Each is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3is selected from optionally substituted alkyl. In some embodiments, R 3 is each independently selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each independently selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0194] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0195] 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, halogen, optionally substituted C 1-2 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 4 is hydrogen, halogen, -CN, an optionally substituted C 1-2 alkyl, and an optionally substituted C 3-4 carbon ring. In some embodiments, R 4 is selected from hydrogen and an optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not an optionally substituted phenyl. In some embodiments, R 4 is not an optionally substituted alkyl.

[0196] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5 is 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 5 is hydrogen, halogen, an optionally substituted C 1-2 alkyl, an optionally substituted C 3-4 carbon ring, and an optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is hydrogen, halogen, and an optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0197] 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, 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, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0198] 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.

[0199] R 12 can be any suitable functional group known to those skilled in the art. In some embodiments, R 12 is optionally substituted heterocycloalkyl, or R 12 and R 13 together form an optionally substituted heterocycle. In some embodiments, R12 is an optionally substituted 5- to 6-membered heterocyclic ring, or R 12 and R 13 together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 12 is an optionally substituted 5- to 6-membered heterocyclic ring. In some embodiments, R 12 is selected from an optionally substituted piperidine, an optionally substituted piperazine, and an optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 12 is selected from an optionally substituted piperidine and an optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 12 is selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0200] R 13 can be any suitable functional group known to those skilled in the art. In some embodiments, R 13 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, or R 12 and R 13 together form an optionally substituted heterocyclic ring. In some embodiments, R 13 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 13 is selected from methyl, ethyl, and propyl.

[0201] In some embodiments, R 12 and R 13 together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 12 and R 13 together form an optionally substituted heterocyclic ring. In some embodiments, R 12 and R13 is

[0202]

Chem.

[0203]

Chem.

[0204] The variable q can be any number known to those skilled in the art. In some embodiments, q is selected from 0 to 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0205] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (ICC)

[0206]

Chem.

[0207] Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each may be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-, selected from Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0208] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 , -O-, and -S(O)2-, selected from Z 5 is further selected from a bond. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R2 )-, -NS(O2)R 3 is selected from -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 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0209] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0210] In some embodiments, R 2 are each independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, or two R2 The substituents combine to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0211] In some embodiments, R 2 is each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 is each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0212] In some embodiments, R 3 is each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0213] In some embodiments, R 3is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0214] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[0215] 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, optionally substituted C 1-2 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, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0216] 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, 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, halogen, optionally substituted C 1-2 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 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0217] 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.

[0218] R 12 can be any suitable functional group known to those skilled in the art. In some embodiments, R 12 is optionally substituted heterocycloalkyl, or R 12 and R 13 together form an optionally substituted heterocycle. In some embodiments, R 12 is an optionally substituted 5- to 6-membered heterocycle, or R 12 and R 13 together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, R 12 is an optionally substituted 5- to 6-membered heterocycle. In some embodiments, R 12 is selected from optionally substituted piperidine, optionally substituted piperazine, and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R12 is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 12 is selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0219] R 13 can be any suitable functional group known to those skilled in the art. In some embodiments, R 13 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, or R 12 and R 13 together form an optionally substituted heterocyclic ring. In some embodiments, R 13 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 13 is selected from methyl, ethyl, and propyl.

[0220] In some embodiments, R 12 and R 13 together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 12 and R 13 together form an optionally substituted heterocyclic ring. In some embodiments, R 12 and R 13 are

[0221]

Chemical formula

[0222]

Chemical formula

[0223] The variable q can be any number known to those skilled in the art. In some embodiments, q is selected from 0 to 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1.

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

[0225]

Chemical formula

[0226] In some embodiments, two R 2 substituents combine to form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, two R 2 substituents combine to form an optionally substituted heterocycle. In some embodiments, two R 2 substituents combine to form an optionally substituted carbocycle. In some embodiments, two R 2 substituents are this

[0227]

Chemical formula

[0228] [Chemical formula] become integrated so as to be

[0229] Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each may be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 、-O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0230] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 、-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 selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3, -O-, and -S(O)2-, and Z is further selected from bonds. In some embodiments, Z 5 is further selected from bonds. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each independently is selected from -C(R 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from bonds.

[0231] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0232] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, fluoro, or two R 2The substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0233] In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are independently selected from hydrogen and fluoro.

[0234] In some embodiments, R 3 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 are each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 are each, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 are each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0235] In some embodiments, R 3is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0236] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[0237] 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, optionally substituted C 1-2 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, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0238] 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, 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, halogen, optionally substituted C 1-2 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 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0239] 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.

[0240] R 14 can be any suitable functional group known to those skilled in the art. In some embodiments, R 14 is selected from -SOR 16 - and optionally substituted heterocycloalkyl. In some embodiments, R 14 is -SOR 16 -. In some embodiments, R 14 is selected from optionally substituted heterocycloalkyl.

[0241] R 15 can be any suitable functional group known to those skilled in the art. In some embodiments, R 15 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 15 is selected from hydrogen, halogen, and optionally substituted C 1-4It is selected from alkyl. In some embodiments, R 15 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is optionally substituted C 1-4 alkyl. In some embodiments, R 15 is methyl, ethyl, and propyl.

[0242] R 16 can be any suitable functional group known to those skilled in the art. In some embodiments, R 16 is selected from 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 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 16 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 16 is selected from methyl, ethyl, and propyl.

[0243] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IDD)

[0244]

Chemical formula

[0245] Z 1 、Z 2 、Z 3 、Z 4 、 and Z 5 each may be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、 and Z 5 each is independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 2 、-O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each may be any functional group as described above.

[0246] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、 and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 、-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 is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 、-O-, and -S(O)2-, and Z 5 is further selected from a bond. In some embodiments, Z 1 、Z 2 、Z 3 、Z4 and Z 5 Each of which is independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0247] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0248] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen and fluoro, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle.

[0249] In some embodiments, R 2are each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 are each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 are each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 are independently selected from hydrogen and fluoro.

[0250] In some embodiments, R 3 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 are each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 are each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 are each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0251] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0252] R 4 can be any suitable functional group known to those skilled in the art. In some embodiments, R 4 is 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 hydrogen, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[0253] 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 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 5 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0254] 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, 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, halogen, optionally substituted C 1-2 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, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0255] 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. R 15 can be any suitable functional group known to those skilled in the art. In some embodiments, R 15 is selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 15 is selected from hydrogen, halogen, and optionally substituted C 1-4 alkyl. In some embodiments, R 15 is selected from hydrogen and optionally substituted C 1-4 alkyl. In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is optionally substituted C 1-4 alkyl. In some embodiments, R 15 is methyl, ethyl, and propyl.

[0256] R 16 can be any suitable functional group known to those skilled in the art. In some embodiments, R 16 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 16is optionally substituted C 3-6 a carbocyclic ring, and an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 16 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 16 is selected from methyl, ethyl, and propyl.

[0257] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IE)

[0258]

Chemical formula

[0259] In some embodiments, two R 2 substituents combine to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, two R 2 substituents combine to form an optionally substituted heterocyclic ring. In some embodiments, two R 2 substituents combine to form an optionally substituted carbocyclic ring. In some embodiments, two R 2 substituents are this

[0260] [Chemistry] The structure is

[0261] [Chemistry] become integrated so as to be.

[0262] Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each can be any suitable functional group known to those skilled in the art. In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each is independently selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 、-O-, -S-, -S(O)-, and -S(O)2-, and Z 5 is further selected from a bond. Z 1 and Z 2 each can be any functional group as described above.

[0263] In some embodiments, Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 、-O-, and -S(O)2-, and Z 5 is further selected from a bond. In some embodiments, Z 1 、Z 2 、Z 3 、Z4 and Z 5 Each of which is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 , -O-, and -S(O)2-, and Z 5 is further selected from bonds. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 Each of which is independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from bonds.

[0264] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0265] In some embodiments, each R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle. In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, each R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2The substituents combine to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 2 is each independently selected from hydrogen, fluoro, or two R 2 substituents combine to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0266] In some embodiments, R 2 is each independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is each independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2 is each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0267] In some embodiments, R 3 is each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is each independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each selected from cyclopropyl and cyclobutyl. In some embodiments, R 3is cyclopropyl.

[0268] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0269] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[0270] 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, optionally substituted C 1-2 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, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0271] 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, optionally substituted C 1-4 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0272] 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. R 14 can be any suitable functional group known to those skilled in the art. In some embodiments, R 14 is -SOR 16 - and optionally substituted heterocycloalkyl. In some embodiments, R 14 is -SOR 16 -. In some embodiments, R 14 is selected from optionally substituted heterocycloalkyl.

[0273] R 17 can be any suitable functional group known to those skilled in the art. In some embodiments, R 17 is -SOR 19 -, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycloalkyl. In some embodiments, R17 is -SOR 19 - is selected from optionally substituted alkyl and optionally substituted 3- to 5-membered heterocycloalkyl. In some embodiments, R 17 is -SOR 19 - is selected from -SOR, methyl, and optionally substituted 4-membered heterocycloalkyl. In some embodiments, R 17 is -SOR 19 - is selected from -SOR, methyl, and 1-(methylsulfonyl)azetidine. In some embodiments, R 17 is -SOR 19 - In some embodiments, R 17 is methyl. In some embodiments, R 17 is 1-(methylsulfonyl)azetidine.

[0274] R 18 can be any suitable functional group known to those skilled in the art. In some embodiments, R 18 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 18 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 18 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 18 is selected from methyl, ethyl, and propyl.

[0275] R 19 can be any suitable functional group known to those skilled in the art. In some embodiments, R 19 is selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocyclic ring, and optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 19 is selected from optionally substituted C 3-6It is a carbon ring and an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 19 is an optionally substituted alkyl. In some embodiments, R 19 is selected from methyl, ethyl, and propyl. In some embodiments, R 19 is methyl.

[0276] The variable r can be any suitable number known to those skilled in the art. In some embodiments, r is selected from 0 to 5. In some embodiments, r is selected from 0 to 3. In some embodiments, r is selected from 0 to 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0.

[0277] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has the structure of formula (IEE)

[0278]

Chemical formula

[0279] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 each can be any suitable functional group known to those skilled in the art. In some embodiments, each of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is independently -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R2 )-, -NS(O2)R 2 selected from -O-, -S-, -S(O)-, and -S(O)2-, where Z 5 is further selected from a bond. Z 1 and Z 2 each can be any functional group as described above.

[0280] In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each are independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 , -O-, and -S(O)2-, where Z 5 is further selected from a bond. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each are independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 , -O-, and -S(O)2-, where Z 5 is further selected from a bond. In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S(O)2-, where Z 5 is further selected from a bond.

[0281] 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 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0282] In some embodiments, R 2 is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, chloro, cyclopropyl, cyclobutyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. In some embodiments, R 2 is independently selected from hydrogen and fluoro, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0283] In some embodiments, R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. In some embodiments, R 2 is independently selected from hydrogen, fluoro, and -OH. In some embodiments, R 2is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R 2 is independently selected from hydrogen and fluoro.

[0284] In some embodiments, R 3 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is independently selected from optionally substituted alkyl, optionally substituted C 3-4 carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 3 is selected from optionally substituted alkyl. In some embodiments, R 3 is each independently selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is each independently selected from cyclopropyl and cyclobutyl. In some embodiments, R 3 is cyclopropyl.

[0285] In some embodiments, R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 is selected from -(CH2)2OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In some embodiments, R 3 is methyl.

[0286] 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, halogen, optionally substituted C 1-2 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 C 1-2 alkyl, and optionally substituted C 3-4 carbocycle. In some embodiments, R 4 is selected from hydrogen and optionally substituted C1 alkyl. In some embodiments, R 4 is selected from hydrogen, methyl, and -CHF2. In some embodiments, R 4 is selected from hydrogen, halogen, and -CN. In some embodiments, R 4 is selected from hydrogen. In some embodiments, R 4 is not optionally substituted phenyl. In some embodiments, R 4 is not optionally substituted alkyl.

[0287] R 5 can be any suitable functional group known to those skilled in the art. In some embodiments, R 5is 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, optionally substituted C 1-2 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, and optionally substituted C 1-2 alkyl. In some embodiments, R 5 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 5 is selected from hydrogen and fluoro.

[0288] 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, 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, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments, R 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl. In some embodiments, R 6 is selected from hydrogen, fluoro, chloro, methyl, ethyl, and propyl. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen.

[0289] 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. R 14 can be any suitable functional group known to those skilled in the art. In some embodiments, R 14 is selected from -SOR 16 - and optionally substituted heterocycloalkyl. In some embodiments, R 14 is -SOR 16 -. In some embodiments, R 14 is selected from optionally substituted heterocycloalkyl.

[0290] R 18 can be any suitable functional group known to those skilled in the art. In some embodiments, R 18 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl. In some embodiments, R 18 is selected from halogen and optionally substituted C 1-4 alkyl. In some embodiments, R 18 is selected from optionally substituted C 1-4 alkyl. In some embodiments, R 18 is selected from methyl, ethyl, and propyl.

[0291] R 19 can be any suitable functional group known to those skilled in the art. In some embodiments, R 19 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6Selected from a carbon ring and an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 19 is an optionally substituted C 3-6 carbon ring and an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 19 is an optionally substituted alkyl. In some embodiments, R 19 is selected from methyl, ethyl, and propyl. In some embodiments, R 19 is methyl.

[0292] The variable r can be any suitable number known to those skilled in the art. In some embodiments, r is selected from 0 to 5. In some embodiments, r is selected from 0 to 3. In some embodiments, r is selected from 0 to 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0.

[0293] In some embodiments, the compound is

[0294]

Chemical formula

[0295] In some embodiments, the compound is

[0296]

Chemical formula

[0297] In some embodiments, the compound is

[0298]

Chemical formula

[0299] In some embodiments, the compound is

[0300]

Chem.

[0301] In some embodiments, the compound is

[0302]

Chem.

[0303] In some embodiments, the compound is

[0304]

Chem.

[0305] Further embodiments of the compounds of the present disclosure include the following.

[0306] Embodiment 1 relates to a compound having the structure of formula (I)

[0307]

Chem.

[0308]

Chemical formula

[0309] Embodiment 2 relates to the compound according to Embodiment 1 having the structure of formula (I)

[0310]

Chemical formula

[0311] Embodiment 3 is formula (IA), (IB), (IC), (ID), or (IE)

[0312] [Chemical formula] Regarding the compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt or solvate thereof having any one of the following structures: In the formula, R 8 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, R 9 is optionally substituted C 3-6 carbocycle, optionally substituted C 5-6 heteroaryl, and 3- to 6-membered heterocycloalkyl, R 10 is optionally substituted alkyl or optionally substituted heterocycloalkyl, R 11 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, R 12 is selected from optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl, or R 12 and R 13 together form an optionally substituted heterocyclic ring, R 13 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, n is selected from 0 to 9, R 14 is selected from -SOR 16 - and optionally substituted heterocycloalkyl, R 15 is hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl, R 16 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6Selected from a carbon ring and an optionally substituted 3- to 6-membered heterocycloalkyl, R 17 is -SOR 19 -, and is selected from an optionally substituted alkyl, an optionally substituted carbon ring, and an optionally substituted heterocycloalkyl, R 18 is halogen, -CN, and an optionally substituted C 1-4 alkyl, R 19 is an optionally substituted C 1-4 alkyl, an optionally substituted C 3-6 carbon ring, and an optionally substituted 3- to 6-membered heterocycloalkyl, r is selected from 0 to 5, p is selected from 0 to 4, q is selected from 0 to 2, and, when the compound is a compound of formula (IA), (i) Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbon ring, or (ii) R 4 is selected from hydrogen, halogen, and -CN.

[0313] Embodiment 4 relates to the compound according to Embodiment 3 having the structure of formula (IA) or a pharmaceutically acceptable salt or solvate thereof.

[0314] Embodiment 5 relates to the compound according to Embodiment 3 having the structure of formula (IB) or a pharmaceutically acceptable salt or solvate thereof.

[0315] Embodiment 6 relates to the compound according to Embodiment 3 having the structure of formula (IC) or a pharmaceutically acceptable salt or solvate thereof.

[0316] Embodiment 7 relates to the compound according to Embodiment 3 having the structure of formula (IE) or a pharmaceutically acceptable salt or solvate thereof.

[0317] Embodiment 8 relates to the compound according to any one of Embodiments 1 to 7 or a pharmaceutically acceptable salt or solvate thereof, where Z 1 and Z 2 are each independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-.

[0318] Embodiment 9 relates to the compound according to Embodiment 8 or a pharmaceutically acceptable salt or solvate thereof, where Z 1 and Z 2 are each independently -C(R 2 )2-.

[0319] Embodiment 10 relates to the compound according to Embodiment 9 or a pharmaceutically acceptable salt or solvate thereof, where each of a and b is independently selected from 1 and 2.

[0320] Embodiment 11 relates to the compound according to any one of Embodiments 1 to 10 or a pharmaceutically acceptable salt or solvate thereof, where Y 1 is selected from -C(R 2 )2-, -NR 3 -, -NS(O2)R 2 , -O-, -S(O)2-, and -S-.

[0321] Embodiment 12 relates to the compound according to Embodiment 11 or a pharmaceutically acceptable salt or solvate thereof, where Y 1 is selected from -C(R 2 )2- and -NR 3 .

[0322] Embodiment 13 relates to the compound according to any one of Embodiments 1 to 12 or a pharmaceutically acceptable salt or solvate thereof, where R 2Each is independently selected from hydrogen, OH, halogen, -CN, optionally substituted alkyl, optionally substituted -O-alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0323] Embodiment 14 relates to the compound according to Embodiment 13 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Each is independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0324] Embodiment 15 relates to the compound according to Embodiment 14 or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 Each is independently selected from hydrogen, -CN, and cyclopropyl.

[0325] Embodiment 16 relates to the compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, wherein two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0326] Embodiment 17 relates to the compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Each is independently selected from fluoro, optionally substituted alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0327] Embodiment 18 relates to the compound according to Embodiment 17 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Each is selected from methyl, methoxyethylene, CD3, cyclopropyl, and cyclobutyl.

[0328] Embodiment 19 relates to the compound described in Embodiment 18 or a pharmaceutically acceptable salt or solvate thereof, where R 3 is cyclopropyl

[0329] Embodiment 20 relates to a compound described in Embodiments 1 to 3 or a pharmaceutically acceptable salt or solvate thereof having any one of the structures of formula (IAA), (IBB), (ICC), (IDD), or (IEE)

[0330]

Chemical formula

[0331] Embodiment 21 relates to the compound according to Embodiment 20 having the structure of formula (IAA) or a pharmaceutically acceptable salt or solvate thereof.

[0332] Embodiment 22 relates to the compound according to Embodiment 20 having the structure of formula (IBB) or a pharmaceutically acceptable salt or solvate thereof.

[0333] Embodiment 23 relates to the compound according to Embodiment 20 having the structure of formula (ICC) or a pharmaceutically acceptable salt or solvate thereof.

[0334] Embodiment 24 relates to the compound according to Embodiment 20 having the structure of formula (IEE) or a pharmaceutically acceptable salt or solvate thereof.

[0335] Embodiment 25 relates to the compound according to any one of Embodiments 16 to 24 or a pharmaceutically acceptable salt or solvate thereof, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 3 , -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0336] Embodiment 26 relates to the compound according to Embodiment 25 or a pharmaceutically acceptable salt or solvate thereof, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond.

[0337] Embodiment 27 relates to the compound according to any one of Embodiments 16 to 26 or a pharmaceutically acceptable salt or solvate thereof, R 2 are each independently selected from hydrogen, halogen, -CN, OH, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0338] Embodiment 28 relates to the compound according to Embodiment 27 or a pharmaceutically acceptable salt or solvate thereof, R 2 are each hydrogen, fluoro, CN, cyclopropyl, cyclobutyl, -C 1-4 alkyl, -C 1-4 haloalkyl, -O-C1-4 Alkyl, -C 1-4 Alkylene - O - C 1-3 Alkyl, -C 1-4 It is selected from alkylene - OH, optionally substituted oxetane, and optionally substituted azetidine.

[0339] Embodiment 29 relates to the compound according to any one of Embodiments 16 to 28 or a pharmaceutically acceptable salt or solvate thereof, and R 3 is hydrogen, -(CH2)2OMe, -S(O)2CH3, -C 1-4 Alkylene - O - C 1-3 Alkyl, C 1-4 is selected from alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0340] Embodiment 30 relates to the compound according to Embodiment 29 or a pharmaceutically acceptable salt or solvate thereof, and R 3 is hydrogen, -(CH2)2OMe, C 1-4 is selected from alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0341] Embodiment 31 relates to the compound according to Embodiment 30 or a pharmaceutically acceptable salt or solvate thereof, and R 3 is selected from hydrogen, methyl, ethyl, propyl, CD3, and cyclopropyl.

[0342] Embodiment 32 relates to the compound according to any one of Embodiments 16 to 31 or a pharmaceutically acceptable salt or solvate thereof, and each of a, b, c, and d is independently selected from 1 and 2.

[0343] Embodiment 33 relates to the compound or its pharmaceutically acceptable salt or solvate described in Embodiment 1 or 2, wherein A is selected from optionally substituted cyclohexane, optionally substituted pyridine, optionally substituted piperidine, optionally substituted tetrahydropyran, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azetidine, and optionally substituted tetrahydroisoquinoline.

[0344] Embodiment 34 relates to the compound or its pharmaceutically acceptable salt or solvate described in Embodiment 33, wherein A is optionally substituted piperidine.

[0345] Embodiment 35 relates to the compound or its pharmaceutically acceptable salt or solvate described in Embodiment 34, wherein A is substituted with -SO2R 9 and R 9 is selected from optionally substituted C 3-6 carbocyclic ring, optionally substituted C 5-6 heteroaryl, and 3- to 6-membered heterocycloalkyl.

[0346] Embodiment 36 relates to the compound or its pharmaceutically acceptable salt or solvate described in Embodiment 34 or 35, wherein m is selected from 0 to 1.

[0347] Embodiment 37 relates to the compound or its pharmaceutically acceptable salt or solvate described in any one of Embodiments 34 to 36, wherein each R 1 is independently selected from optionally substituted alkyl, optionally substituted carbocyclic ring, and optionally substituted heterocyclic ring.

[0348] Embodiment 38 relates to the compound or its pharmaceutically acceptable salt or solvate described in Embodiment 37, wherein each R 1 is independently selected from optionally substituted alkyl and optionally substituted heterocyclic ring.

[0349] Embodiment 39 relates to the compound described in Embodiment 37 or a pharmaceutically acceptable salt or solvate thereof, where R 1 is independently selected from methyl, ethyl, and optionally substituted diazaspiro[3.3]heptane.

[0350] Embodiment 40 relates to the compound described in any one of Embodiments 1 to 13 and 34 to 39 or a pharmaceutically acceptable salt or solvate thereof, where Z 1 and Z 2 are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-.

[0351] Embodiment 41 relates to the compound described in Embodiment 40 or a pharmaceutically acceptable salt or solvate thereof, where Z 1 and Z 2 are each -C(R 2 )2-.

[0352] Embodiment 42 relates to the compound described in Embodiment 40 or 41 or a pharmaceutically acceptable salt or solvate thereof, where each of a and b is independently selected from 1 and 2.

[0353] Embodiment 43 relates to the compound described in any one of Embodiments 1 to 13 and 34 to 42 or a pharmaceutically acceptable salt or solvate thereof, where Y 1 is selected from -C(R 2 )2-, -NR 3 ]-, -O-, and -S-.

[0354] Embodiment 44 relates to the compound described in Embodiment 43 or a pharmaceutically acceptable salt or solvate thereof, where Y 1 is selected from -C(R 2 )2- and -NR 3 .

[0355] Embodiment 45 relates to the compound described in Embodiment 44 or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring.

[0356] Embodiment 46 relates to the compound described in Embodiment 46 or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring.

[0357] Embodiment 47 relates to the compound described in any one of Embodiments 1 to 19 and 34 to 46 or a pharmaceutically acceptable salt or solvate thereof,

[0358]

Chemical formula

[0359] Embodiment 48 relates to the compound described in any one of Embodiments 1 to 19 and 34 to 46 or a pharmaceutically acceptable salt or solvate thereof, with respect to Formulas (I), (IB), (IC), (ID), and (IE)

[0360]

Chemical formula

[0361]

Chemical formula

[0362] Embodiment 48(a) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to formulas (I), (IB), (IC), (ID), and (IE)

[0363]

Chemical formula

[0364]

Chemical formula

[0365] Embodiment 48(b) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to formulas (I), (IB), (IC), (ID), and (IE)

[0366]

Chemical formula

[0367]

Chemical formula

[0368] Embodiment 48(c) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to formulas (I), (IB), (IC), (ID), and (IE)

[0369]

Chemical formula

[0370]

Chemical formula

[0371] Embodiment 48(d) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by the formulas (I), (IB), (IC), (ID), and (IE)

[0372]

Chemical formula

[0373]

Chemical formula

[0374] Embodiment 48(e) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by the formulas (I), (IB), (IC), (ID), and (IE)

[0375]

Chemical formula

[0376]

Chemical formula

[0377] Embodiment 48(f) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by the formulas (I), (IB), (IC), (ID), and (IE)

[0378]

Chemical formula

[0379]

Chemical formula

[0380] Embodiment 48(g) relates to a compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and for formulas (I), (IB), (IC), (ID), and (IE),

[0381]

Chemical formula

[0382]

Chemical formula

[0383] Embodiment 48(h) relates to a compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and for formulas (I), (IB), (IC), (ID), and (IE),

[0384]

Chemical formula

[0385]

Chemical formula

[0386] Embodiment 48(i) relates to a compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and for formulas (I), (IB), (IC), (ID), and (IE),

[0387]

Chemical formula

[0388]

Chemical formula

[0389] Embodiment 48(j) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the formulas (I), (IB), (IC), (ID), and (IE)

[0390]

Chemical formula

[0391]

Chemical formula

[0392] Embodiment 48(k) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the formulas (I), (IB), (IC), (ID), and (IE)

[0393]

Chemical formula

[0394]

Chemical formula

[0395] Embodiment 48(l) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the formulas (I), (IB), (IC), (ID), and (IE)

[0396]

Chemical formula

[0397]

Chemical formula

[0398] Embodiment 48(m) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by the formulas (I), (IB), (IC), (ID), and (IE)

[0399]

Chemical formula

[0400]

Chemical formula

[0401] Embodiment 48(n) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by the formulas (I), (IB), (IC), (ID), and (IE)

[0402]

Chemical formula

[0403]

Chemical formula

[0404] Embodiment 48(o) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by the formulas (I), (IB), (IC), (ID), and (IE)

[0405]

Chemical formula

[0406]

Chemical formula

[0407] Embodiment 48(p) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by formulas (I), (IB), (IC), (ID), and (IE)

[0408]

Chemical formula

[0409]

Chemical formula

[0410] Embodiment 48(q) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by formulas (I), (IB), (IC), (ID), and (IE)

[0411]

Chemical formula

[0412]

Chemical formula

[0413] Embodiment 48(r) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by formulas (I), (IB), (IC), (ID), and (IE)

[0414]

Chemical formula

[0415]

Chemical formula

[0416] Embodiment 48(s) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and for formulas (I), (IB), (IC), (ID), and (IE),

[0417]

Chemical formula

[0418]

Chemical formula

[0419] Embodiment 48(t) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and for formulas (I), (IB), (IC), (ID), and (IE),

[0420]

Chemical formula

[0421]

Chemical formula

[0422] Embodiment 48(u) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and for formulas (I), (IB), (IC), (ID), and (IE),

[0423]

Chemical formula

[0424]

Chemical formula

[0425] Embodiment 48(v) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formula (I), (IB), (IC), (ID), and (IE)

[0426]

Chemical formula

[0427]

Chemical formula

[0428] Embodiment 48(w) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formula (I), (IB), (IC), (ID), and (IE)

[0429]

Chemical formula

[0430]

Chemical formula

[0431] Embodiment 48(x) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formula (I), (IB), (IC), (ID), and (IE)

[0432]

Chemical formula

[0433]

Chemical formula

[0434] Embodiment 48(y) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0435]

Chemical formula

[0436]

Chemical formula

[0437] Embodiment 48(z) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0438]

Chemical formula

[0439]

Chemical formula

[0440] Embodiment 48(aa) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0441]

Chemical formula

[0442]

Chemical formula

[0443] Embodiment 48(ab) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formula (IA), (IB), (IC), (ID), and (IE)

[0444]

Chem.

[0445]

Chem.

[0446] Embodiment 48(ac) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formula (IA), (IB), (IC), (ID), and (IE)

[0447]

Chem.

[0448]

Chem.

[0449] Embodiment 48(ad) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formula (IA), (IB), (IC), (ID), and (IE)

[0450]

Chem.

[0451]

Chem.

[0452]

Chemical formula

[0453]

Chemical formula

[0454] Embodiment 48(af) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0455]

Chemical formula

[0456]

Chemical formula

[0457] Embodiment 48(ag) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0458]

Chemical formula

[0459]

Chemical formula

[0460] Embodiment 48(ah) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by formulas (IA), (IB), (IC), (ID), and (IE)

[0461]

Chemical formula

[0462]

Chemical formula

[0463] Embodiment 48(ai) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by formulas (IA), (IB), (IC), (ID), and (IE)

[0464]

Chemical formula

[0465]

Chemical formula

[0466] Embodiment 48(aj) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and to the N-containing heterocycles as depicted by formulas (IA), (IB), (IC), (ID), and (IE)

[0467]

Chemical formula

[0468]

Chemical formula

[0469] Embodiment 48(ak) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0470]

Chemical formula

[0471]

Chemical formula

[0472] Embodiment 48(al) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0473]

Chemical formula

[0474]

Chemical formula

[0475] Embodiment 48(am) relates to the compound described in Embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, and the N-containing heterocycles depicted as in Formulae (IA), (IB), (IC), (ID), and (IE)

[0476]

Chemical formula

[0477]

Chemical formula

[0478] Embodiment 49 relates to the compound according to any one of Embodiments 1 to 32, 34 to 48, or 48(a) to 48(aj), or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0479] Embodiment 50 relates to the compound according to Embodiment 49, or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen and optionally substituted C1 alkyl.

[0480] Embodiment 51 relates to the compound according to Embodiment 50, or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen, methyl, and -CHF2.

[0481] Embodiment 52 relates to the compound according to any one of Embodiments 1 to 32, 34 to 48, or 48(a) to 48(aj), or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen, halogen, and -CN.

[0482] Embodiment 53 relates to the compound according to any one of Embodiments 1 to 32, 34 to 48, or 48(a) to 48(aj), or a pharmaceutically acceptable salt or solvate thereof, where R 4 is selected from hydrogen.

[0483] Embodiment 54 relates to the compound according to any one of Embodiments 1 to 32, 34 to 48, or 48(a) to 48(aj), or a pharmaceutically acceptable salt or solvate thereof, where R 4 is not optionally substituted phenyl.

[0484] Embodiment 55 relates to a compound according to any one of Embodiments 1 to 32, 34 to 48, or 48(a) to 48(aj), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is not optionally substituted alkyl.

[0485] Embodiment 56 relates to a compound according to any one of Embodiments 1 to 32, 34 to 39, or 50 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0486] Embodiment 57 relates to a compound according to Embodiment 56, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen, halogen, and optionally substituted C 1-2 alkyl.

[0487] Embodiment 58 relates to a compound according to Embodiment 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from hydrogen and fluoro.

[0488] Embodiment 59 relates to a compound according to any one of Embodiments 1 to 32, 34 to 39, or 50 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0489] Embodiment 60 relates to a compound according to Embodiment 59, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen, halogen, and optionally substituted C 1-2 alkyl.

[0490] Embodiment 61 relates to the compound described in Embodiment 60 or a pharmaceutically acceptable salt or solvate thereof, where R 6 is hydrogen.

[0491] Embodiment 62 relates to the compound described in any one of Embodiments 1 to 32, 34 to 39, or 50 to 61 or a pharmaceutically acceptable salt or solvate thereof, where R 7 is hydrogen.

[0492] Embodiment 63 relates to the compound described in any one of Embodiments 3 to 4, 8 to 21, or 25 to 32 or a pharmaceutically acceptable salt or solvate thereof, where R 9 is selected from cyclopentyl, methylcyclopentyl, cyclobutylmethylene, cyclopentylmethylene, and n-methylpyrazolyl.

[0493] Embodiment 63(a) relates to the compound described in Embodiment 63 or a pharmaceutically acceptable salt or solvate thereof, where R 9 is cyclopentyl.

[0494] Embodiment 63(b) relates to the compound described in Embodiment 63 or a pharmaceutically acceptable salt or solvate thereof, where R 9 is methylcyclopentyl.

[0495] Embodiment 63(c) relates to the compound described in Embodiment 63 or a pharmaceutically acceptable salt or solvate thereof, where R 9 is cyclobutylmethylene.

[0496] Embodiment 63(d) relates to the compound described in Embodiment 63 or a pharmaceutically acceptable salt or solvate thereof, where R 9 is cyclopentylmethylene.

[0497] Embodiment 63(e) relates to the compound described in Embodiment 63 or a pharmaceutically acceptable salt or solvate thereof, where R9 is n-methylpyrazole.

[0498] Embodiment 64 relates to the compound according to Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, and the compound is selected from Table 1.

[0499] Embodiment 65 relates to the compound according to Embodiment 2 or a pharmaceutically acceptable salt or solvate thereof, and the compound is selected from Table 1.

[0500] Embodiment 66 relates to the compound according to Embodiment 3 or a pharmaceutically acceptable salt or solvate thereof, and the compound is selected from Table 1.

[0501] Embodiment 66(a) relates to the compound (IA) according to Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0502] Embodiment 66(b) relates to the compound (IB) according to Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0503] Embodiment 66(c) relates to the compound (IC) according to Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0504] Embodiment 66(d) relates to the compound (ID) according to Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0505] Embodiment 66(e) relates to the compound (IE) according to Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0506] Embodiment 67 relates to the compound according to Embodiment 20 or a pharmaceutically acceptable salt or solvate thereof, and the compound is selected from Table 1.

[0507] Embodiment 67(a) relates to a compound (IAA) described in Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0508] Embodiment 67(b) relates to a compound (IBB) described in Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0509] Embodiment 67(c) relates to a compound (ICC) described in Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0510] Embodiment 67(d) relates to a compound (IDD) described in Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0511] Embodiment 67(e) relates to a compound (IEE) described in Embodiment 66 selected from the compounds in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0512] 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 14 C are enriched in the content. 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. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. 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.

[0513] 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, the compounds having this structure are within the scope of the present disclosure, except for substitution with carbon enriched in carbon.

[0514] 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 125 I are all contemplated. All variations of the isotopes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0515] In certain embodiments, the compounds disclosed herein are 2 exchanged with 1It has some or all of the H atoms. Methods for synthesizing compounds containing deuterium are known in the art and include, as a non-limiting example, the following synthetic methods.

[0516] Deuterium-substituted compounds are synthesized using a variety of methods as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0517] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein for synthesizing compounds containing deuterium. Many deuterium-containing reagents and building blocks are commercially available from chemical supply companies such as Aldrich Chemical Co.

[0518] 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 anhydrates), stereopolymorphs, and amorphous forms of the above compounds, as well as mixtures thereof.

[0519] 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 appropriate counterions, such as bromide, chloride, or fluoride, particularly halides such as bromide.

[0520] 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 appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by formation of diastereomers 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.

[0521] 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.

[0522] 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.

[0523] Prodrug forms of the compounds described herein that produce a compound as described herein when the prodrug is 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.

[0524] Prodrugs are often useful because, depending on the situation, they may be easier to administer than the parent drug. A prodrug can be, for example, bioavailable by oral administration, while the parent drug is not. A prodrug may help enhance the cellular permeability of the compound as compared to the parent drug. A prodrug is further characterized by improved solubility in a pharmaceutical composition as compared to the parent drug. A prodrug may be designed as a reversible drug derivative for use as a modifying agent to enhance the transport of the drug to a site-specific tissue or to increase the retention of the drug inside the cell.

[0525] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical. In some embodiments, the prodrug design increases effective water solubility. (See, for example, 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 of manufacturing the above-defined compounds. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are successfully synthesized from readily available starting materials.

[0526] 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).

[0527] Therapeutic use Methods of administration of the compounds of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or pharmaceutically acceptable salts described herein can be used for the treatment of cancer. In some embodiments, methods of treating solid tumors are disclosed herein. Examples of cancers include, but are not limited to, ovarian cancer, breast cancer, colon cancer, and brain tumors.

[0528] In some embodiments, methods of treating cancer by administration of the compounds of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or pharmaceutically acceptable salts are disclosed herein. In some embodiments, methods of treating cancer comprising administering to a subject in need thereof a pharmaceutical composition described herein are disclosed herein. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumors. In some embodiments, the cancer is ovarian cancer or breast cancer.

[0529] In some embodiments, methods of inhibiting cyclin-dependent kinase (CDK) in cells by administration of a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or a pharmaceutically acceptable salt thereof are disclosed herein. In some embodiments, methods of inhibiting cyclin-dependent kinase (CDK) 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.

[0530] The CDK can be any suitable CDK known to those skilled 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 69 relates to a method of treating cancer comprising administering to a subject in need of treatment a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 67 or any lower-level embodiment thereof, or a pharmaceutical composition described in Embodiment 68. Embodiment 70 relates to the method described in Embodiment 69, wherein the cancer is a solid tumor. Embodiment 71 relates to the method described in Embodiment 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumor. Embodiment 72 relates to the method described in Embodiment 71, wherein the cancer is ovarian cancer or breast cancer. Embodiment 73 relates to a method of inhibiting cyclin-dependent kinase (CDK) in cells using any one of the compounds or pharmaceutically acceptable salts of the compounds described in any one of Embodiments 1 to 67 or any lower-level embodiment thereof, or a pharmaceutical composition described in Embodiment 68. Embodiment 74 relates to the method described in Embodiment 73, and the CDK is selected from CDK2, CDK4, CD6, or any combination thereof. Embodiment 75 relates to the method described in Embodiment 74, and the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6. Embodiment 76 relates to the method described in Embodiment 75, and the CDK is CDK2 / 4 / 6.

[0531] Pharmaceutical formulation 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), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) 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 a 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), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) described herein or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient is disclosed herein.

[0532] A pharmaceutical composition comprising a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or a pharmaceutically acceptable salt thereof 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 in pharmaceutically acceptable salt form. Further embodiments of the pharmaceutical formulations of the present disclosure include the following. Embodiment 68 relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt described in any one of Embodiments 1 to 67 or any sub-embodiment thereof and a pharmaceutically acceptable excipient.

[0533] A method for formulating a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or a pharmaceutically acceptable salt thereof can 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 with a suitable vehicle, such as pyrogen-free sterile water, before use.

[0534] A pharmaceutical composition comprising a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) 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., hydroxyethylmethylcellulose or gelatin microcapsules and poly-(methylmethacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions.

[0535] The compositions and formulations can be sterilized. Sterilization can be achieved by filtration by sterile filtration.

[0536] A composition comprising a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or a pharmaceutically acceptable salt 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 may be lyophilized or in powder form for reconstitution prior to use with a suitable vehicle, such as sterile water free of pyrogens.

[0537] For parenteral administration, the compounds of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or pharmaceutically acceptable salts thereof can be formulated in unit dose injectable forms (e.g., solutions, suspensions, emulsions) together with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be essentially non-toxic and non-therapeutic. The vehicles can be water, physiological 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 carriers. The vehicle can contain trace amounts of additives (e.g., buffers and preservatives) such as substances that enhance isotonicity and chemical stability.

[0538] In one embodiment, the invention relates to methods and compositions of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) 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.

[0539] In one embodiment, the compositions of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) 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 can further contain non-release controlling excipients.

[0540] In another embodiment, the compositions of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) are provided in enteric-coated dosage forms. These enteric-coated dosage forms can further include 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 include 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 include glycerol monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[0541] In another embodiment, the compositions of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) are enteric-coated controlled-release tablets for oral administration. The composition can further include carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow iron oxide.

[0542] Sustained-release preparations can be prepared containing a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or a pharmaceutically acceptable salt thereof. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers which 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 can 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 DEPOTM (trademark) (i.e., injectable microspheres composed of a lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0543] A pharmaceutical formulation comprising a compound of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE), 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. The formulation can be a lyophilized formulation or an aqueous solution. The acceptable carrier, excipient, and / or stabilizer can be non-toxic to the recipient at the dosages and concentrations 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.

[0544] In another embodiment, a composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) 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.

[0545] In another embodiment, a composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) is provided in a foaming form. These foaming forms can also include non-release controlling excipients.

[0546] In another embodiment, the composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) 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.

[0547] In another embodiment, the composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) is 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.

[0548] In some embodiments, the compositions of (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) provided herein can be in unit dosage form or multiple dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for administration to a human or non-human animal and individually packaged. Each unit dosage 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, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, the unit dosage form can be administered in its fraction or multiple. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, which can be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment, the multiple dosage forms contain different pharmaceutically active agents.

[0549] In some embodiments, the compositions of (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) can further be formulated as a controlled release dosage form, including immediate release, delayed release, sustained release, extended release, slow release, pulsed release, controlled release, sustained release, accelerated release, and high speed release, targeted release, programmed release, and as a gastric retention dosage form. 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 incorporated herein by reference in its entirety).

[0550] Combination therapy Combination therapy, for example, co - administering the disclosed compounds and additional active agents as part of a specific treatment regimen intended to produce beneficial effects from the co - action of these therapeutic agents is also contemplated herein. 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, depending on the selected combination, hours, days, weeks, months, or years). Combination therapy is intended to include administration of multiple therapeutic agents in a sequential manner, i.e., administration where each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents or at least two of the therapeutic agents in a substantially simultaneous manner.

[0551] Substantially simultaneous administration is achieved, for example, by administering to the subject a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent) or 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 tissues. 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.

[0552] The components of the combination are administered to the patient simultaneously or sequentially. The components are present in the same pharmaceutically acceptable carrier and are thus understood to be administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially.

[0553] Additional embodiments Embodiment 101. Formula (I)

[0554] [Chemistry] a compound having the structure of or a pharmaceutically acceptable salt or solvate thereof, wherein, A is a ring selected from an optionally substituted carbocycle, an optionally substituted 4- to 6-membered heterocycle, and an optionally substituted isoindoline; Z 1 , Z 2 , and Y 1 each independently is selected from -C(R 2 )2-, -C(O)-, -NR 3 -, -N(C(O)R 2 ), -NS(O2)R 2 , -O-, -S-, -S(O)-, and -S(O)2-; each of a and b independently is selected from 1, 2, 3, and 4; R 1 each independently is selected from halogen, -CN, -NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle; m is selected from 0 to 5; R 2 each independently is selected from hydrogen, halogen, -CN, -OH, -O-C 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocycle or an optionally substituted carbocycle, or the substituents of R 2 and R 3 together form an optionally substituted heterocycle; R 3 each independently is selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4Selected from a carbon ring and an optionally substituted 3- to 4-membered heterocycloalkyl, R 4 is 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, R 5 and each of R 6 is independently 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, and R 7 is selected from hydrogen and an optionally substituted C 1-4 alkyl, and when A is an optionally substituted phenyl, m is 1 to 5 and at least one R 1 is heterocycloalkyl, when A is an optionally substituted pyridine or an optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen, and -CN, when A is an optionally substituted piperidine sulfonamide, (i) Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbon ring, or (ii) R 4 is selected from hydrogen, halogen, and -CN, a compound or a pharmaceutically acceptable salt or solvate thereof.

[0555] Embodiment 102. Formula (IA)

[0556]

Chemical formula

[0557] Embodiment 103. Z 1 and Z 2 are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-. The compound according to Embodiment 1 or 3 or a pharmaceutically acceptable salt or solvate thereof.

[0558] Embodiment 104. Z 1 and Z 2 are independently -C(R 2 )2-. The compound according to Embodiment 4 or a pharmaceutically acceptable salt or solvate thereof.

[0559] Embodiment 105. Each of a and b is independently selected from 1 and 2. The compound according to Embodiment 9 or a pharmaceutically acceptable salt or solvate thereof.

[0560] Embodiment 106. Y 1 is -C(R 2 )2-, -NR 3The compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, selected from -, -O-, and -S-.

[0561] Embodiment 107.Y 1 is the compound according to Embodiment 11, or a pharmaceutically acceptable salt or solvate thereof, selected from -C(R 2 )2- and -NR 3 .

[0562] Embodiment 108.R 2 Each is independently the compound according to any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0563] Embodiment 109.R 2 Each is independently the compound according to Embodiment 13, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0564] Embodiment 110.R 2 Each is independently the compound according to Embodiment 14, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, -CN, and cyclopropyl.

[0565] Embodiment 111.R 3 Each is the compound according to any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0566] Embodiment 112.R 3 Each is the compound according to Embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, selected from cyclopropyl and cyclobutyl.

[0567] Embodiment 113.R 3 The compound according to Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein it is cyclopropyl.

[0568] Embodiment 114. Formula (IAA)

[0569]

Chemical formula

[0570] Embodiment 115.Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each is independently selected from -C(R 2 )2-, -NR3 -, -N(C(O)R 2 )-, -NS(O2)R 3 , -O-, and -S(O)2- selected, and Z 5 is further selected from a bond, the compound according to Embodiment 20 or a pharmaceutically acceptable salt or solvate thereof.

[0571]

[0439] Embodiment 116. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each of which is independently selected from -C(R 2 )2-, -NR 3 -, -N(C(O)R 2 )-, -NS(O2)R 3 , -O-, and -S(O)2- selected, and Z 5 is further selected from a bond, the compound according to Embodiment 21 or a pharmaceutically acceptable salt or solvate thereof.

[0572] Embodiment 117. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each of which is independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S(O)2- selected, and Z 5 is further selected from a bond, the compound according to Embodiment

[0439] or a pharmaceutically acceptable salt or solvate thereof.

[0573] Embodiment 118. R 2 each is independently selected from hydrogen, halogen, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, the compound according to Embodiments 20 to 26 or a pharmaceutically acceptable salt or solvate thereof.

[0574] Embodiment 119.R 2 Each is selected from hydrogen and fluoro, or two R 2 substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, and is the compound according to Embodiment 27 or a pharmaceutically acceptable salt or solvate thereof.

[0575] Embodiment 120.R 3 is selected from hydrogen, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine, and is the compound according to any one of Embodiments 20 to 28 or a pharmaceutically acceptable salt or solvate thereof.

[0576] Embodiment 121.R 3 is selected from hydrogen, -(CH2)2OMe, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine, and is the compound according to Embodiment 29 or a pharmaceutically acceptable salt or solvate thereof.

[0577] Embodiment 122.R 3 is selected from -(CH2)2OMe and cyclopropyl, and is the compound according to Embodiment 30 or a pharmaceutically acceptable salt or solvate thereof.

[0578] Each of a, b, c, and d in Embodiment 123 is independently selected from 1 and 2, and is the compound according to any one of Embodiments 20 to 31 or a pharmaceutically acceptable salt or solvate thereof.

[0579]

[0447] Embodiment 124. The compound is

[0580]

Chemical formula

[0581] Embodiment 125. The compound is

[0582]

Chem.

[0447] , or a pharmaceutically acceptable salt or solvate thereof, selected from

[0583] Embodiment 126. Formula (IB)

[0584]

Chem.

[0585]

[0450] Embodiment 127. Z 1 and Z 2 are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-, a compound according to Embodiment

[0449] , or a pharmaceutically acceptable salt or solvate thereof.

[0586]

[0451] Embodiment 128. Z 1 and Z 2 are independently -C(R 2 )2-, a compound according to Embodiment

[0450] , or a pharmaceutically acceptable salt or solvate thereof.

[0587]

[0452] Embodiment 129. Each of a and b is independently selected from 1 and 2, a compound according to Embodiment

[0451] , or a pharmaceutically acceptable salt or solvate thereof.

[0588]

[0453] Embodiment 130.Y 1 is a compound according to any one of Embodiments

[0449] to

[0452] , or a pharmaceutically acceptable salt or solvate thereof, selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-.

[0589]

[0454] Embodiment 131.Y 1 is -C(R 2 )2- and is a compound according to Embodiment

[0453] , or a pharmaceutically acceptable salt or solvate thereof.

[0590]

[0455] Embodiment 132.R 2 is, independently of one another, selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and is a compound according to any one of Embodiments

[0449] to

[0454] , or a pharmaceutically acceptable salt or solvate thereof.

[0591]

[0456] Embodiment 133.R 2 is, independently of one another, selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and is a compound according to Embodiment

[0455] , or a pharmaceutically acceptable salt or solvate thereof.

[0592]

[0457] Embodiment 134.R 2 is, independently of one another, selected from hydrogen, -CN, and cyclopropyl, and is a compound according to Embodiment

[0456] , or a pharmaceutically acceptable salt or solvate thereof.

[0593]

[0458] Embodiment 135.R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, and is a compound according to any one of Embodiments

[0449] to

[0457] , or a pharmaceutically acceptable salt or solvate thereof.

[0594]

[0459] Embodiment 136.R 3 is a compound according to Embodiment

[0458] selected from cyclopropyl and cyclobutyl, or a pharmaceutically acceptable salt or solvate thereof.

[0595]

[0460] Embodiment 137.R 3 is cyclopropyl, a compound according to Embodiment

[0459] or a pharmaceutically acceptable salt or solvate thereof.

[0596]

[0461] Embodiment 138. Formula (IBB)

[0597]

Chemical formula

[0449] or a pharmaceutically acceptable salt or solvate thereof.

[0598]

[0462] Embodiment 139.Z1 , Z 2 , Z 3 , Z 4 , and Z 5 Each of which is independently selected from -C(R 2 )2-, -NR 3 -, -NS(O2)R 3 , -O-, and -S(O)2-, and Z 5 is further selected from a bond, a compound according to embodiment

[0461] or a pharmaceutically acceptable salt or solvate thereof.

[0599]

[0463] Embodiment 140. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 Each of which is independently selected from -C(R 2 )2-, -NS(O2)R 3 , -O-, and -S(O)2-, and Z 5 is further selected from a bond, a compound according to embodiment

[0462] or a pharmaceutically acceptable salt or solvate thereof.

[0600]

[0464] Embodiment 141. R 2 Each is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, a compound according to any one of embodiments

[0461] to

[0463] or a pharmaceutically acceptable salt or solvate thereof.

[0601]

[0465] Embodiment 142. R 2 Each is independently selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, a compound according to embodiment

[0464] or a pharmaceutically acceptable salt or solvate thereof.

[0602]

[0466] Embodiment 143. R 2is independently a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment

[0465] selected from hydrogen, fluoro, -CN, and cyclopropyl.

[0603]

[0467] Embodiment 144.R 3 is a compound or a pharmaceutically acceptable salt or solvate thereof as described in any one of Embodiments

[0461] to

[0466] selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0604]

[0468] Embodiment 145.R 3 is a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment

[0467] selected from hydrogen, methyl, ethyl, and propyl.

[0605]

[0469] Embodiment 146.R 3 is a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiment

[0468] which is methyl.

[0606]

[0470] Each of Embodiments 147.a, b, c, and d is independently a compound or a pharmaceutically acceptable salt or solvate thereof as described in Embodiments

[0461] to

[0469] selected from 1 and 2.

[0607]

[0471] Embodiment 148. The compound is

[0608]

Chemical formula

[0449] to

[0470] selected from

[0609]

[0472] Embodiment 149. Formula (IC)

[0610]

Chemical formula

[0611]

[0473] Embodiment 150.Z 1 and Z 2 are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-, a compound according to Embodiment

[0472] or a pharmaceutically acceptable salt or solvate thereof.

[0612]

[0474] Embodiment 151.Z 1 and Z 2 are independently -C(R 2 )2-, a compound according to Embodiment

[0473] or a pharmaceutically acceptable salt or solvate thereof.

[0613]

[0475] In Embodiment 152, each of a and b is independently selected from 1 and 2, a compound according to Embodiment

[0474] or a pharmaceutically acceptable salt or solvate thereof.

[0614]

[0476] Embodiment 153.Y 1 is -C(R 2 )2-, -NR 3 -, -NS(O2)R 2The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments

[0472] to

[0475] , selected from -O- and -S-.

[0615]

[0477] Embodiment 154.Y 1 is -C(R 2 )2-, -NR 3 , and -NS(O2)R 2 The compound or a pharmaceutically acceptable salt or solvate thereof according to embodiment

[0476] , selected from.

[0616]

[0478] Embodiment 155.R 2 Each R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments

[0472] to

[0477] .

[0617]

[0479] Embodiment 156.R 2 Each R is selected from hydrogen, fluoro, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. The compound or a pharmaceutically acceptable salt or solvate thereof according to embodiment

[0478] .

[0618]

[0480] Embodiment 157.R 2 Each R is selected from hydrogen, fluoro, -CN, and cyclopropyl. The compound or a pharmaceutically acceptable salt or solvate thereof according to embodiment

[0479] .

[0619]

[0481] Embodiment 158.R 3 R is selected from optionally substituted alkyl. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments

[0472] to

[0480] .

[0620]

[0482] Embodiment 159.R 3The compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0481] , wherein the group is methyl.

[0621]

[0483] Embodiment 160. Formula (ICC)

[0622]

Chemical Structure

[0623]

[0484] Embodiment 161. Z 1 、Z 2 、Z 3 、Z 4 、and Z 5 each independently is -C(R 2 )2-, -NR 3 -, -N(C(O)R 2)-, -NS(O2)R 3 , -O-, and -S(O)2-, and Z 5 is further selected from a bond, a compound according to Embodiment

[0483] or a pharmaceutically acceptable salt or solvate thereof.

[0624]

[0485] Embodiment 162. Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each of which is independently selected from -C(R 2 )2-, -NR 3 -, and -NS(O2)R 3 , and Z 5 is further selected from a bond, a compound according to Embodiment

[0484] or a pharmaceutically acceptable salt or solvate thereof.

[0625]

[0486] Embodiment 163. R 2 each is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl, a compound according to any one of Embodiments

[0483] to

[0485] or a pharmaceutically acceptable salt or solvate thereof.

[0626]

[0487] Embodiment 164. R 2 each is independently selected from hydrogen, fluoro, and -OH, a compound according to Embodiment

[0486] or a pharmaceutically acceptable salt or solvate thereof.

[0627]

[0488] Embodiment 165. R 3 is independently selected from hydrogen and optionally substituted alkyl, a compound according to any one of Embodiments

[0483] to

[0487] or a pharmaceutically acceptable salt or solvate thereof.

[0628]

[0489] Embodiment 166. R 3is independently a compound according to Embodiment

[0488] selected from hydrogen, methyl, ethyl, and propyl, or a pharmaceutically acceptable salt or solvate thereof.

[0629]

[0490] Embodiment 167.R 3 is methyl, a compound according to Embodiment

[0489] , or a pharmaceutically acceptable salt or solvate thereof.

[0630]

[0491] Embodiment 168.R 12 is an optionally substituted 5- to 6-membered heterocyclic ring, or R 12 and R 13 together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, a compound according to any one of Embodiments

[0472] to

[0490] , or a pharmaceutically acceptable salt or solvate thereof.

[0631]

[0492] Embodiment 169.R 12 is an optionally substituted piperidine, an optionally substituted azaspiro[3.3]heptane, or R 12 and R 13 together form an optionally substituted heterocyclic ring, a compound according to Embodiment

[0491] , or a pharmaceutically acceptable salt or solvate thereof.

[0632]

[0493] Embodiment 170.R 13 and R 12 together form an optionally substituted heterocyclic ring, a compound according to any one of Embodiments

[0472] to

[0492] , or a pharmaceutically acceptable salt or solvate thereof.

[0633]

[0494] Embodiment 171. The compound is

[0634]

Chemical formula

[0472] to

[0493] , selected from

[0635]

[0495] Embodiment 172. Formula (ID)

[0636]

Chemical Structure

[0637]

[0496] Embodiment 173. Formula (IDD)

[0638]

Chemical Structure

[0495] or a pharmaceutically acceptable salt or solvate thereof.

[0639]

[0497] Embodiment 174. Formula (IE)

[0640] [Chemical formula] Its pharmaceutically acceptable salt or solvate having the structure of, wherein, R 17 is selected from -SOR 19 -, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycloalkyl, R 18 is selected from halogen, -CN, and optionally substituted C 1-4 alkyl, R 19 is optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, and, r is selected from 0 to 5, its pharmaceutically acceptable salt or solvate.

[0641]

[0498] Embodiment 175.Z 1 and Z 2 are independently selected from -C(R 2 )2-, -NR 3 -, -O-, and -S-, the compound according to Embodiment

[0497] or its pharmaceutically acceptable salt or solvate.

[0642]

[0499] Embodiment 176.Z 1 and Z 2 are independently -C(R 2 )2-, the compound according to Embodiment

[0498] or its pharmaceutically acceptable salt or solvate.

[0643]

[0500] In Embodiment 177, each of a and b is independently selected from 1 and 2, the compound according to Embodiment

[0499] or its pharmaceutically acceptable salt or solvate.

[0644]

[0501] Embodiment 178.Y 1is -C(R 2 )2-, -NR 3 -, -NS(O2)R 2 , -O-, and -S(O)2-, a compound according to any one of embodiments

[0497] to

[0500] or a pharmaceutically acceptable salt or solvate thereof.

[0645]

[0502] Embodiment 179. R 2 is each independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, a compound according to any one of embodiments

[0497] to

[0501] or a pharmaceutically acceptable salt or solvate thereof.

[0646]

[0503] Embodiment 180. R 3 is selected from optionally substituted alkyl, a compound according to any one of embodiments

[0497] to

[0502] or a pharmaceutically acceptable salt or solvate thereof.

[0647]

[0504] Embodiment 181. r is 0, a compound according to any one of embodiments

[0497] to

[0503] or a pharmaceutically acceptable salt or solvate thereof.

[0648]

[0505] Embodiment 182. R 17 is -SOR 19 -, optionally substituted alkyl, and optionally substituted 3- to 5-membered heterocycloalkyl, a compound according to any one of embodiments

[0497] to

[0504] or a pharmaceutically acceptable salt or solvate thereof.

[0649]

[0506] Embodiment 183. R 17 is -SOR 19 -, methyl, and optionally substituted 4-membered heterocycloalkyl, a compound according to embodiment

[0505] or a pharmaceutically acceptable salt or solvate thereof.

[0650]

[0507] Embodiment 184. Formula (IEE)

[0651]

Chemical Structure

[0497] or a pharmaceutically acceptable salt or solvate thereof.

[0652]

[0508] Embodiment 185. Z 1 Z 2 Z 3 Z 4 Z 5 each of which is independently selected from -C(R 2 )2-, -NR 3 -, -NS(O2)R 3 -, -O-, and -S(O)2-, and Z 5 is further selected from a bond, a compound according to Embodiment

[0507] or a pharmaceutically acceptable salt or solvate thereof.

[0653]

[0509] Embodiment 186. Z 1 Z 2 Z 3 Z 4 Z 5 each of which is independently selected from -C(R 2 )2-, -NR 3 -, -NS(O2)R 3 -, -, and -S(O)2-, and Z 5 is further selected from a bond, a compound according to Embodiment

[0508] or a pharmaceutically acceptable salt or solvate thereof.

[0654]

[0510] Embodiment 187. R 2The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments

[0507] to

[0509] , which is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl.

[0655]

[0511] Embodiment 188.R 2 The compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0510] , which is independently selected from hydrogen and fluoro.

[0656]

[0512] Embodiment 189.R 3 The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments

[0507] to

[0511] , which is optionally substituted alkyl.

[0657]

[0513] Embodiment 190.R 3 The compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0512] , which is methyl, ethyl, or propyl.

[0658]

[0514] Embodiment 191.R 3 The compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0513] , which is methyl.

[0659]

[0515] Embodiment 192.R 19 The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments

[0507] to

[0504] , which is optionally substituted alkyl.

[0660]

[0516] Embodiment 193.R 19 The compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment

[0515] , which is methyl.

[0661]

[0517] Embodiment 194. The compound is

[0662] [Chemistry] A compound according to any one of embodiments

[0497] to

[0516] , or a pharmaceutically acceptable salt or solvate thereof, selected from , , .

[0663]

[0518] Embodiment 195.A is a compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, selected from optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azetidine, and optionally substituted tetrahydroisoquinoline.

[0664]

[0519] Embodiment 196.A is a compound according to Embodiment 33, or a pharmaceutically acceptable salt or solvate thereof, substituted with -SO2Me.

[0665]

[0520] Embodiment 197.m is selected from 0 to 1, and is a compound according to Embodiment 33 or 35, or a pharmaceutically acceptable salt or solvate thereof.

[0666]

[0521] Embodiment 198.R 1 Each is independently selected from optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle, and is a compound according to any one of Embodiments 33 to 36, or a pharmaceutically acceptable salt or solvate thereof.

[0667]

[0522] Embodiment 199.R 1 Each is independently selected from optionally substituted alkyl and optionally substituted heterocycle, and is a compound according to Embodiment 37, or a pharmaceutically acceptable salt or solvate thereof.

[0668]

[0523] Embodiment 200.R 1 Each is independently selected from methyl, ethyl, and optionally substituted diazaspiro[3.3]heptane, and is a compound according to Embodiment 37, or a pharmaceutically acceptable salt or solvate thereof.

[0669]

[0524] Embodiment 201.Z 1 and Z 2 are independently, -C(R 2 )2-, -NR 3 -, -O-, and -S- selected from any one of Compounds described in Embodiments 1 to 19,

[0449] to

[0460] ,

[0472] to

[0482] ,

[0495] ,

[0497] to

[0506] , and 33 to 38, or a pharmaceutically acceptable salt or solvate thereof.

[0670]

[0525] Embodiment 202.Z 1 and Z 2 are independently, -C(R 2 )2- as described in Embodiment 40, or a pharmaceutically acceptable salt or solvate thereof.

[0671]

[0526] For each of a and b in Embodiment 203, they are independently selected from 1 and 2, the compound described in Embodiment 40 or 41, or a pharmaceutically acceptable salt or solvate thereof.

[0672]

[0527] Embodiment 204.Y 1 is, -C(R 2 )2-, -NR 3 -, -O-, and -S- selected from any one of Compounds described in Embodiments 1 to 19,

[0449] to

[0460] ,

[0472] to

[0482] ,

[0495] ,

[0497] to

[0506] , and 33 to 42, or a pharmaceutically acceptable salt or solvate thereof.

[0673]

[0528] Embodiment 205.Y 1 is, -C(R 2 )2- and -NR 3 selected from, the compound described in Embodiment 43, or a pharmaceutically acceptable salt or solvate thereof.

[0674]

[0529] Embodiment 206.Y 1 is -C(R 2) is 2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring, the compound according to embodiment 44 or a pharmaceutically acceptable salt or solvate thereof.

[0675]

[0530] Embodiment 207.Y 1 is -C(R 2 )2-, and the two R 2 substituents together form a ring selected from an optionally substituted heterocyclic ring, the compound according to embodiment 45 or a pharmaceutically acceptable salt or solvate thereof.

[0676]

[0531] Embodiment 208. In formula (I), (IB), (IC), (ID), and (IE)

[0677]

Chemical formula

[0449] to

[0460] ,

[0472] to

[0482] ,

[0495] ,

[0497] to

[0506] , and 33 to 43 or a pharmaceutically acceptable salt or solvate thereof.

[0678]

[0532] Embodiment 209. In formula (I), (IB), (IC), (ID), and (IE)

[0679]

Chemical formula

[0680]

Chemical formula

[0681]

[0533] Embodiment 210. The compound is

[0682]

Chemical formula

[0683]

[0534] Embodiment 211. R 4 is hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, a compound according to any one of embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , or 33 to 109, or a pharmaceutically acceptable salt or solvate thereof.

[0684]

[0535] Embodiment 212. R 4 is selected from hydrogen and optionally substituted C1 alkyl, a compound according to embodiment 49, or a pharmaceutically acceptable salt or solvate thereof.

[0685]

[0536] Embodiment 213. R 4 is selected from hydrogen, methyl, and -CHF2, a compound according to embodiment 50, or a pharmaceutically acceptable salt or solvate thereof.

[0686]

[0537] Embodiment 214. R 4 is selected from hydrogen, halogen, and -CN, a compound according to any one of embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , or 33 to 48, or a pharmaceutically acceptable salt or solvate thereof.

[0687]

[0538] Embodiment 215.R 4 is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , or 33 to 48, which is selected from hydrogen.

[0688]

[0539] Embodiment 216.R 4 is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , or 33 to 48, which is not an optionally substituted phenyl.

[0689]

[0540] Embodiment 217.R 4 is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , or 33 to 48, which is not an optionally substituted alkyl.

[0690]

[0541] Embodiment 218.R 5 is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , 33 to 39, or 49 to 117, which is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0691]

[0542] Embodiment 219.R 5 is a compound or a pharmaceutically acceptable salt or solvate thereof according to Embodiment 56, which is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl.

[0692]

[0543] Embodiment 220.R 5 is a compound as described in Embodiment 57 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen and fluorine.

[0693]

[0544] Embodiment 221.R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 alkyl, optionally substituted C 3-4 carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, and is a compound as described in any one of Embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , 33 to 39, or 49 to 58, or a pharmaceutically acceptable salt or solvate thereof.

[0694]

[0545] Embodiment 222.R 6 is selected from hydrogen, halogen, and optionally substituted C 1-2 alkyl, and is a compound as described in Embodiment 59 or a pharmaceutically acceptable salt or solvate thereof.

[0695]

[0546] Embodiment 223.R 6 is hydrogen, and is a compound as described in Embodiment 60 or a pharmaceutically acceptable salt or solvate thereof.

[0696]

[0547] Embodiment 224.R 7 is hydrogen, and is a compound as described in any one of Embodiments 1 to 32,

[0449] to

[0470] ,

[0472] to

[0493] ,

[0495] to

[0516] , 33 to 39, or 49 to 61, or a pharmaceutically acceptable salt or solvate thereof.

[0697]

[0548] Embodiment 225. A pharmaceutical composition comprising a compound or salt according to any one of Embodiments 1 to 62, and a pharmaceutically acceptable excipient.

[0698]

[0549] Method 226 for treating cancer, comprising the step of administering the pharmaceutical composition according to Embodiment 68 to a subject in need of treatment.

[0699]

[0550] Method 227 according to Embodiment 69, wherein the cancer is a solid tumor.

[0700]

[0551] Method according to Embodiment 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumor.

[0701]

[0552] Method 229 according to Embodiment 71, wherein the cancer is ovarian cancer or breast cancer.

[0702]

[0553] Method for inhibiting cyclin-dependent kinase (CDK) in cells using the compound or salt according to any one of Embodiments 1 to 62, or the pharmaceutical composition according to Embodiment 68.

[0703]

[0554] Method 231 according to Embodiment 73, wherein the CDK is selected from CDK2, CDK4, CD6, or any combination thereof.

[0704]

[0555] Method 232 according to Embodiment 74, wherein the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6.

[0705]

[0556] Method 233 according to Embodiment 75, wherein the CDK is CDK2 / 4 / 6.

Examples

[0706] Although the present invention has been outlined above, it will be more readily understood by reference to the following examples. These examples are included solely for the purpose of exemplifying specific aspects and embodiments of the present invention and are not intended to limit the present invention in any way.

[0707] The following synthetic schemes are provided for illustrative purposes and are not limiting. The following examples illustrate various methods for producing the compounds described herein. It will be understood that those skilled in the art will be able to produce these compounds by similar methods or by combining other methods known to those skilled in the art. It will also be understood that those skilled in the art will be able to produce them in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as necessary. Generally, 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.

[0708] General synthetic schemes 1-3

[0709] [Chemical formula]

[0710] [Chemical formula]

[0711] [Chemical formula]

[0712] Intermediate Intermediate 1: 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine

[0713] [Chemical formula]

[0714] Step 1: Methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate

[0715] [Chemical formula]

[0716] To a stirred mixture of methyl 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylate (7.8 g, 29.64 mmol) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.45 g, 44.46 mmol) in tetrahydrofuran (60 mL), sodium carbonate (4.71 g, 44.46 mmol) and Pd(dppf)Cl2 (1.08 g, 1.48 mmol) in water (20 mL) were added under a nitrogen atmosphere. The resulting mixture was heated to 65 °C and stirred for 18 h. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 85:15) to give methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (5.30 g, yield 70.3%). LCMS(ESI) m / z = 255 [M+H] + .

[0717] Step 2: (E)-5-(2-Ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide

[0718]

Chem.

[0719] To a stirred mixture of methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (4.8 g, 18.87 mmol) in methanol (5 mL) was added a solution of ammonium in methanol (7 M, 50 mL, 350 mmol). The resulting mixture was heated to 85 °C and stirred overnight in a sealed tube. The resulting mixture was cooled to room temperature and concentrated under vacuum to afford the crude title product (4.2 g). The crude product was used directly in the next step without further purification.

[0720] LCMS(ESI) m / z = 240 [M+H] + .

[0721] Step 3: 2-(Methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

[0722]

Chem.

[0723] To a stirred mixture of (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (4.2 g, 17.55 mmol) in toluene (50 mL) was added p-toluenesulfonic acid (0.30 g, 1.75 mmol). The resulting mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to afford the crude product. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the crude title product (4.4 g). The crude product was used directly in the next step without further purification. LCMS(ESI) m / z = 194 [M+H] + .

[0724] Step 4: 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine

[0725]

Chem.

[0726] A mixture of 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (4.2 g, 21.73 mmol) in phosphorus oxychloride (150 mL) was heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under high vacuum. The residue was carefully quenched by the addition of saturated aqueous sodium bicarbonate solution (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, filtered, and concentrated under vacuum to give the crude product. Purification of the residue by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) afforded 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (3.70 g, 92.4% yield). LCMS(ESI) m / z = 212 [M+H] + .

[0727] Intermediate 2: 6-Methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

[0728] Reaction Scheme

[0729]

Chemical Structure

[0730] Detailed Procedure Step 1: 5-Bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide

[0731]

Chemical Structure

[0732] Oxalyl dichloride (13.25 g, 104.4 mmol) was added to a solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (20 g, 80.3 mmol) in DCM (800 mL) at 0 °C. Droplets of DMF were added and the resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (800 mL) and aniline (11.96 g, 128.5 mmol) and Et3N (17.06 g, 168.6 mmol) were added at 0 °C. The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched by the addition of aqueous HCl (0.5 N, 500 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were washed with water (2 × 500 mL) and brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26 g of crude). The crude product was used as such in the next step. LCMS (ESI-MS) m / z = 324.0, 326.0 [M+H] + .

[0733] Step 2: 6-Methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

[0734]

Chemical Structure

[0735] To a solution of 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26 g, 80.2 mmol) in ACN (270 mL) were added pentane-2,4-dione (16.06 g, 160.4 mmol), CuI (1.53 g, 8.02 mmol), and Cs2CO3 (52.26 g, 160.4 mmol). The resulting mixture was heated to 85 °C and stirred overnight. Ammonium acetate (101.8 g, 1.72 mol) and acetic acid (200 mL) were added, and the resulting mixture was heated to 85 °C and stirred for 5 h. After cooling to room temperature, the reaction mixture was concentrated under high vacuum until most of the liquid had evaporated. The residue was then neutralized by the addition of saturated aqueous NaOH at 0 °C (ca. 500 mL) followed by saturated aqueous NaHCO3 at 0 °C until the pH value was adjusted to 6 - 7. The aqueous layer was extracted with DCM (2 × 1 L). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The residue was purified by flash column chromatography eluting with 20% - 80% ethyl acetate in petroleum ether followed by 0% - 10% MeOH in DCM to give the desired product 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (5.8 g, 35% yield over 3 steps). 1 H NMR (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 9.07 (s, 1H), 6.31 (s, 1H), 2.58 (s, 3H), 2.22 (s, 3H). LCMS (ESI-MS) m / z = 208.0 [M + H] + .

[0736] Intermediate 3: 8-Chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine 8-Chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine

[0737]

Chemical Structure

[0738] To a solution of 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (4 g, 19.30 mmol) in toluene (20 mL), POCl3 (32.00 mL) was added. The mixture was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure, quenched with water (200 mL), and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (0 - 20%) to give 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.01 g, 46.4% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.79 (d, J = 0.6 Hz, 1H), 2.66 (s, 3H), 2.60 (s, 3H). LCMS (ESI-MS) m / z = 226.0 [M+H] + .

[0739] Intermediate 4: 8-Chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine and 8-chloro-6-methyl-2-(methylsulfinyl)pyrido[3,4-d]pyrimidine

[0740]

Chemical Structure

[0741] 3-Chloroperoxybenzoic acid (6.88 g, 39.87 mmol) was added to 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (3.0 g, 13.29 mmol) in dichloromethane (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, warmed to room temperature, and stirred for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL). The resulting mixture was extracted with dichloromethane (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA 0% - 100% in PE) to give crude 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine and 8-chloro-6-methyl-2-(methylsulfinyl)pyrido[3,4-d]pyrimidine (1.07 g, yield 30.4%). 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.09 - 8.06 (m, 1H), 3.54 (s, 3H), 2.81 - 2.66 (m, 3H). LCMS (ESI-MS) m / z = 257.9 [M + H] + .

[0742] Intermediate 5: 8-Bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0743] Reaction Scheme

[0744]

Chem.

[0745] Detailed Procedure Step 1: 8-Bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine

[0746]

Chem.

[0747] POBr3 (50 mL, 174.4 mmol) was added to 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (5 g, 24.12 mmol) in MeCN (50 mL). The mixture was stirred at 70 °C for 3 h and concentrated under reduced pressure. The residue was quenched with an aqueous sodium bicarbonate solution at 0 °C and extracted with EA (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (0 - 20%) to obtain 8-bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.2 g, yield 33.8%). LCMS (ESI-MS) m / z = 270.0, 272.0 [M+H] + .

[0748] Step 2: 8-Bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

[0749]

Chemical formula

[0750] 3-Chloroperoxybenzoic acid (2.81 g, 16.28 mmol) was added to 8-bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.2 g, 8.14 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then warmed to room temperature and stirred for 2 h. The reaction was quenched with a saturated aqueous sodium bicarbonate solution (200 mL). The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA 0 - 100% in PE) to obtain crude 8-bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1.3 g, yield 52.8%). LCMS (ESI-MS) m / z = 302.0, 304.0 [M+H] +.

[0751] Step 3: 8-Bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0752]

Chem.

[0753] To a solution of 8-bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1.3 g, 4.30 mmol) in DMSO (10 mL) was added 1-(methylsulfonyl)piperidin-4-amine (0.77 g, 4.30 mmol), K2CO3 (1.19 g, 8.60 mmol), and CsF (1.31 g, 8.60 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 0 - 20%) to give 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (206.1 mg, yield 10.8%). 1 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.12 - 7.96 (m, 1H), 7.57 - 7.54 (m, 1H), 4.09 - 3.94 (m, 1H), 3.64 - 3.51 (m, 2H), 2.90 (s, 6H), 2.57 - 2.45 (m, 2H), 2.18 - 2.01 (m, 2H), 1.71 - 1.56 (m, 2H). LCMS (ESI-MS) m / z = 400.0, 402.0 [M + H] + .

[0754] Intermediate 6: 8-Chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0755]

Chem.

[0756] A mixture of 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1 g, 3.88 mmol), 1-(methylsulfonyl)piperidin-4-amine (0.8 g, 4.26 mmol), DIEA (1.50 g, 11.64 mmol), and CsF (1.77 g, 11.64 mmol) in DMSO (5 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 1:1) to give 8-chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (505.8 mg, yield 33.3%). LCMS (ESI-MS) m / z = 356.0 [M+H] + .

[0757] Intermediate 7: 8-Chloro-6-cyclopropyl-2-methanesulfonylpyrido[3,4-d]pyrimidine

[0758]

Chem.

[0759] Step 1: 5-Bromo-2-(methylsulfanyl)-N-phenylpyrimidine-4-carboxamide

[0760]

Chem.

[0761] A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (15.0 g, 60.222 mmol) in anhydrous dichloromethane (225.0 ml) was cooled to 0 °C. Oxalyl chloride (6.624 ml, 78.288 mmol) and 1 drop of anhydrous dimethylformamide were added under an argon atmosphere, and the reaction mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was concentrated under reduced pressure, and the residue was redissolved in anhydrous dichloromethane (225.0 ml) and cooled to 0 °C. Aniline (9.329 ml, 102.377 mmol) and triethylamine (18.467 ml, 132.488 mmol) were slowly added, and the reaction mixture was stirred at room temperature for an additional 18 hours. The reaction mixture was quenched with 0.5 M aqueous HCl, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 200 ml), the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel (from hexane to hexane / EtOAc 4:1) to give the title compound (17.34 g, 89% yield). 1 1H NMR (300 MHz, chloroform-d) δ 9.63 (bs, 1H), 8.86 (s, 1H), 7.77 - 7.71 (m, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 2.66 (s, 3H). UPLC (ESI) [M + H] + = 323.70 and 325.70 (Br isotope pattern).

[0762] Step 2: 6-Cyclopropyl-2-(methylsulfanyl)-7H,8H-pyrido[3,4-d]pyrimidin-8-one

[0763]

Chemical Structure

[0764] A solution of 5-bromo-2-(methylsulfanyl)-N-phenylpyrimidine-4-carboxamide (10.0 g, 30.845 mmol), 1,3-dicyclopropylpropane-1,3-dione (7.633 ml, 61.69 mmol), cesium carbonate (20.1 g, 61.69 mmol), and copper(I) iodide (0.587 g, 3.085 mmol) in anhydrous acetonitrile (88.13 ml) was stirred at 85 °C for 18 h. Then, acetic acid (88.13 ml) and ammonium acetate (35.665 g, 462.677 mmol) were added and the reaction mixture was stirred at 85 °C for an additional 18 h. Acetonitrile was removed by concentrating the reaction mixture under reduced pressure, and the acetic acid-containing mixture was diluted with water (100 ml) and extracted with dichloromethane (3 × 100 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel (from hexane / EtOAc 3:2 to EtOAc) to give the title compound (4.76 g, 66% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 12.01 (bs, 1H), 9.06 (s, 1H), 6.21 (s, 1H), 2.58 (s, 3H), 1.88 (tt, J = 8.3, 5.1 Hz, 1H), 1.04 - 0.92 (m, 2H), 0.89 - 0.77 (m, 2H). UPLC (ESI) [M+H] + = 233.90.

[0765] Step 3: 8-Chloro-6-cyclopropyl-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine

[0766]

Chem.

[0767] A solution of 6-cyclopropyl-2-(methylsulfanyl)-7H,8H-pyrido[3,4-d]pyrimidin-8-one (4.76 g, 20.404 mmol) in phosphorus oxychloride (32.428 ml, 346.864 mmol) was stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (50 ml) and quenched with saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 50 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel (from hexane to hexane / EtOAc 7:3) to give the title compound (4.58 g, 89% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.87 (s, 1H), 2.66 (s, 3H), 2.38 - 2.19 (m, 1H), 1.14 - 1.02 (m, 2H), 0.97 (ddd, J = 7.2, 5.1, 2.9 Hz, 2H). UPLC (ESI) [M+H] + = 251.85.

[0768] Step 4: 8-Chloro-6-cyclopropyl-2-methanesulfonylpyrido[3,4-d]pyrimidine

[0769]

Chemical Structure

[0770] To a solution of 8-chloro-6-cyclopropyl-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine (2.5 g, 9.931 mmol) in dichloromethane (125.0 ml) was added m-chloroperbenzoic acid (8.569 g, 49.656 mmol) portionwise, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by slowly adding 10% aqueous Na2S2O3 solution (50 ml) and extracted with dichloromethane (3 × 70 ml). The combined organic layers were washed with saturated aqueous NaHCO3 solution, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel (from hexane / EtOAc 4:1 to hexane / EtOAc 2:3) to give the title compound (2.54 g, 89% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.12 (s, 1H), 3.52 (s, 3H), 2.42 (dq, J = 8.4, 4.7, 4.1 Hz, 1H), 1.17 (dt, J = 7.9, 3.0 Hz, 2H), 1.09 - 1.02 (m, 2H). UPLC (ESI) [M + H] + = 283.80.

[0771] Intermediate 8: 8-Chloro-6-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0772]

Chemical Structure

[0773] A solution of 8-chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (100 mg, 352 μmol) in anhydrous dimethyl sulfoxide (1.8 mL) was charged with 1-(methylsulfonyl)piperidin-4-amine (69.1 mg, 388 μmol), cesium fluoride (161 mg, 1.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (137 mg, 184 μL, 1.06 mmol). The reaction vial was capped and stirred at 30 °C for 72 h. The crude mixture was then diluted with water (50.0 mL) and extracted with dichloromethane (3 × 20.0 mL). The combined organic fractions were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo. The crude material was purified by silica gel flash chromatography (heptane / EtOAc 1:1) to afford the title compound (62.0 mg, 46% yield). LCMS(ESI)[M+H] + =382.10

[0774] Intermediate 9: 8-Chloro-6-(difluoromethyl)-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine

[0775] Reaction Scheme

[0776]

Chem.

[0777] Detailed Procedure Step 1: Methyl 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylate

[0778]

Chem.

[0779] To a solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (15.0 g, 60.222 mmol) in methanol (600.0 mL) was slowly added sulfuric acid (98%, 3.852 mL, 72.266 mmol). The reaction mixture was stirred at 65 °C for 16 h. Then, the reaction mixture was poured into ice water and extracted with dichloromethane (300 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the title compound (15.02 g, yield 95%). The crude material was used in the next step without further purification. 1 1H NMR (300 MHz, chloroform-d) δ 8.73 (s, 1H), 4.02 (s, 3H), 2.59 (s, 3H). UPLC (ESI) [M + H] + = 262.70 and 264.65 (Br isotope pattern).

[0780] Step 2: Methyl 5-(3-methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxylate

[0781]

Chemical Structure

[0782] A solution of bis(benzonitrile)palladium chloride (0.729 g, 1.9 mmol), copper(I) iodide (0.362 g, 1.9 mmol), and tri-tert-butylphosphonium tetrafluoroborate (1.103 g, 3.801 mmol) in anhydrous dioxane (50.0 mL) was purged with argon for 10 minutes. Then, N,N-diisopropylethylamine (23.171 mL, 133.024 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Next, methyl 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylate (5.0 g, 19.003 mmol) and 3-methoxyprop-1-yne (4.814 mL, 57.01 mmol) were added slowly and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and washed with ethyl acetate (50 mL) and dichloromethane (50 mL). The filtrate was concentrated under reduced pressure and purified by automated flash column chromatography on silica gel (from hexane to hexane / EtOAc 7:3) to afford the title compound (2.47 g, 52% yield). 1 H NMR (300 MHz, chloroform-d) δ 8.73 (s, 1H), 4.39 (s, 2H), 4.01 (s, 3H), 3.50 (s, 3H), 2.63 (s, 3H). UPLC (ESI) [M+H] + = 252.80.

[0783] Step 3: 5-(3-Methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxamide

[0784]

Chem.

[0785] A solution of methyl 5-(3-methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxylate (2.47 g, 9.79 mmol) in ammonia (7.0 N solution in methanol, 34.965 ml, 244.758 mmol) was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude title compound (2.28 g, yield 98%). The crude product was used in the next step without further purification. 1 H NMR (300 MHz, chloroform-d) δ 8.78 (s, 1H), 7.55 (s, 1H), 5.58 (s, 1H), 4.44 (s, 2H), 3.53 (s, 3H), 2.63 (s, 3H). UPLC (ESI) [M+H] + = 237.85.

[0786] Step 4: 6-(Methoxymethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one

[0787]

Chemical Structure

[0788] To a solution of 5-(3-methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxamide (1.580 g, 6.660 mmol) in toluene (28.56 ml) was added p-toluenesulfonic acid monohydrate (0.916 g, 4.815 mmol). The reaction mixture was stirred at 110 °C for 48 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (from hexane / EtOAc 7:3 to hexane / EtOAc 3:7) to give the title compound (0.685 g, yield 43%). 1 H NMR (300 MHz, chloroform-d) δ 8.85 (s, 1H), 6.53 (t, J = 1.2 Hz, 1H), 4.31 (d, J = 1.2 Hz, 2H), 3.53 (s, 3H), 2.70 (s, 3H).

[0789] Step 5: 6-(Hydroxymethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one

[0790]

Chem.

[0791] A solution of 6-(methoxymethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one (1.275 g, 5.373 mmol) in anhydrous dichloromethane (44.78 mL) was cooled to -78 °C. Then, boron tribromide (1.0 M solution in dichloromethane, 32.247 mL, 32.247 mmol) was added dropwise via an addition funnel, and the reaction mixture was stirred at the same temperature for 20 minutes. Then, the reaction mixture was warmed to -20 °C and stirred for an additional 2 hours and 30 minutes. The reaction mixture was quenched by dropwise addition of methanol and then saturated aqueous NaHCO3 (until gas evolution ceased). The mixture was extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (from hexane / EtOAc 7:3 to hexane / EtOAc 1:9) to give the title compound (0.787 g, 59% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 6.74 (d, J = 1.2 Hz, 1H), 5.74 (t, J = 6.0 Hz, 1H), 4.30 (dd, J = 6.0, 1.2 Hz, 2H), 2.61 (s, 3H).

[0792] Step 6: 2-(Methylsulfanyl)-8-oxo-8H-pyrano[3,4-d]pyrimidine-6-carbaldehyde

[0793]

Chem.

[0794] A solution of 6-(hydroxymethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one (0.787 g, 3.173 mmol) in anhydrous dichloromethane (15.74 mL) was cooled to 0 °C. Then Dess-Martin periodinane (2.692 g, 6.347 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The solid was filtered off, and the filtrate was washed with 0.5 M aqueous NaOH solution, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (from hexane / EtOAc 8:2 to hexane / EtOAc 4:6) to give the title compound (0.738 g, 100% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.35 (s, 1H), 7.78 (s, 1H), 2.65 (s, 3H).

[0795] Step 7: 6-(Difluoromethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one

[0796]

Chemical formula

[0797] A solution of 2-(methylsulfanyl)-8-oxo-8H-pyrano[3,4-d]pyrimidine-6-carbaldehyde (0.738 g, 3.167 mmol) in dichloromethane (22.13 mL) was cooled to 0 °C. Then DAST (0.418 mL, 3.167 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched by the dropwise addition of 10% aqueous Na2S2O3 solution (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (15 mL × 3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the title compound (0.784 g, 92% yield). The crude material was used in the next step without further purification. 11H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.25 (d, J = 1.6 Hz, 1H), 6.94 (t, J = 52.7 Hz, 1H), 2.63 (s, 3H). UPLC (ESI) [M+H] + = 244.85.

[0798] Step 8: 6-(Difluoromethyl)-2-(methylsulfanyl)-7H,8H-pyrido[3,4-d]pyrimidin-8-one

[0799]

Chem.

[0800] A solution of 6-(difluoromethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one (0.734 g, 2.703 mmol) in ammonia (7.0 N solution in methanol, 21.242 ml, 148.691 mmol) was stirred at 80 °C for 16 h. The volatiles were removed under reduced pressure to afford the crude title compound (0.704 g, 96% yield) as a dark solid. The crude product was used in the next step without further purification. 1 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.88 (t, J = 53.8 Hz, 1H), 2.62 (s, 3H). UPLC (ESI) [M+H] + = 243.75.

[0801] Step 9: 8-Chloro-6-(difluoromethyl)-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine

[0802]

Chem.

[0803] A solution of 6-(difluoromethyl)-2-(methylsulfanyl)-7H,8H-pyrido[3,4-d]pyrimidin-8-one (0.704 g, 2.605 mmol) in phosphorus oxychloride (7.306 mL, 78.148 mmol) was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (15 mL) and washed with saturated aqueous NaHCO3 (15 mL). The aqueous layer was extracted with ethyl acetate (15 mL × 3), and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (from hexane to hexane / EtOAc 7:3) to give the title compound (0.277 g, yield 41%). 1 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.37 (s, 1H), 7.17 (t, J = 54.5 Hz, 1H), 2.71 (s, 3H). UPLC (ESI) [M + H] + = 261.80.

[0804] Intermediate 10: N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)formamide

[0805] Reaction Scheme

[0806]

Chemical Structure

[0807] Detailed Procedure Step 1: tert-Butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0808]

Chemical Structure

[0809] 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 give tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield).

[0810] LCMS(ESI) m / z = 321 [M+H] + .

[0811] Step 2: 2-(6-Nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0812]

Chemical Structure

[0813] 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 give the crude 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate salt (6 g). The crude product was used directly in the next step without further purification. LCMS(ESI) m / z = 221 [M+H] +.

[0814] Step 3: 2-Ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0815]

Chem.

[0816] A solution of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g, 18.9 mmol) in methanol (100 mL) was treated with triethylamine (5.73 g, 56.7 mmol) for 10 minutes, and 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 hours and concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 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, 58.9% yield) as an orange solid. LCMS(ESI) m / z = 249 [M+H] + .

[0817] Step 4: 5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine

[0818]

Chem.

[0819] A solution of 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 16.11 mmol), ammonium chloride (4.31 g, 80.55 mmol), iron powder (9.00 g, 161.100 mmol), and water (20 mL) in ethanol (60 mL) was stirred 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 give 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine (2 g, yield 56.6%). LCMS (ESI) m / z = 219 [M+H] + .

[0820] Step 5: N-(5-(6-e...

Claims

1. A compound having the structure of formula (I0), or a pharmaceutically acceptable salt or solvate thereof, wherein 【Chemical 1】 in the formula,[[]] A is a ring selected from an optionally substituted carbocycle, an optionally substituted 4- to 8-membered heterocycle, an optionally substituted tetrahydro-triazolopyrazine, and an optionally substituted isoindoline; each of a and b is independently selected from 1, 2, 3, and 4; Z ０ is -C(H)- or nitrogen, Z １ , Z ２ , and Y １ each of which is independently, -C(R ２ ), ２ -, -C(O)-, -NR ３ -, -N(C(O)R ２ ), -, -NS(O ２ )R ２ , -O-, -S-, -S(O)-, and -S(O ２ )- selected from m is selected from 0 to 5; R １ each independently represents a halogen, -CN, -NO ２ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle, and is selected from

2. R ２ is each independently selected from hydrogen, halogen, -CN, -OH, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted -O-cycloalkyl, and optionally substituted heterocycloalkyl, or two R ２ substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R ２ and R ３ substituents together form an optionally substituted heterocyclic ring, R ３ is each independently selected from hydrogen, optionally substituted alkyl, optionally substituted C ３－４ carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl, 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, 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, and When A is phenyl optionally substituted, m is 1 to 5, and at least one R １ is heterocycloalkyl, When A is pyridine optionally substituted, pyridazine optionally substituted, or pyrimidine optionally substituted, R ４ is selected from hydrogen, halogen, and -CN, When A is a piperidine sulfonamide optionally substituted, (i) Y １ is -C(R ２ ) ２ -, and the two R ２ substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring, or (ii) R ４ is selected from hydrogen, halogen, methyl, and -CN, and A - R １ is [Chemical 2] and Z ０ when is CH, R ４ is methyl or cyclopropyl, a compound or a pharmaceutically acceptable salt or solvate thereof. A compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein in the formula,[[]] [Chemical Formula 3] A is a ring selected from an optionally substituted carbocycle, an optionally substituted 4- to 6-membered heterocycle, and an optionally substituted isoindoline, as claimed in claim 1.

3. Having one or more structures of formula (IA), (IB), (IC), (ID), or (IE), wherein in the formula,[[]] n is selected from 0 to 9; 【Chemical Formula 4】 r is selected from 0 to 5; p is selected from 0 to 4; R ８ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R ９ is selected from optionally substituted C ３－６ carbocycles, optionally substituted C ５－６ heteroaryls, and 3- to 6-membered heterocycloalkyls, R １０ is optionally substituted alkyl or optionally substituted heterocycloalkyl, R １１ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R １２ is selected from optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl, or R １２ and R １３ together form an optionally substituted heterocyclic ring, R １３ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, q is selected from 0 to 2; R １４ is selected from -SOR １６ - and optionally substituted heterocycloalkyl, R １５ is selected from hydrogen, halogen, -CN, and optionally substituted C １－４ alkyl, R １６ is selected from optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, R １７ is selected from -SOR １９ -, optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycloalkyl, R １８ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R １９ is selected from optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl,

4. A compound having the structure of formula (IA), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 3.

5. When the compound is a compound of formula (IA), (i) Y １ is -C(R ２ ), ２ and the two R ２ substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring, or (ii) R ４ is selected from hydrogen, halogen, and -CN, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof. A compound having the structure of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 3.

6. A compound having the structure of formula (IC), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 3.

7. A compound having the structure of formula (IE), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 3.

8.

9.

10. A compound, or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 9, wherein each of a and b is independently selected from 1 and 2. Z １ and Z ２ are independently, -C(R ２ ), ２ -, -NR ３ -, -O-, and -S-, the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.

11. Z １ and Z ２ each independently is -C(R ２ ) ２ -, the compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof.

12.

13.

14. Y １ is -C(R ２ ) ２ --, --NR ３ -, -NS(O ２ ) R ２ , -O-, -S(O) ２ 11. The compound of any one of claims 1 to 10, wherein the compound is selected from -, -, -S-, - ...

15. Y １ is -C(R ２ ) ２ - and -NR ３ 12. The compound of claim 11, selected from: or a pharma- ceutically acceptable salt or solvate thereof.

16. R ２ Each independently is selected from hydrogen, OH, halogen, -CN, optionally substituted alkyl, optionally substituted -O-alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or solvate thereof.

17. R ２ Each independently is selected from hydrogen, halogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, the compound according to claim 13, or a pharmaceutically acceptable salt or solvate thereof.

18. R ２ is each independently selected from hydrogen, -CN, and cyclopropyl, a compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof.

19. Two Rs ２ The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15, wherein the two R substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

20. R ３ is each independently selected from hydrogen, optionally substituted alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof. Having one or more structures of formula (IAA), (IBB), (ICC), (IDD), or (IEE), wherein R ３ is each selected from methyl, methoxyethylene, CD ３ , cyclopropyl, and cyclobutyl, a compound according to claim 17 or a pharmaceutically acceptable salt or solvate thereof. in the formula,[[]] R ３ The compound according to claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R is cyclopropyl. n is selected from 0 to 9; p is selected from 0 to 4; [Chemical Formula 5] q is selected from 0 to 2; each of a, b, c, and d is independently selected from 1, 2, 3, and 4, and the compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 3. R ８ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R ９ is selected from optionally substituted C ３－６ carbocyclic ring, optionally substituted C ５－６ heteroaryl, and 3- to 6-membered heterocycloalkyl, R １０ is an optionally substituted heterocycloalkyl, R １１ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R １２ is optionally substituted heterocycloalkyl, or R １２ and R １３ together form an optionally substituted heterocycle, R １３ is selected from halogen, -CN, and optionally substituted C １－４ alkyl, R １５ is selected from hydrogen, halogen, -CN, 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 １９ is optionally substituted C １－４ alkyl, optionally substituted C ３－６ carbocycle, and optionally substituted 3- to 6-membered heterocycloalkyl, selected from

21. ​ ​ Z １ , Z ２ , Z ３ , Z ４ , and Z ５ Each of the groups independently represents -C(R ２ ) ２ -, -C(O)-, -NR ３ -, -N(C(O)R ２ ) -, -NS(O ２ ) R ３ , -O-, -S-, -S(O)-, and -S(O) ２ -, Z ５ is further selected from a bond, and ​ ​ The compound according to claim 20 having the structure of formula (IAA) or a pharmaceutically acceptable salt or solvate thereof.

22. The compound according to claim 20 having the structure of formula (IBB) or a pharmaceutically acceptable salt or solvate thereof.

23. The compound according to claim 20 having the structure of formula (ICC) or a pharmaceutically acceptable salt or solvate thereof.

24. The compound according to claim 20 having the structure of formula (IEE) or a pharmaceutically acceptable salt or solvate thereof.

25. Z １ , Z ２ , Z ３ , Z ４ , and Z ５ each of which is independently selected from -C(R ２ ), -NR ２ -, -N(C(O)R ３ ), -NS(O ２ ), -NS(O ２ )R ３ , -O-, and -S(O ２ ), and Z ５ is further selected from linkages, a compound according to any one of claims 20 to 24 or a pharmaceutically acceptable salt or solvate thereof.

26. Z １ , Z ２ , Z ３ , Z ４ , and Z ５ Each of the groups independently represents -C(R ２ ) ２ --, --NR ３ -, -O-, and -S(O) ２ -, Z ５ 26. The compound of claim 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is further selected from a bond.

27. R ２ Each R is independently selected from hydrogen, halogen, -CN, OH, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R ２ substituents together form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. The compound according to any one of claims 20 to 26, or a pharmaceutically acceptable salt or solvate thereof.

28. R ２ is each selected from hydrogen, fluoro, CN, cyclopropyl, cyclobutyl, -C １－４ alkyl, -C １－４ haloalkyl, -O-C １－４ alkyl, -C １－４ alkylene-O-C １－３ alkyl, -C １－４ alkylene-OH, an optionally substituted oxetane, and an optionally substituted azetidine, the compound according to claim 27 or a pharmaceutically acceptable salt or solvate thereof.

29. R ３ is selected from hydrogen, -(CH ２ ) ２ OMe, -S(O) ２ CH ３ , -C １－４ alkylene - O - C １－３ alkyl, C １－４ alkyl, cyclopropyl, cyclobutyl, an optionally substituted oxetane, and an optionally substituted azetidine, and is a compound according to any one of claims 20 to 28 or a pharmaceutically acceptable salt or solvate thereof.

30. R ３ is hydrogen, -(CH ２ ) ２ OMe, C １－４ alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine, the compound according to claim 29 or a pharmaceutically acceptable salt or solvate thereof.

31. R ３ is hydrogen, methyl, ethyl, propyl, CD ３ , and the compound according to claim 30 or a pharmaceutically acceptable salt or solvate thereof selected from cyclopropyl.

32. Each of a, b, c, and d is independently selected from 1 and 2, and the compound according to any one of claims 20 to 31 or a pharmaceutically acceptable salt or solvate thereof.

33. A is selected from optionally substituted cyclohexane, optionally substituted pyridine, optionally substituted piperidine, optionally substituted tetrahydropyran, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azetidine, and optionally substituted tetrahydroisoquinoline, and the compound according to claim 1 or 2 or a pharmaceutically acceptable salt or solvate thereof.

34. A is optionally substituted piperidine, and the compound according to claim 1 or 2 or a pharmaceutically acceptable salt or solvate thereof.

35. A is SO ２ R ９ is replaced, and R ９ is an optionally substituted C ３－６ carbocyclic ring, an optionally substituted C ５－６ heteroaryl, and a 3- to 6-membered heterocycloalkyl, the compound according to claim 34 or a pharmaceutically acceptable salt or solvate thereof.

36. m is selected from 0 to 1, and the compound according to claim 34 or 35 or a pharmaceutically acceptable salt or solvate thereof.

37. R １ is independently selected from optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle, the compound according to any one of claims 34 to 36 or a pharmaceutically acceptable salt or solvate thereof.

38. R １ is each independently selected from optionally substituted alkyl and optionally substituted heterocycle, the compound according to claim 37 or a pharmaceutically acceptable salt or solvate thereof.

39. R １ is each independently selected from methyl, ethyl, and optionally substituted diazaspiro[3.3]heptane, the compound according to claim 37 or a pharmaceutically acceptable salt or solvate thereof.

40. Z １ and Z ２ each independently is selected from -C(R ２ ) ２ -, -NR ３ -, -O-, and -S-, and a compound according to any one of claims 1 to 13 and 34 to 39 or a pharmaceutically acceptable salt or solvate thereof.

41. Z １ and Z ２ each is, -C(R ２ ) ２ - is the compound according to claim 40, or a pharmaceutically acceptable salt or solvate thereof.

42. Each of a and b is independently selected from 1 and 2, and the compound according to claim 40 or 41 or a pharmaceutically acceptable salt or solvate thereof.

43. Y １ is -C(R ２ ) ２ --, --NR ３ 43. The compound of any one of claims 1 to 13 and 34 to 42, or a pharma- ceutically acceptable salt or solvate thereof, selected from -, -O-, and -S-.

44. Y １ is a compound according to claim 43, or a pharmaceutically acceptable salt or solvate thereof, selected from -C(R ２ ) ２ - and -NR ３ ​

45. Y １ is -C(R ２ ), ２ and the two R ２ substituents together form a ring selected from an optionally substituted heterocyclic ring and an optionally substituted carbocyclic ring, the compound according to claim 44 or a pharmaceutically acceptable salt or solvate thereof.

46. Y １ is -C(R ２ ), ２ and the two R ２ substituents together form a ring selected from optionally substituted heterocycles, the compound according to claim 45, or a pharmaceutically acceptable salt or solvate thereof.

47. In formulas (IA), (IB), (IC), (ID), and (IE) 【Chemical Formula 6】 The N-containing heterocycle as depicted is selected from optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted morpholine, optionally substituted tetrahydrothienopyrrole dioxide, and optionally substituted dihydroindole, and is the compound according to any one of claims 1 to 19 and 34 to 46 or a pharmaceutically acceptable salt or solvate thereof.

48. In formula (IA), (IB), (IC), (ID), and (IE) 【Chemical 7】 The N-containing heterocycle as depicted is 【Chemical 8】 selected from and is the compound according to any one of claims 1 to 19 and 34 to 46 or a pharmaceutically acceptable salt or solvate thereof.

49. R ４ is hydrogen, halogen, optionally substituted C １－２ alkyl, optionally substituted C ３－４ carbocyclic ring, and optionally substituted 3- to 4-membered heterocycloalkyl selected from the group consisting of the compounds according to any one of claims 1 to 32 or 34 to 48, or a pharmaceutically acceptable salt or solvate thereof.

50. R ４ is selected from hydrogen and optionally substituted C １ alkyl, the compound according to claim 49, or a pharmaceutically acceptable salt or solvate thereof.

51. R ４ is hydrogen, methyl, and -CHF ２ selected from the compound according to claim 50 or a pharmaceutically acceptable salt or solvate thereof.

52. R ４ is a compound according to any one of claims 1 to 32 or 34 to 48, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen, halogen, and -CN.

53. R ４ is a compound according to any one of claims 1 to 32 or 34 to 48, or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen.

54. R ４ A compound according to any one of claims 1 to 32 or 34 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein R is not phenyl optionally substituted.

55. R ４ The compound according to any one of claims 1 to 32 or 34 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein R is not an optionally substituted alkyl.

56. R ５ is hydrogen, halogen, optionally substituted C １－２ alkyl, optionally substituted C ３－４ carbocycle, and optionally substituted 3- to 4-membered heterocycloalkyl, a compound according to any one of claims 1 to 32, 34 to 39, or 50 to 55, or a pharmaceutically acceptable salt or solvate thereof.

57. R ５ is selected from hydrogen, halogen, and optionally substituted C １－２ alkyl, the compound according to claim 56, or a pharmaceutically acceptable salt or solvate thereof.

58. R ５ is a compound according to claim 57 or a pharmaceutically acceptable salt or solvate thereof, selected from hydrogen and fluoro.

59. R ６ is hydrogen, halogen, optionally substituted C １－２ 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 32, 34 to 39, or 50 to 58, or a pharmaceutically acceptable salt or solvate thereof.

60. R ６ is selected from hydrogen, halogen, and optionally substituted C １－２ alkyl, the compound according to claim 59, or a pharmaceutically acceptable salt or solvate thereof.

61. R ６ The compound according to claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.

62. R ７ is hydrogen, a compound according to any one of claims 1 to 32, 34 to 39, or 50 to 61, or a pharmaceutically acceptable salt or solvate thereof.

63. R ９ is a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 3 to 4, 8 to 21, or 25 to 32, selected from cyclopentyl, methylcyclopentyl, cyclobutylmethylene, cyclopentylmethylene, and n-methylpyrazolyl.

64. The compound is selected from Table 1 and is the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

65. The compound is selected from Table 1 and is the compound according to claim 2 or a pharmaceutically acceptable salt or solvate thereof.

66. The compound is selected from Table 1 and is the compound according to claim 3 or a pharmaceutically acceptable salt or solvate thereof.

67. The compound is selected from Table 1 and is the compound according to claim 20 or a pharmaceutically acceptable salt or solvate thereof.

68. A pharmaceutical composition comprising the compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

69. A method for treating cancer, comprising administering the compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 68, to a subject in need of treatment.

70. The method according to claim 66, wherein the cancer is a solid tumor.

71. The method according to claim 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain tumor.

72. The method according to claim 71, wherein the cancer is ovarian cancer or breast cancer.

73. A method for inhibiting cyclin-dependent kinase (CDK) in cells using the compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 68.

74. The method according to claim 73, wherein the CDK is selected from CDK2, CDK4, CD6, or any combination thereof.

75. The method according to claim 74, wherein the CDK is selected from CDK2 / 4, CDK2 / 6, CDK4 / 6, and CDK2 / 4 / 6.

76. The method according to claim 75, wherein the CDK is CDK2 / 4 / 6.

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