Azaquinazoline compounds and methods of use

Abstract

Disclosed herein are substituted azaquinazoline compounds, conjugates, and pharmaceutical compositions for use in the treatment of cancer. In addition, the disclosed compounds may be used to inhibit CDK. In certain aspects, the present disclosure relates generally 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

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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 foregoing patent applications are incorporated herein by reference. Background Art

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

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

[0005] Disorders of the cell cycle mechanism are characteristic of cancer, leading to overactivation of CDK and uncontrolled cell division and proliferation. Genetic changes of genes encoding cyclin D, CDK4 / 6 and CDK4 / 6 inhibitor proteins (such as p21, p27) all contribute to tumorigenesis. Cyclin E (regulatory cyclin of CDK2) is often overexpressed in cancer. Since tumor development is closely related to gene mutation and disorder of CDK and its regulatory factors, CDK inhibitors can be used for anticancer treatment. Since the early 1990s, CDK inhibitors have been developed as cancer therapy, with a variety of FDA-approved drugs (Palbociclib, ribocicilib and abemaciclib). However, these early generation CDK inhibitors on the market have poor selectivity and high toxicity (such as bone marrow suppression), leading to adverse reactions, limiting clinical dose levels to further benefit patients. The medical needs of developing novel CDK inhibitors with better selectivity and fewer side effects for normal cells remain unmet. Summary of the invention

[0006] 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 to treat abnormal cell growth, such as cancer, in a subject in need thereof.

[0007] In some aspects, a method of treating cancer may comprise administering 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) to an individual in need thereof.

[0008] In certain aspects, the present disclosure provides a compound represented by formula (I0):

[0009]

[0010] in,

[0011] A is a ring selected from optionally substituted carbocycle, optionally substituted 4- to 8-membered heterocycle, and optionally substituted isoindoline;

[0012] Z 0 is –C(H)- or nitrogen;

[0013] Z 1 , Z 2 and Y 1 Each of which is independently selected from -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 -;

[0014] Each of a and b is independently selected from 1, 2, 3 and 4;

[0015] Each R 1 independently selected from halogen, -CN, -NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle;

[0016] m is selected from 0 to 5;

[0017] Each R 2 R is 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 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 2 and R 3 The substituents are taken together to form an optionally substituted heterocyclic ring;

[0018] Each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0019] R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0020] R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0021] R 7 is selected from hydrogen and optionally substituted C1-4 Alkyl, and

[0022] Wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R 1 is a heterocycloalkyl group,

[0023] Wherein if A is an optionally substituted pyridine, an optionally substituted pyridazine or an optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen and -CN,

[0024] Wherein if A is an optionally substituted piperidine sulfonamide, then (i) Y 1 Yes-C(R 2 ) 2 - and two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen, methyl and -CN, and

[0025] If AR 1 yes And Z 0 is CH, then R 4 It is methyl or cyclopropyl.

[0026] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0027] In some aspects, the present disclosure provides a method of treating cancer, comprising administering a compound or pharmaceutical composition described herein to a subject in need thereof. In some aspects, the present disclosure provides a method of inhibiting cyclin-dependent kinases (CDKs) using a compound or pharmaceutically acceptable salt or pharmaceutical composition described herein. DETAILED DESCRIPTION

[0028] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, those skilled in the art will now appreciate that various modifications, changes and substitutions will be appreciated. It should be understood that various alternatives to the embodiments of the present invention described herein may be used to practice the present invention. The following claims are intended to define the scope of the present invention, and thus encompass methods and structures and their equivalents within the scope of these claims.

[0029] The basic functions of cell regulation, cell division and cell proliferation are controlled by cyclin-dependent kinases (CDKs) activated by regulatory subunits such as cyclins. Due to the role of CDKs in cell regulation, CDK inhibitors can be used to treat cancer. It has been shown that increased activity or transient abnormal activation of CDKs leads to the development of tumors; the development of tumors is often associated with changes in CDKs or CDK regulatory factors.

[0030] CDK binds to cyclin (which is a regulatory protein), and in the absence of cyclin, it has very little kinase activity. Cyclin-CDK complexes are active kinases, usually regulated by phosphorylation and other binding proteins. Currently, 21 CDKs and 5 CDK-like genes are known in the human genome. Although many CDKs are related to transcription, CDK2, CDK4 and CDK6 are 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.

[0031] Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. Cyclin E is a cyclin partner of CDK2, which binds to CDK2 to form an active kinase complex. The CDK2-cyclin E complex is important in the regulation of G1 / S transition, centrosome duplication, and histone biosynthesis. Progressive phosphorylation can release the G1 transcription factor E2F and promote entry into the S phase. Another cyclin partner of CDK2 (cyclin A) can bind and activate CDK2 during the initial stage of the S phase, and promote endogenous substrate phosphorylation, which allows DNA replication and E2F inactivation to complete the S phase.

[0032] 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 the phosphorylation of Rb protein and inhibiting the proliferation of Rb-positive tumor cells. In addition to cell cycle activity, CDK4 and CDK6 inhibitors can also inhibit tumor growth through other mechanisms, including but not limited to inducing senescence, promoting anti-tumor immune responses, regulating cell metabolism, and enhancing leukocyte stasis caused by signal transduction pathway inhibitors.

[0033] definition

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0035] As used in the specification and claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0036] As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings indicated below.

[0037] “Amino” refers to –NH 2 Free radicals.

[0038] "Cyano" refers to the -CN free radical.

[0039] "Nitro" refers to -NO 2 Free radicals.

[0040] "Oxa" refers to the -O- radical.

[0041] "Oxo" refers to the =0 free radical.

[0042] "Thio" refers to the =S free radical.

[0043] "Imino" refers to a =NH radical.

[0044] "Oximo" refers to a =N-OH free radical.

[0045] "Hydrazino" refers to =N-NH 2 Free radicals.

[0046] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 In certain embodiments, an alkyl group contains from one to thirteen carbon atoms (e.g., C 1 -C 13 In certain embodiments, an alkyl group contains from one to eight carbon atoms (e.g., C 1 -C 8 In other embodiments, the alkyl group contains from one to five carbon atoms (e.g., C 1 -C 5 In other embodiments, the alkyl group contains from one to four carbon atoms (e.g., C 1 -C 4 In other embodiments, the alkyl group contains from one to three carbon atoms (e.g., C 1 -C 3 In other embodiments, the alkyl group contains one to two carbon atoms (e.g., C 1 -C 2 In other embodiments, the alkyl group contains one carbon atom (e.g., C 1 In other embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C 5 -C 15In other embodiments, the alkyl group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkyl group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkyl group contains three to five carbon atoms (e.g., C 3 -C 5 In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond.

[0047] "Heteroalkyl" refers to an alkyl group as defined above, having one or more carbon atoms substituted with a heteroatom, such as where the heteroatom is independently selected from N, O and S at each substitution position. Additional heteroatoms may also be available, including but not limited to B, Al, Si and P. The heteroatoms may also be oxidized, such as but not limited to -S(O)- and -S(O) 2 -. For example, heteroalkyl groups may include ethers, thioethers, and alkyl-amines. A heteroalkyl group is composed of a specified number of carbon atoms and may include one or more heteroatoms selected from O, N, Si, and S, wherein the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. Two heteroatoms may be consecutive, such as -CH 2 NHOCH 3 and -CH 2 OSi(CH 3 ) 3 The heteroalkyl group may include any specified number of carbon atoms as defined herein and in the definition of alkyl.

[0048] "Alkoxy" means a radical of the formula -O-alkyl bonded through an oxygen atom wherein alkyl is an alkyl chain as defined above.

[0049] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In certain embodiments, alkenyl comprises two to eight carbon atoms. In other embodiments, alkenyl comprises two to four carbon atoms. Alkenyl is attached to the remainder of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc.

[0050] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having two to twelve carbon atoms. In certain embodiments, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group comprises two to six carbon atoms. In other embodiments, the alkynyl group comprises two to four carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0051] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a free radical group consisting only of carbon and hydrogen, contains no unsaturation, and has one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule by a single bond and to the free radical by a single bond. The attachment point of the alkylene chain to the rest of the molecule and to the free radical is through one carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene group contains one to eight carbon atoms (e.g., C 1 -C 8 In other embodiments, the alkylene group contains one to five carbon atoms (e.g., C 1 -C 5 In other embodiments, the alkylene group contains one to four carbon atoms (e.g., C 1 -C 4 In other embodiments, the alkylene group contains one to three carbon atoms (e.g., C 1 -C 3 In other embodiments, the alkylene group contains one to two carbon atoms (e.g., C 1 -C 2 In other embodiments, the alkylene group contains one carbon atom (e.g., C 1 In other embodiments, the alkylene group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkylene group contains three to five carbon atoms (e.g., C 3 -C 5 alkylene).

[0052] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a free radical radical consisting solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and has two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule by a single bond and to the free radical by a single bond. In certain embodiments, an alkenylene group comprises two to eight carbon atoms (e.g., C 2 -C 8 In other embodiments, the alkenylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkenylene group contains two to four carbon atoms (e.g., C 2 -C 4 In other embodiments, the alkenylene group contains two to three carbon atoms (e.g., C 2 -C 3 In other embodiments, the alkenylene group contains five to eight carbon atoms (e.g., C 5 -C 8 In other embodiments, the alkenylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkenylene group contains three to five carbon atoms (e.g., C 3 -C 5 alkenylene).

[0053] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a free radical radical consisting of only carbon and hydrogen, contains at least one carbon-carbon triple bond, and has two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule by a single bond and to the free radical by a single bond. In certain embodiments, an alkynylene group comprises two to eight carbon atoms (e.g., C 2 -C 8 In other embodiments, the alkynylene group contains two to five carbon atoms (e.g., C 2 -C 5 In other embodiments, the alkynylene group contains two to four carbon atoms (e.g., C 2 -C 4 In other embodiments, the alkynylene group contains two to three carbon atoms (e.g., C 2 -C 3 In other embodiments, the alkynylene group contains two carbon atoms (e.g., C 2 In other embodiments, the alkynylene group contains five to eight carbon atoms (e.g., C 5 -C 8In other embodiments, the alkynylene group contains three to five carbon atoms (e.g., C 3 -C 5 alkynylene).

[0054] "Heteroalkylene" refers to a straight or branched divalent heteroalkyl chain that connects the rest of the molecule to a free radical consisting of heteroatoms such as N, O and S. Other heteroatoms may also be available, including but not limited to B, Al, Si and P. The heteroalkylene chain is attached to the rest of the molecule by a single bond and to the free radical by a single bond. In certain embodiments, the heteroalkylene comprises one heteroatom. In certain embodiments, the heteroalkylene comprises two heteroatoms. In certain embodiments, the heteroalkylene comprises three heteroatoms. In certain embodiments, the heteroalkylene comprises four heteroatoms. In certain embodiments, the heteroalkylene comprises five heteroatoms. In certain embodiments, the heteroatom may be N, O, S, Si or P, or a combination thereof. In certain embodiments, the heteroatom may be N, O or S, or a combination thereof. In certain embodiments, the heteroatom may be N, O or a combination thereof.

[0055] The term "C x-y ” or “C x -C y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched chain alkyl groups containing 1 to 6 carbons.

[0056] The term "C x-y "Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond respectively.

[0057] As used herein, the term "carbocycle" refers to a saturated ring, an unsaturated ring or an aromatic ring, wherein each atom of the ring is carbon.Carbocycles include 3-10-membered monocyclic rings, 5-12-membered bicyclic rings, 5-12-membered spirobicyclic rings and 5-12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from a saturated ring, an unsaturated ring and an aromatic ring. In an exemplary embodiment, an aromatic ring, such as a phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane or cyclohexene. Where valence permits, a bicyclic carbocycle includes any combination of saturated bicyclic rings, unsaturated bicyclic rings and aromatic bicyclic rings. Bicyclic carbocycles also include spirobicyclic rings such as spiropentanes. Bicyclic carbocycles include any combination of ring sizes, such as 3-3 spirocyclic ring systems, 4-4 spirocyclic ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl.

[0058] 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 and contains five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0059] 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 3-10-membered monocyclic rings, 5-12-membered bicyclic rings, 5-12-membered spirobicyclic rings, and 5-12-membered bridged rings. In certain embodiments, cycloalkyl comprises three to ten carbon atoms. In other embodiments, cycloalkyl comprises five to seven carbon atoms. Cycloalkyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, etc.

[0060] The term "cycloalkenyl" refers to a saturated ring, wherein each atom of the ring is carbon, and there is at least one double bond between two ring carbons. Cycloalkenyl can include monocycles and polycycles, such as 3 to 10 monocycles, 6 to 12 bicycles and 5 to 12 bridged rings. In other embodiments, cycloalkenyl comprises five to seven carbon atoms. Cycloalkenyl can be attached to the rest of the molecule by a single bond. The example of monocyclic cycloalkenyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0061] The term "halo", or alternatively "halogen" or "halide" means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro or bromo.

[0062] The term "haloalkyl" refers to an alkyl radical as defined above substituted with one or more halo radicals, for example trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl radical is optionally further substituted as described herein.

[0063] As used herein, the term "heterocycle" refers to a saturated ring, an unsaturated ring or an aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycles include 3 to 10-membered monocycles, 6 to 12-membered bicyclics, 5 to 12-membered spiral bicyclics and 5 to 12-membered bridged rings. Where valence permits, monocyclic heterocycles include any saturated ring, unsaturated ring and aromatic ring. Monocyclic heterocycles include but are not limited to oxetanes, azetidines, furans, tetrahydrofurans, pyrroles, pyrrolidines, pyrans, piperidines, piperazines, imidazoles, thiazoles, morpholines, pyridines and pyrimidines. Where valence permits, bicyclic heterocycles include any combination of saturated bicyclics, unsaturated bicyclics and aromatic bicyclics. In exemplary embodiments, aromatic rings, such as pyridyl, can be fused to saturated or unsaturated rings, such as cyclohexane, cyclopentane, morpholine, piperidines or cyclohexene. Bicyclic heterocycles 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. Bicyclic heterocycles also include spiro bicycles, for example, 5- to 12-membered spiro bicycles such as, but not limited to, 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 1-thia-6-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-thia-6-oxaspiro[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.

[0064] The term "heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring radical containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl radical is attached to the rest of the molecule through any atom of the ring. Examples of heteroaryls include, but are not limited to, aza-. phenyl, phenyl, phenyl, phenyl, phenyl, phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl , phenyl

[0065] The term "heterocycloalkyl" refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycloalkyl can include monocycles and polycycles, such as 3 to 10 monocycles, 6 to 12 bicycles, 5 to 12 spiral bicycles and 5 to 12 bridged rings. The heteroatoms in the heterocycloalkyl free radical are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Where valence permits, heterocycloalkyl is attached to the remainder of the molecule by any atom of heterocycloalkyl (such as any carbon or nitrogen atom of heterocycloalkyl). Examples of heterocycloalkyl radicals include, but are not limited to, azetidinyl, dioxolanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 3-azabicyclo[3.1.0]hexane, 2-azaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 6-oxa-3-azabicyclo[3.1.0]hexane, [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.

[0066] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom, and at least one double bond is present between two ring carbons. Heterocycloalkenyl does not include heteroaromatic rings. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Heterocycloalkenyl can include monocyclic and polycyclic rings, such as 3-10-membered monocyclic rings, 6-12-membered bicyclic rings and 5-12-membered bridged rings. In other embodiments, the heterocycloalkenyl contains five to seven ring atoms. The heterocycloalkenyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazolin (dihydroisothiazole), oxadiazolin (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0067] The term "substituted" refers to a moiety having a substituent that replaces one or more carbon or substitutable heteroatoms (e.g., NH or NH 2 ) on the hydrogen. It is understood that "substituted" or "substituted by..." includes implicit restrictions, i.e. such substitutions meet the allowed valences of the substituted atom and the substituent, and the substitution produces a stable compound, i.e. a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a portion with a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino or thio group. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, spirocyclic and non-spirocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different.

[0068] In some embodiments, each substituent may include any of the substituents described herein, such as halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oxime (=N-OH), hydrazino (=N-NH 2 ),-R b -OR a , -R b -OC(O)-R a , -R b-OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oxime (=N-OH), hydrazino (=N-NH 2 ),-R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(Ra ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a The alkyl radicals may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oxime (=N-OH), hydrazino (=N-NH 2 ),-R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2); and where each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0069] Double bonds of oxygen atoms, such as oxo groups, are represented herein as "=O" and "(O)". Double bonds of nitrogen atoms are represented as "=NR" and "(NR)". Double bonds of sulfur atoms are represented as "=S" and "(S)".

[0070] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0071] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0072] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and cellulose acetate. oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0073] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium and magnesium salts.

[0074] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result including, but not limited to, a therapeutic benefit and / or a preventive benefit for a disease, disorder, or medical condition. Therapeutic benefits may include, for example, eradication or improvement of the underlying disorder being treated. In addition, therapeutic benefits may include, for example, eradication or improvement of one or more physiological symptoms associated with the underlying disorder such that improvement is observed in the subject, although the subject may still be troubled by the underlying disorder. In certain embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a particular disease or to a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not yet have been made. Treatment via administration of the compounds described herein does not require the involvement of a medical professional.

[0075] Abbreviations

[0076]

[0077]

[0078] Compound

[0079] The following is a discussion of compounds and salts thereof that can be used in the disclosed methods. In certain embodiments, the compounds and salts are described in Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) and (IEE).

[0080] In one aspect, disclosed herein are compounds represented by formula (I):

[0081]

[0082] in,

[0083] A is a ring selected from optionally substituted carbocycle, optionally substituted 4- to 6-membered heterocycle, and optionally substituted isoindoline;

[0084] Z 1 , Z 2 and Y 1 Each of which is independently selected from -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 -;

[0085] Each of a and b is independently selected from 1, 2, 3 and 4;

[0086] Each R 1 independently selected from halogen, -CN, -NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle; m is selected from 0 to 5;

[0087] Each R 2 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 2 and R 3 The substituents are taken together to form an optionally substituted heterocyclic ring;

[0088] Each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0089] R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0090] R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0091] R 7 is selected from hydrogen and optionally substituted C 1-4 Alkyl, and

[0092] Wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R 1 is a heterocycloalkyl group,

[0093] Wherein if A is optionally substituted pyridine or optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen and -CN, and wherein if A is an optionally substituted piperidinesulfonamide, then (i) Y 1 Yes-C(R 2 ) 2 - and two R 2The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen and -CN.

[0094] Ring A can be any suitable ring known to those skilled in the art. In some embodiments, A is selected from optionally substituted carbocyclic rings, optionally substituted 4- to 10-membered heterocyclic rings, and optionally substituted isoindoline rings. In some embodiments, A is selected from optionally substituted carbocyclic rings, optionally substituted 4- to 8-membered heterocyclic rings, and optionally substituted isoindoline rings. In some embodiments, A is selected from optionally substituted carbocyclic rings, optionally substituted 4- to 6-membered heterocyclic rings, and optionally substituted isoindoline rings. In some embodiments, A is selected from optionally substituted azetidine, optionally substituted piperidine, optionally substituted azabicyclo [3.1.0] hexane, optionally substituted phenyl, optionally substituted pyridine, optionally substituted pyrazole, optionally substituted isoindoline, and optionally substituted tetrahydroisoquinoline. In some embodiments, A is not optionally substituted pyridine. In some embodiments, A is not optionally substituted pyrimidine.

[0095] In some embodiments, A is replaced by methyl, -SO 2 Me, methylpiperidine, methylpiperazine, methylazaspiro[3.3]heptane, methyldiazaspiro[3.3]heptane, or a combination thereof. In some embodiments, A is methyl, -SO 2 Me, -SO 2 Me, methylpiperidine, methylpiperazine or a combination thereof. In some embodiments, A is methyl, -SO 2 Me or a combination thereof. In some embodiments, A is replaced by -SO 2 Me replaced.

[0096] Z 1 and Z 2 Can be any suitable functional group known to those skilled in the art. 1 and Z 2 are independently selected from -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 -. In some embodiments, Z 1 and Z 2are independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-NS(O 2 )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 Independently -C(R 2 ) 2 -.

[0097] The variables a and b can be any suitable number 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.

[0098] Y 1 Can be any suitable functional group known to those skilled in the art. 1 Selected from -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 -. In some embodiments, Y 1 Selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-NS(O 2 )R 2 -, -O- and -S-. In some embodiments, Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S-. In some embodiments, Y 1 Selected from -C(R 2 ) 2 -and-NR 3 In some embodiments, Y 1 Yes-C(R 2 ) 2 - and two R2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic and optionally substituted carbocyclic. 1 Yes-C(R 2 ) 2 - and two R 2 The substituents are taken together to form a ring selected from an optionally substituted heterocycle.

[0099] In some embodiments, the The N-containing heterocycle 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. In some embodiments, the N-containing heterocycle depicted in Formula (I) 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. The N-containing heterocyclic ring is selected from

[0100] 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.

[0101] R 1 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 1 independently selected from halogen, -CN, -NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle. 1 R is independently selected from optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle. 1 R is independently selected from optionally substituted alkyl and optionally substituted heterocycle. 1 R is independently selected from methyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted azaspiro[3.3]heptane, and optionally substituted diazaspiro[3.3]heptane. 1 independently selected from methyl, ethyl and optionally substituted diazaspiro[3.3]heptane.

[0102] R 2Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 2 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 2 and R 3 The substituents are taken together to form an optionally substituted heterocycle. 2 is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 R is independently selected from hydrogen, halogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 R is independently selected from hydrogen, fluorine, chlorine, bromine, -CN, cyclopropyl, cyclobutyl, oxetane, and azetidine. 2 R is independently selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 2 is selected from hydrogen, fluorine, -CN and cyclopropyl. 2 is selected from hydrogen, -CN and cyclopropyl.

[0103] In some embodiments, or both R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 The substituents are taken together to form an optionally substituted heterocycle. 2 The substituents are taken together to form an optionally substituted carbocyclic ring. 2 The substituents are combined so that The structure is

[0104] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 )2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0105] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0106] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0107] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0108] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0109] R 3 Can be any suitable functional group known to those skilled in the art. In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl, or R 2 and R 3 The substituents are taken together to form an optionally substituted heterocycle. 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0110] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0111] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0112] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0113] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0114] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0115] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IA):

[0116]

[0117] in,

[0118] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0119] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; and

[0120] n is selected from 0 to 9;

[0121] Where (i) Y 1 Yes-C(R 2 ) 2 - and two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen and -CN.

[0122] In some embodiments, or both R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 The substituents are taken together to form an optionally substituted heterocycle. 2 The substituents are taken together to form an optionally substituted carbocyclic ring. 2 The substituents are combined so that The structure is

[0123] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3-、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0124] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0125] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0126] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0127] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0128] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3It is cyclopropyl.

[0129] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0130] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0131] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0132] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0133] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0134] R 8 Can be any suitable functional group known to those skilled in the art. 8 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 8 is selected from halogen and optionally substituted C 1-4 In some embodiments, R8 Selected from optionally substituted C 1-4 In some embodiments, R 8 Selected from methyl, ethyl and propyl.

[0135] R 9 Can be any suitable functional group known to those skilled in the art. 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 9 Selected from optionally substituted C 1-4 Alkyl and optionally substituted C 3-6 In some embodiments, R 9 Selected from optionally substituted C 1-4 In some embodiments, R 9 Selected from methyl, ethyl and propyl.

[0136] 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 selected from 0 or 1. In some embodiments, n is 0.

[0137] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IAA):

[0138]

[0139] in,

[0140] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0141] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl;

[0142] n is selected from 0 to 9;

[0143] 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(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0144] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0145] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0146] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 )2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0147] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0148] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0149] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0150] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0151] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0152] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0153] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0154] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl.6 In some embodiments, R 6 It's hydrogen.

[0155] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0156] R 8 Can be any suitable functional group known to those skilled in the art. 8 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 8 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 8 Selected from optionally substituted C 1-4 In some embodiments, R 8 Selected from methyl, ethyl and propyl.

[0157] R 9 Can be any suitable functional group known to those skilled in the art. 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic, 3- to 6-membered heterocycloalkyl, and optionally substituted C 5-6 In some embodiments, R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted C 5-6 In some embodiments, R 9 is an optionally substituted C 5-6 In some embodiments, R 9 is an optionally substituted C 5 In some embodiments, R 9 is an optionally substituted C 6 In some embodiments, R 9 is an optionally substituted pyrazole. 9 Selected from optionally substituted C 1-4 Alkyl and optionally substituted C 3-6 In some embodiments, R 9 Selected from optionally substituted C1-4 In some embodiments, R 9 is selected from the group consisting of methyl, ethyl and propyl. 9 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 9 It is cyclopropyl and cyclobutyl.

[0158] 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 selected from 0 or 1. In some embodiments, n is 0.

[0159] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IAAA):

[0160]

[0161] in,

[0162] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl.

[0163] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0164] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0165] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 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 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0166] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0167] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0168] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0169] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0170] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0171] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0172] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0173] R 9 Can be any suitable functional group known to those skilled in the art. 9 Selected from optionally substituted optionally substituted C 3-6 In some embodiments, R 9 Selected from optionally substituted optionally substituted C 3-4 In some embodiments, R 9 is selected from optionally substituted cyclopropyl and optionally substituted pyrazole.

[0174] In some embodiments, depicted as The N-containing heterocyclic ring is selected from:

[0175] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IB):

[0176]

[0177] in,

[0178] R 10 is optionally substituted heterocycloalkyl;

[0179] R 11 is selected from halogen, -CN and optionally substituted C 1-4 Alkyl; and

[0180] p is selected from 0 to 4.

[0181] In some embodiments, or both R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 The substituents are taken together to form an optionally substituted heterocycle.2 The substituents are taken together to form an optionally substituted carbocyclic ring. 2 The substituents are combined so that The structure is

[0182] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0183] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0184] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 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 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0185] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0186] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0187] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0188] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0189] In some embodiments, each R 2is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0190] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0191] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0192] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0193] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0194] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0195] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0196] 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.

[0197] R 10 Can be any suitable functional group known to those skilled in the art. 10 is an optionally substituted heterocycloalkyl. 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 Selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0198] R 11 Can be any suitable functional group known to those skilled in the art. 11 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 11 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 11 Selected from optionally substituted C 1-4 In some embodiments, R 11 Selected from methyl, ethyl and propyl.

[0199] 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.

[0200] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IBB):

[0201]

[0202] in,

[0203] R 10 is optionally substituted heterocycloalkyl;

[0204] R 11 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0205] p is selected from 0 to 4;

[0206] 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(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0207] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0208] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3-、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0209] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0210] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 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 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

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

[0212] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0213] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0214] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0215] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0216] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0217] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0218] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0219] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0220] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0221] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0222] 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.

[0223] R 10 Can be any suitable functional group known to those skilled in the art. 10 is an optionally substituted heterocycloalkyl. 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 Selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0224] R 11 Can be any suitable functional group known to those skilled in the art. 11 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 11 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 11 Selected from optionally substituted C 1-4 In some embodiments, R 11 Selected from methyl, ethyl and propyl.

[0225] 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.

[0226] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IC):

[0227]

[0228] in,

[0229] R 12is selected from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl; or R 12 and R 13 taken together to form an optionally substituted heterocyclic ring;

[0230] R 13 is selected from halogen, -CN and optionally substituted C 1-4 Alkyl; and

[0231] q is selected from 0 to 2.

[0232] In some embodiments, or both R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 The substituents are taken together to form an optionally substituted heterocycle. 2 The substituents are taken together to form an optionally substituted carbocyclic ring. 2 The substituents are combined so that The structure is

[0233] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0234] 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 -、-NR3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0235] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0236] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0237] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0238] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0239] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0240] R 4Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0241] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0242] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0243] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0244] R 12 Can be any suitable functional group known to those skilled in the art. 12 is optionally substituted heterocycloalkyl; or R 12 and R 13 are taken together to form an optionally substituted heterocycle. 12 is an optionally substituted 5- to 6-membered heterocyclic ring, or R 12 and R 13 are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. 12 is an optionally substituted 5- to 6-membered heterocyclic ring. 12 is selected from the group consisting of optionally substituted piperidine, optionally substituted piperazine, and optionally substituted 2,6-diazaspiro[3.3]heptane. 12 is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 12 Selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0245] R 13 Can be any suitable functional group known to those skilled in the art. 13 is selected from halogen, -CN and optionally substituted C 1-4 Alkyl; or R 12and R 13 are taken together to form an optionally substituted heterocycle. 13 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 13 Selected from methyl, ethyl and propyl.

[0246] In some embodiments, R 12 and R 13 are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. 12 and R 13 are taken together to form an optionally substituted heterocycle. 12 and R 13 Put together to make The structure is

[0247] 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.

[0248] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (ICC):

[0249]

[0250] in,

[0251] R 12 is optionally substituted heterocycloalkyl; or R 12 and R 13 taken together to form an optionally substituted heterocyclic ring;

[0252] R 13 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0253] q is selected from 0 to 2; and

[0254] 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(O 2 )R 2, -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0255] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0256] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0257] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2)-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0258] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0259] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0260] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0261] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0262] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0263] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0264] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0265] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0266] R 7Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0267] R 12 Can be any suitable functional group known to those skilled in the art. 12 is optionally substituted heterocycloalkyl; or R 12 and R 13 are taken together to form an optionally substituted heterocycle. 12 is an optionally substituted 5- to 6-membered heterocyclic ring, or R 12 and R 13 are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. 12 is an optionally substituted 5- to 6-membered heterocyclic ring. 12 is selected from the group consisting of optionally substituted piperidine, optionally substituted piperazine, and optionally substituted 2,6-diazaspiro[3.3]heptane. 12 is selected from optionally substituted piperidine and optionally substituted 2,6-diazaspiro[3.3]heptane. In some embodiments, R 12 Selected from methylpiperazine and methyl-2,6-diazaspiro[3.3]heptane.

[0268] R 13 Can be any suitable functional group known to those skilled in the art. 13 is selected from halogen, -CN and optionally substituted C 1-4 Alkyl; or R 12 and R 13 are taken together to form an optionally substituted heterocycle. 13 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 13 Selected from methyl, ethyl and propyl.

[0269] In some embodiments, R 12 and R 13 are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring. 12 and R 13 are taken together to form an optionally substituted heterocycle. 12 and R 13 Put together to make The structure is

[0270] 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.

[0271] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (ID):

[0272]

[0273] in,

[0274] R 14 Selected from -SOR 16 - and optionally substituted heterocycloalkyl;

[0275] R 15 is selected from hydrogen, halogen, -CN and optionally substituted C 1-4 Alkyl; and

[0276] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl

[0277] In some embodiments, or both R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 The substituents are taken together to form an optionally substituted heterocycle. 2 The substituents are taken together to form an optionally substituted carbocyclic ring. 2 The substituents are combined so that The structure is

[0278] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0279] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0280] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0281] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0282] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0283] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3It is cyclopropyl.

[0284] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0285] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0286] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0287] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0288] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 It's hydrogen.

[0289] R 14 Can be any suitable functional group known to those skilled in the art. 14 Selected from -SOR 16 and optionally substituted heterocycloalkyl. 14 Yes-SOR 16 -. In some embodiments, R14 is selected from optionally substituted heterocycloalkyl.

[0290] R 15 Can be any suitable functional group known to those skilled in the art. 15 is selected from hydrogen, halogen, -CN and optionally substituted C 1-4 In some embodiments, R 15 is selected from hydrogen, halogen and optionally substituted C 1-4 In some embodiments, R 15 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is an optionally substituted C 1-4 In some embodiments, R 15 They are methyl, ethyl and propyl.

[0291] R 16 Can be any suitable functional group known to those skilled in the art. 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 16 is an optionally substituted C 3-6 In some embodiments, R 16 Selected from optionally substituted C 1-4 In some embodiments, R 16 Selected from methyl, ethyl and propyl.

[0292] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IDD):

[0293]

[0294] in,

[0295] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0296] Z 1 , Z 2 , Z 3 , Z 4 and Z 5Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0297] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0298] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0299] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0300] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0301] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0302] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0303] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0304] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0305] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0306] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 is hydrogen. 15 Can be any suitable functional group known to those skilled in the art. 15 is selected from hydrogen, halogen, -CN and optionally substituted C 1-4In some embodiments, R 15 is selected from hydrogen, halogen and optionally substituted C 1-4 In some embodiments, R 15 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is an optionally substituted C 1-4 In some embodiments, R 15 They are methyl, ethyl and propyl.

[0307] R 16 Can be any suitable functional group known to those skilled in the art. 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 16 is an optionally substituted C 3-6 In some embodiments, R 16 Selected from optionally substituted C 1-4 In some embodiments, R 16 Selected from methyl, ethyl and propyl.

[0308] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IE):

[0309]

[0310] in,

[0311] R 17 Selected from -SOR 19 -, optionally substituted alkyl, optionally substituted carbocycle and optionally substituted heterocycloalkyl;

[0312] R 18 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0313] R 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl; and

[0314] r is selected from 0 to 5.

[0315] In some embodiments, or both R 2The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 The substituents are taken together to form an optionally substituted heterocycle. 2 The substituents are taken together to form an optionally substituted carbocyclic ring. 2 The substituents are combined so that The structure is

[0316] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0317] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0318] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0319] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0320] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0321] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3 It is cyclopropyl.

[0322] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0323] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0324] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0325] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl.6 In some embodiments, R 6 It's hydrogen.

[0326] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 is hydrogen. 14 Can be any suitable functional group known to those skilled in the art. 14 Selected from -SOR 16 and optionally substituted heterocycloalkyl. 14 Yes-SOR 16 -. In some embodiments, R 14 is selected from optionally substituted heterocycloalkyl.

[0327] R 17 Can be any suitable functional group known to those skilled in the art. 17 Selected from -SOR 19 -, optionally substituted alkyl, optionally substituted carbocyclic, and optionally substituted heterocycloalkyl. 17 Selected from -SOR 19 -, optionally substituted alkyl, and optionally substituted 3- to 5-membered heterocycloalkyl. 17 Selected from -SOR 19 -, methyl and optionally substituted 4-membered heterocycloalkyl. 17 Selected from -SOR 19 -, methyl and 1-(methylsulfonyl)azetidine. In some embodiments, R 17 Yes-SOR 19 -. In some embodiments, R 17 In some embodiments, R 17 It is 1-(methylsulfonyl)azetidine.

[0328] R 18 Can be any suitable functional group known to those skilled in the art. 18 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 18 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 18Selected from optionally substituted C 1-4 In some embodiments, R 18 Selected from methyl, ethyl and propyl.

[0329] R 19 Can be any suitable functional group known to those skilled in the art. 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 19 Selected from optionally substituted C 3-6 In some embodiments, R 19 is an optionally substituted alkyl. 19 is selected from the group consisting of methyl, ethyl and propyl. 19 It's methyl.

[0330] 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.

[0331] In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IEE):

[0332]

[0333] in,

[0334] R 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0335] Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of Z can be any suitable functional group known to those skilled in the art. 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-C(O)-、-NR 3-、-N(C(O)R 2 )-、-NS(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 Additionally selected from the group consisting of bonds. 1 and Z 2 Each of can be any functional group as previously described.

[0336] 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0337] The variables a, b, c, and d can be any suitable number known to those skilled in the art. In some embodiments, each of a, b, c, and d is independently selected from 1, 2, 3, and 4. In some embodiments, each of a, b, c, and d is independently 1, 2, and 3. In some embodiments, each of a, b, c, and d is independently selected from 1 and 2.

[0338] In some embodiments, each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen, fluorine, chlorine, cyclopropyl, cyclobutyl or two R 2 The substituents are taken together to form an optionally substituted heterocycle or an optionally substituted carbocycle. 2 are independently selected from hydrogen, fluorine or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0339] In some embodiments, each R 2 is independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl. 2 is independently selected from hydrogen, fluorine and -OH. 2 R is independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 2 are independently selected from hydrogen and fluorine.

[0340] In some embodiments, each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, each R 3 are independently selected from optionally substituted alkyl, optionally substituted C 3-4 In some embodiments, R 3 In some embodiments, each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine. 3 is selected from cyclopropyl and cyclobutyl. 3It is cyclopropyl.

[0341] In some embodiments, R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. In some embodiments, R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl. In some embodiments, R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 3 It's methyl.

[0342] R 4 Can be any suitable functional group known to those skilled in the art. 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-2 Alkyl and optionally substituted C 3-4 In some embodiments, R 4 is selected from hydrogen and optionally substituted C 1 In some embodiments, R 4 Selected from hydrogen, methyl and -CHF 2 In some embodiments, R 4 is selected from hydrogen, halogen and -CN. 4 In some embodiments, R 4 is not optionally substituted phenyl. 4 It is not an optionally substituted alkyl group.

[0343] R 5 Can be any suitable functional group known to those skilled in the art. 5 is selected from hydrogen, halogen, -CN, optionally substituted C1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 5 Selected from hydrogen and fluorine.

[0344] R 6 Can be any suitable functional group known to those skilled in the art. 6 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 In some embodiments, R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 In some embodiments, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl and propyl. 6 In some embodiments, R 6 It's hydrogen.

[0345] R 7 Can be any suitable functional group known to those skilled in the art. 7 is selected from hydrogen and optionally substituted C 1-4 In some embodiments, R 7 is selected from the group consisting of hydrogen, methyl, ethyl and propyl. 7 is hydrogen. 14 Can be any suitable functional group known to those skilled in the art. 14 Selected from -SOR 16 and optionally substituted heterocycloalkyl. 14 Yes-SOR 16 -. In some embodiments, R 14 is selected from optionally substituted heterocycloalkyl.

[0346] R 18 Can be any suitable functional group known to those skilled in the art. 18 is selected from halogen, -CN and optionally substituted C 1-4 In some embodiments, R 18 is selected from halogen and optionally substituted C 1-4 In some embodiments, R 18 Selected from optionally substituted C 1-4 In some embodiments, R 18 Selected from methyl, ethyl and propyl.

[0347] R 19 Can be any suitable functional group known to those skilled in the art. 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In some embodiments, R 19 Selected from optionally substituted C 3-6 In some embodiments, R 19 is an optionally substituted alkyl. 19 is selected from the group consisting of methyl, ethyl and propyl. 19 It's methyl.

[0348] 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.

[0349] In some embodiments, the compound is selected from:

[0350] In some embodiments, the compound is selected from:

[0351] In some embodiments, the compound is selected from:

[0352] In some embodiments, the compound is selected from:

[0353] In some embodiments, the compound is selected from:

[0354] In some embodiments, the compound is selected from:

[0355] Other embodiments of the compounds of the present disclosure include the following:

[0356] Embodiment 1 relates to a compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure of formula (I):

[0357]

[0358] in,

[0359] A is a ring selected from optionally substituted carbocycle, optionally substituted 4- to 8-membered heterocycle, optionally substituted tetrahydrotriazolopyrazine, and optionally substituted isoindoline;

[0360] Z 0 is –C(H)- or nitrogen;

[0361] Z 1 , Z 2 and Y 1 Each of which is independently selected from -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 -;

[0362] Each of a and b is independently selected from 1, 2, 3 and 4;

[0363] Each R 1 independently selected from halogen, -CN, -NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle;

[0364] m is selected from 0 to 5;

[0365] Each R 2 R is 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 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 2 and R 3The substituents are taken together to form an optionally substituted heterocyclic ring;

[0366] Each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0367] R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0368] R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0369] R 7 is selected from hydrogen and optionally substituted C 1-4 Alkyl, and

[0370] Wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R 1 is a heterocycloalkyl group,

[0371] Wherein if A is an optionally substituted pyridine, an optionally substituted pyridazine or an optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen and -CN,

[0372] Wherein if A is an optionally substituted piperidine sulfonamide, then (i) Y 1 Yes-C(R 2 ) 2 - and the two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen, methyl and -CN, and

[0373] If AR 1 yes And Z 0 is CH, then R 4 is methyl or cyclopropyl.

[0374] Embodiment 2 relates to a compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, which has the structure of Formula (I):

[0375]

[0376] wherein 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 ring.

[0377] Embodiment 3 relates to a compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having a structure of any one of Formula (IA), (IB), (IC), (ID) or (IE):

[0378]

[0379] in,

[0380] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0381] R 9 Selected from optionally substituted C 3-6 Carbocyclic, optionally substituted C 5-6 heteroaryl and 3- to 6-membered heterocycloalkyl;

[0382] R 10 is optionally substituted alkyl or optionally substituted heterocycloalkyl;

[0383] R 11 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0384] R 12 is selected from optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl; or R 12 and R 13 taken together to form an optionally substituted heterocyclic ring;

[0385] R 13 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0386] n is selected from 0 to 9;

[0387] R 14 Selected from -SOR 16 - and optionally substituted heterocycloalkyl;

[0388] R 15 is selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl;

[0389] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl;

[0390] R 17 Selected from -SOR 19 -, optionally substituted alkyl, optionally substituted carbocycle and optionally substituted heterocycloalkyl;

[0391] R 18 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0392] R 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl;

[0393] r is selected from 0 to 5;

[0394] p is selected from 0 to 4;

[0395] q is selected from 0 to 2; and

[0396] When the compound is a compound of formula (IA), (i) Y 1 Yes-C(R 2 ) 2 - and the two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen and -CN.

[0397] Embodiment 4 relates to a compound according to Embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IA).

[0398] Embodiment 5 relates to a compound according to Embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IB).

[0399] Embodiment 6 relates to a compound according to Embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IC).

[0400] Embodiment 7 relates to a compound according to Embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IE).

[0401] Embodiment 8 relates to a compound according to any one of Embodiments 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 and Z 2 Independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0402] Embodiment 9 relates to a compound according to Embodiment 8, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 and Z 2 Independently -C(R 2 ) 2 -.

[0403] Embodiment 10 relates to a compound according to Embodiment 9, or a pharmaceutically acceptable salt or solvate thereof, wherein each of a and b is independently selected from 1 and 2.

[0404] Embodiment 11 relates to a compound according to any one of Embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -、-NS(O 2 )R 2 、-O-、-S(O) 2 -and-S-.

[0405] Embodiment 12 relates to a compound according to Embodiment 11, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Selected from -C(R 2 ) 2 -and-NR 3 .

[0406] Embodiment 13 relates to a compound according to any one of Embodiments 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 are independently selected from hydrogen, OH, halogen, -CN, optionally substituted alkyl, optionally substituted -O-alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0407] Embodiment 14 relates to a compound according to Embodiment 13, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 are independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0408] Embodiment 15 relates to a compound according to Embodiment 14, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 are independently selected from hydrogen, -CN and cyclopropyl.

[0409] Embodiment 16 relates to a compound according to any one of Embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein both R 2The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0410] Embodiment 17 relates to a compound according to any one of Embodiments 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is selected from fluoro, optionally substituted alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0411] Embodiment 18 relates to a compound according to Embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 Selected from methyl, methoxyethylene, CD 3 , cyclopropyl and cyclobutyl.

[0412] Embodiment 19 relates to a compound according to Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is cyclopropyl.

[0413] Embodiment 20 relates to a compound according to any one of Embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of any one of Formula (IAA), (IBB), (ICC), (IDD) or (IEE):

[0414]

[0415] in,

[0416] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0417] R 9 Selected from optionally substituted C 3-6 Carbocyclic, optionally substituted C 5-6 heteroaryl and 3- to 6-membered heterocycloalkyl;

[0418] R 10 is optionally substituted heterocycloalkyl;

[0419] R 11 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0420] R 12 is optionally substituted heterocycloalkyl; or R 12 and R 13 taken together to form an optionally substituted heterocyclic ring;

[0421] R 13 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0422] R 15 is selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl;

[0423] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl;

[0424] R 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl;

[0425] n is selected from 0 to 9;

[0426] p is selected from 0 to 4;

[0427] q is selected from 0 to 2;

[0428] 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(O 2 )R 3 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0429] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0430] Embodiment 21 relates to a compound according to Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IAA).

[0431] Embodiment 22 relates to a compound according to Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IBB).

[0432] Embodiment 23 relates to a compound according to Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (ICC).

[0433] Embodiment 24 relates to a compound according to Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IEE).

[0434] Embodiment 25 relates to a compound according to any one of Embodiments 16-24, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-N(C(O)R 2 )-、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0435] Embodiment 26 relates to a compound according to Embodiment 25, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -, -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0436] Embodiment 27 relates to a compound according to any one of Embodiments 16-26, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 are independently selected from hydrogen, halogen, -CN, OH, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0437] Embodiment 28 relates to a compound according to Embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 is selected from hydrogen, fluorine, CN, cyclopropyl, cyclobutyl, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-3 Alkyl, -C1-4 alkylene-OH, optionally substituted oxetane, and optionally substituted azetidine.

[0438] Embodiment 29 relates to a compound according to any one of Embodiments 16-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, -S(O) 2 CH 3 , -C 1-4 Alkylene-OC 1-3 Alkyl, C 1-4 alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0439] Embodiment 30 relates to a compound according to Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, C 1-4 alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0440] Embodiment 31 relates to a compound according to Embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from hydrogen, methyl, ethyl, propyl, CD 3 and cyclopropyl.

[0441] Embodiment 32 relates to a compound according to any one of embodiments 16-31, or a pharmaceutically acceptable salt or solvate thereof, wherein each a, b, c and d is independently selected from 1 and 2.

[0442] Embodiment 33 relates to a compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, 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.

[0443] Embodiment 34 relates to a compound according to Embodiment 33, or a pharmaceutically acceptable salt or solvate thereof, wherein A is an optionally substituted piperidine.

[0444] Embodiment 35 relates to a compound according to Embodiment 34, or a pharmaceutically acceptable salt or solvate thereof, wherein A is -SO 2 R 9 Substitution, where R 9Selected from optionally substituted C 3-6 Carbocyclic, optionally substituted C 5-6 Heteroaryl and 3- to 6-membered heterocycloalkyl

[0445] Embodiment 36 relates to a compound according to Embodiment 34 or 35, or a pharmaceutically acceptable salt or solvate thereof, wherein m is selected from 0 to 1.

[0446] Embodiment 37 relates to a compound according to any one of Embodiments 34-36, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 are independently selected from optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle.

[0447] Embodiment 38 relates to a compound according to Embodiment 37, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 are independently selected from optionally substituted alkyl and optionally substituted heterocycle.

[0448] Embodiment 39 relates to a compound according to Embodiment 37, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 independently selected from methyl, ethyl and optionally substituted diazaspiro[3.3]heptane.

[0449] Embodiment 40 relates to a compound according to any one of Embodiments 1-13 and 34-39, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 and Z 2 Independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0450] Embodiment 41 relates to a compound according to Embodiment 40, or a pharmaceutically acceptable salt or solvate thereof, wherein Z 1 and Z 2 Each is -C(R 2 ) 2 -.

[0451] Embodiment 42 relates to a compound according to embodiment 40 or 41, or a pharmaceutically acceptable salt or solvate thereof, wherein each of a and b is independently selected from 1 and 2.

[0452] Embodiment 43 relates to a compound according to any one of Embodiments 1-13 and 34-42, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3-, -O-, and -S-.

[0453] Embodiment 44 relates to a compound according to Embodiment 43, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Selected from -C(R 2 ) 2 -and-NR 3 -.

[0454] Embodiment 45 relates to a compound according to Embodiment 44, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Yes-C(R 2 ) 2 - and two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocycle and optionally substituted carbocycle.

[0455] Embodiment 46 relates to a compound according to Embodiment 46, or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 Yes-C(R 2 ) 2 - and the two R 2 The substituents are taken together to form a ring selected from an optionally substituted heterocycle.

[0456] Embodiment 47 relates to a compound according to any one of Embodiments 1-19 and 34-46, or a pharmaceutically acceptable salt or solvate thereof, wherein depicted is The N-containing heterocycle 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 indoline.

[0457] Embodiment 48 relates to a compound according to any one of Embodiments 1-19 and 34-46, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is selected from

[0458] Embodiment 48(a) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0459] Embodiment 48(b) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0460] Embodiment 48(c) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0461] Embodiment 48(d) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0462] Embodiment 48(e) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0463] Embodiment 48(f) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0464] Embodiment 48(g) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0465] Embodiment 48(h) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0466] Embodiment 48(i) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0467] Embodiment 48(j) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0468] Embodiment 48(k) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0469] Embodiment 48(1) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0470] Embodiment 48(m) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0471] Embodiment 48(n) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0472] Embodiment 48(o) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0473] Embodiment 48(p) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0474] Embodiment 48(q) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0475] Embodiment 48(r) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0476] Embodiment 48(s) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0477] Embodiment 48(t) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0478] Embodiment 48(u) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0479] Embodiment 48(v) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0480] Embodiment 48(w) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0481] Embodiment 48(x) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0482] Embodiment 48(y) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0483] Embodiment 48(z) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0484] Embodiment 48(aa) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0485] Embodiment 48(ab) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0486] Embodiment 48(ac) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0487] Embodiment 48(ad) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is Embodiment 48(ae) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0488] Embodiment 48(af) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0489] Embodiment 48(ag) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0490] Embodiment 48(ah) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0491] Embodiment 48(ai) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0492] Embodiment 48(aj) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0493] Embodiment 48(ak) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0494] Embodiment 48(al) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0495] Embodiment 48(am) relates to a compound according to Embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound depicted in Formula (IA), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is

[0496] Embodiment 49 relates to a compound according to any one of Embodiments 1-32, 34-48 or 48(a)-48(aj), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0497] Embodiment 50 relates to a compound according to Embodiment 49, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from hydrogen and optionally substituted C 1 alkyl.

[0498] Embodiment 51 relates to a compound according to Embodiment 50, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 Selected from hydrogen, methyl and -CHF 2 .

[0499] Embodiment 52 relates to a compound according to any one of Embodiments 1-32, 34-48 or 48(a)-48(aj), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from hydrogen, halogen and -CN.

[0500] Embodiment 53 relates to a compound according to any one of Embodiments 1-32, 34-48 or 48(a)-48(aj), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 Selected from hydrogen.

[0501] Embodiment 54 relates to a compound according to any one of Embodiments 1-32, 34-48 or 48(a)-48(aj), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is not optionally substituted phenyl.

[0502] Embodiment 55 relates to a compound according to any one of Embodiments 1-32, 34-48 or 48(a)-48(aj), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is not an optionally substituted alkyl group.

[0503] Embodiment 56 relates to a compound according to any one of Embodiments 1-32, 34-39 or 50-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0504] Embodiment 57 relates to a compound according to Embodiment 56, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 alkyl.

[0505] Embodiment 58 relates to a compound according to Embodiment 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 Selected from hydrogen and fluorine.

[0506] Embodiment 59 relates to a compound according to any one of Embodiments 1-32, 34-39 or 50-58, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0507] Embodiment 60 relates to a compound according to Embodiment 59, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 alkyl.

[0508] Embodiment 61 relates to a compound according to Embodiment 60, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It's hydrogen.

[0509] Embodiment 62 relates to a compound according to any one of Embodiments 1-32, 34-39 or 50-61, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 It's hydrogen.

[0510] Embodiment 63 relates to a compound according to any one of Embodiments 3-4, 8-21 or 25-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 Selected from cyclopentyl, methylcyclopentyl, cyclobutylmethylene, cyclopentylmethylene and n-methylpyrazolyl.

[0511] Embodiment 63(a) relates to a compound according to Embodiment 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It is cyclopentyl.

[0512] Embodiment 63(b) relates to a compound according to Embodiment 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It is methylcyclopentyl.

[0513] Embodiment 63(c) relates to a compound according to Embodiment 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It is cyclobutylmethylene.

[0514] Embodiment 63(d) relates to a compound according to Embodiment 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It is cyclopentylmethylene.

[0515] Embodiment 63(e) relates to a compound according to Embodiment 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 It is n-methylpyrazolyl.

[0516] Embodiment 64 relates to a compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from Table 1.

[0517] Embodiment 65 relates to a compound according to Embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from Table 1.

[0518] Embodiment 66 relates to a compound according to Embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from Table 1.

[0519] Embodiment 66(a) of the present disclosure is directed to Embodiment 66 of Formula (IA) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0520] Embodiment 66(b) of the present disclosure is directed to Embodiment 66 of Formula (IB) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0521] Embodiment 66(c) of the present disclosure relates to Embodiment 66 of Formula (IC) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0522] Embodiment 66(d) of the present disclosure is directed to Embodiment 66 of Formula (ID) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0523] Embodiment 66(e) of the present disclosure relates to Embodiment 66 of Formula (IE) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0524] Embodiment 67 relates to a compound according to Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from Table 1.

[0525] Embodiment 67(a) of the present disclosure is directed to Embodiment 66 of Formula (IAA) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0526] Embodiment 67(b) of the present disclosure is directed to Embodiment 66 of Formula (IBB) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0527] Embodiment 67(c) of the present disclosure relates to Embodiment 66 of Formula (ICC) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0528] Embodiment 67(d) of the present disclosure is directed to Embodiment 66 of Formula (IDD) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0529] Embodiment 67(e) of the present disclosure relates to Embodiment 66 of Formula (IEE) or a pharmaceutically acceptable salt thereof selected from the compounds in Table 1.

[0530] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, such as 2 H. 3 H. 11 C. 13 C and / or 14C content. In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and or efficacy, thereby increasing the duration of action of the drug.

[0531] Unless otherwise specified, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of hydrogen by deuterium or tritium, or the enrichment of carbon by 13 C or 14 Compounds having the present structures except for substitution of the carbon atom at C are within the scope of this disclosure.

[0532] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Isotopic substitutions are contemplated by: 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. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0533] In certain embodiments, some or all of the compounds disclosed herein have 1 H atoms are 2H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and include, by way of non-limiting example only, the following synthetic methods.

[0534] Deuterium substituted compounds are synthesized using various methods, such as those described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development [in Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0535] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Company.

[0536] The compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0537] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficient acidity, sufficient basicity, or both functional groups can react with any of a variety of inorganic bases, and inorganic and organic acids to form salts. Alternatively, inherently charged compounds (such as those with quaternary nitrogen) can form salts with appropriate counterions, for example, halides such as bromide, chloride, or fluoride, particularly bromide.

[0538] The compounds described herein may exist in some cases as diastereomers, enantiomers or other stereoisomeric forms. The compounds presented herein include all diastereomers, enantiomers and epimeric forms and suitable mixtures thereof. The separation of stereoisomers can be carried out by chromatography or by forming diastereomers and separating by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated herein by reference for the present disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0539] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0540] In certain embodiments, the compound or the salt of the compound can be a prodrug, for example, wherein the hydroxyl in the parent compound exists as an ester or carbonate, or the carboxylic acid present in the parent compound exists as an ester. The term "prodrug" is intended to include compounds that are converted into medicaments of the present disclosure under physiological conditions. One method of preparing a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to display the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, such as a specific target cell in the host animal. For example, esters or carbonates (for example, esters of alcohol or carboxylic acids or esters of carbonates and phosphonic acids) are preferred prodrugs of the present disclosure.

[0541] Prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrug is metabolized in vivo to produce a compound as described herein. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0542] Prodrugs are often useful because, in some cases, they can be more easily administered than the parent drug. For example, they can be bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cell permeability of the compound relative to the parent drug. The solubility of the prodrug in a pharmaceutical composition can also be improved compared to the parent drug. Prodrugs can be designed as reversible drug derivatives, used as modifiers to enhance the transport of drugs to specific tissues or to increase the retention of drugs within cells.

[0543] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACSSymposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers. in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for the present disclosure). According to another embodiment, the present disclosure provides a method for producing the above-defined compounds. These compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0544] Synthetic chemistry 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 PGM Wuts, Protective Groups in Organic Synthesis, 2nd Edition (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0545] Therapeutic applications

[0546] The methods of administering a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE) or a pharmaceutically acceptable salt discussed herein can be used to treat cancer. In some embodiments, methods of treating solid tumors are disclosed herein. Examples of cancer include, but are not limited to, ovarian cancer, breast cancer, colon cancer, and brain cancer.

[0547] In some embodiments, disclosed herein are methods of treating cancer by administering a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE), or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein are methods of treating cancer comprising administering a pharmaceutical composition described herein to a subject in need thereof. 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 cancer. In some embodiments, the cancer is ovarian cancer or breast cancer.

[0548] In some embodiments, disclosed herein are methods of inhibiting cyclin-dependent kinases (CDKs) in cells by administering a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE), or (IEE). In some embodiments, disclosed herein are methods of inhibiting cyclin-dependent kinases (CDKs) in cells using a compound or pharmaceutically acceptable salt of any of the compounds described herein or a pharmaceutical composition described herein.

[0549] The CDK can be any suitable CDK known to those skilled in the art. In some embodiments, the CDK is selected from CDK 2, CDK 4, CD6, or any combination thereof. In some embodiments, the CDK is selected from CDK2, CDK4, CDK6, CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK 2 / 4 / 6. In some embodiments, the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK 2 / 4 / 6.

[0550] Other embodiments of therapeutic applications of the present disclosure include the following:

[0551] Embodiment 69 relates to a method of treating cancer, comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-67 or any sub-embodiments thereof, or a pharmaceutical composition according to Embodiment 68.

[0552] Embodiment 70 relates to the method according to embodiment 69, wherein the cancer is a solid tumor.

[0553] Embodiment 71 relates to the method according to embodiment 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer and brain cancer.

[0554] Embodiment 72 relates to the method according to embodiment 71, wherein the cancer is ovarian cancer or breast cancer.

[0555] Embodiment 73 relates to a method of inhibiting cyclin-dependent kinase (CDK) in a cell using a compound according to any one of Embodiments 1 to 67 or any sub-embodiments thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 68.

[0556] Embodiment 74 relates to the method according to embodiment 73, wherein the CDK is selected from CDK 2, CDK 4, CD6 or any combination thereof.

[0557] Embodiment 75 relates to the method according to embodiment 74, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6 and CDK 2 / 4 / 6.

[0558] Embodiment 76 relates to the method according to embodiment 75, wherein the CDK is CDK 2 / 4 / 6.

[0559] Pharmaceutical preparations

[0560] The compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to subjects in need thereof. The pharmaceutical composition may comprise at least a compound or a pharmaceutically acceptable salt of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) as described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents and / or thickening agents. In some embodiments, disclosed herein are pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt as described herein and a pharmaceutically acceptable excipient. In some embodiments, disclosed herein are pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt as described herein and a pharmaceutically acceptable excipient.

[0561] Pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) can be formulated using one or more physiologically acceptable carriers comprising excipients and adjuvants. Depending on the chosen route of administration, the formulation can be modified. Pharmaceutical compositions comprising the compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or embedding the conjugate. Pharmaceutical compositions can also include the compound, salt or conjugate in free base form or in pharmaceutically acceptable salt form.

[0562] Other embodiments of the pharmaceutical formulations disclosed herein include the following:

[0563] Embodiment 68 relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to any one of Embodiments 1 to 67 or any sub-embodiments thereof and a pharmaceutically acceptable excipient.

[0564] Methods for formulating a compound or pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) may include formulating any compound, salt or conjugate with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semisolid or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, solid compositions also contain non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, the compound, salt or conjugate may be lyophilized or in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0565] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredient may be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in a coarse emulsion.

[0566] The compositions and formulations may be sterile. Sterilization may be accomplished by filtration via sterile filtration.

[0567] Compositions comprising a compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) or a pharmaceutically acceptable salt thereof may be formulated for administration as an injection. Non-limiting examples of injection formulations may include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. The suspension may also contain a suitable stabilizer. The injection may be formulated as a bolus injection or a continuous infusion. Alternatively, the composition may be lyophilized or in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0568] For parenteral administration, the compound of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) or a pharmaceutically acceptable salt can be formulated in a unit dose injectable form (e.g., solution, suspension, emulsion) in combination with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic and non-therapeutic. The vehicle can be water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain small amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0569] 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 a subject through a mucosal layer in the oral cavity or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosal layer in the stomach and / or intestine.

[0570] In one embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in a modified release dosage form. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multi-particulate devices, and combinations thereof. The composition may also contain a non-release controlling excipient.

[0571] In another embodiment, the composition of formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in an enteric coated dosage form. These enteric coated dosage forms may also contain non-release controlling excipients. In one embodiment, the composition is in the form of enteric coated granules as a controlled release capsule for oral administration. The composition may also contain cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric coated pellets as a controlled release capsule for oral administration. The composition may also contain glyceryl monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc or triethyl citrate.

[0572] In another embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is an enteric coated controlled release tablet for oral administration. The composition may also include carnauba wax, cross-linked polyvinylpyrrolidone, diacetyl monoglyceride, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide or yellow iron oxide.

[0573] Sustained release formulations comprising a compound or a pharmaceutically acceptable salt of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) can also be prepared. Examples of sustained release formulations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of 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-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPO TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(–)-3-hydroxybutyric acid.

[0574] Pharmaceutical formulations 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 prepared for storage by mixing the compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient and / or stabilizer. The formulation may be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients and / or stabilizers may be non-toxic to the recipient at the dosages and concentrations used. Acceptable carriers, excipients and / or stabilizers may include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycols.

[0575] In another embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) may also include calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide and triethyl citrate.

[0576] In another embodiment, the composition of Formula (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) is provided in an effervescent dosage form. These effervescent dosage forms may also contain non-release controlling excipients.

[0577] 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 other embodiments, the dosage form can be capable of providing a discontinuous release compound in the form of at least two consecutive pulses, and the time interval between the consecutive pulses is 0.1 to 24 hours. The composition can contain one or more release-controlling and non-release-controlling excipients, such as those excipients suitable for rupturable semipermeable membranes and swellable materials.

[0578] 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, enclosed in an intermediate reaction layer, which comprises a gastro-resistant polymer layering material that is partially neutralized with a base and has cation exchange capacity and a gastro-resistant outer layer.

[0579] 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 form. As used herein, unit dosage form refers to physically discrete units suitable for administration to human or non-human animal subjects and individually packaged. Each unit dose can contain a predetermined amount of active ingredient, which is sufficient to produce the desired therapeutic effect in combination 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, unit dosage forms can be administered in parts or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, which can be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment, multiple dosage forms contain different pharmaceutically active agents.

[0580] In some embodiments, the composition of (I), (IA), (IAA), (IAAA), (IB), (IBB), (IC), (ICC), (ID), (IDD), (IE) or (IEE) can also be formulated as modified release dosage forms, including immediate release, delayed release, extended release, sustained release, sustained release, pulsed release, controlled release, extended release, accelerated release and fast release, targeted release, programmed release and gastric retention dosage forms. These dosage forms can be prepared according to known methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126, which are incorporated herein by reference in their entirety).

[0581] Combination therapy

[0582] Combination therapy is also contemplated herein, e.g., co-administering the disclosed compounds and additional active agents as part of a specific treatment regimen, with the intent to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action caused by the combination of therapeutic agents. The combined administration of these therapeutic agents is typically performed over a specified time period (typically hours, days, weeks, months, or years, depending on the selected combination). Combination therapy is intended to include administering multiple therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, as well as administering these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0583] Substantially simultaneous administration is achieved, for example, by administering to a subject a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or a single formulation (e.g., capsule) for each therapeutic agent in multiples. The sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0584] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that the components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially.

[0585] Additional embodiments

[0586] Embodiment 101. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

[0587]

[0588] in,

[0589] A is a ring selected from optionally substituted carbocycle, optionally substituted 4- to 6-membered heterocycle, and optionally substituted isoindoline;

[0590] Z 1 , Z 2 and Y 1 Each of which is independently selected from -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 -;

[0591] Each of a and b is independently selected from 1, 2, 3 and 4;

[0592] Each R 1 independently selected from halogen, -CN, -NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, and optionally substituted heterocycle;

[0593] m is selected from 0 to 5;

[0594] Each R 2 independently selected from hydrogen, halogen, -CN, -OH, -OC 1-4 alkyl, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring, or R 2 and R 3 The substituents are taken together to form an optionally substituted heterocyclic ring;

[0595] Each R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0596] R 4 is selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl;

[0597] R 5 , R 6 Each of which is independently selected from hydrogen, halogen, -CN, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl; and

[0598] R 7 is selected from hydrogen and optionally substituted C 1-4 Alkyl, and

[0599] Wherein if A is an optionally substituted phenyl, m is 1 to 5 and at least one R 1 is a heterocycloalkyl group,

[0600] Wherein if A is optionally substituted pyridine or optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen and -CN, and

[0601] Wherein if A is an optionally substituted piperidine sulfonamide, then (i) Y 1 Yes-C(R 2 ) 2 - and the two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen and -CN.

[0602] Embodiment 102. The compound according to Embodiment 101, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IA):

[0603]

[0604] in,

[0605] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0606] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl; and

[0607] n is selected from 0 to 9;

[0608] Where (i) Y 1 Yes-C(R 2 ) 2 - and the two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocyclic ring and optionally substituted carbocyclic ring, or (ii) R 4 is selected from hydrogen, halogen and -CN.

[0609] Embodiment 103. A compound or salt according to Embodiment 1 or 3, wherein Z 1 and Z 2 Independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0610] Embodiment 104. A compound or salt according to Embodiment 4, wherein Z 1 and Z 2 Independently -C(R 2 ) 2 -.

[0611] Embodiment 105. The compound or salt of Embodiment 9, wherein each of a and b is independently selected from 1 and 2.

[0612] Embodiment 106. A compound or salt according to any one of Embodiments 1-10, wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0613] Embodiment 107. The compound or salt according to Embodiment 11, wherein Y 1 Selected from -C(R 2 ) 2 -and-NR 3 .

[0614] Embodiment 108. A compound or salt according to any one of Embodiments 1-12, wherein each R 2 are independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0615] Embodiment 109. The compound or salt according to Embodiment 13, wherein each R 2 are independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0616] Embodiment 110. The compound according to Embodiment 14, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 are independently selected from hydrogen, -CN and cyclopropyl.

[0617] Embodiment 111. A compound or salt according to Embodiment 1-15, wherein each R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0618] Embodiment 112. The compound or salt according to Embodiment 17, wherein each R 3 Selected from cyclopropyl and cyclobutyl.

[0619] Embodiment 113. A compound or salt according to Embodiment 18, wherein R 3 It is cyclopropyl.

[0620] Embodiment 114. A compound according to Embodiment 1 or 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IAA):

[0621]

[0622] in,

[0623] R 8 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0624] R 9 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Carbocyclic and 3- to 6-membered heterocycloalkyl;

[0625] n is selected from 0 to 9;

[0626] 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(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0627] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0628] Embodiment 115. The compound or salt according to Embodiment 20, wherein 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0629] Embodiment 116. A compound or salt according to Embodiment 21, wherein 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0630] Embodiment 117. A compound or salt according to Embodiment

[0439] , wherein 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 -, where Z 5 Additionally selected from keys.

[0631] Embodiment 118. A compound or salt according to Embodiment 20-26, wherein each R 2 are independently selected from hydrogen, halogen, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0632] Embodiment 119. The compound or salt according to Embodiment 27, wherein each R 2 Selected from hydrogen, fluorine, or two R 2 The substituents are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0633] Embodiment 120. A compound or salt according to any one of Embodiments 20-28, wherein R 3 is selected from hydrogen, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0634] Embodiment 121. A compound or salt according to Embodiment 29, wherein R 3 Selected from hydrogen, -(CH 2 ) 2 OMe, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0635] Embodiment 122. The compound or salt according to Embodiment 30, wherein R 3 Selected from -(CH 2 ) 2 OMe and cyclopropyl.

[0636] Embodiment 123. A compound or salt according to any one of Embodiments 20-31, wherein each a, b, c and d is independently selected from 1 and 2.

[0637] Embodiment 124. The compound or salt according to any one of Embodiments 1-32, wherein the compound is selected from:

[0638]

[0639] Embodiment 125. The compound or salt of Embodiment

[0447] , wherein the compound is selected from:

[0640]

[0641] Embodiment 126. The compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IB):

[0642]

[0643] in,

[0644] R 10 is optionally substituted heterocycloalkyl;

[0645] R 11 is selected from halogen, -CN and optionally substituted C 1-4 Alkyl; and

[0646] p is selected from 0 to 4.

[0647] Embodiment 127. A compound or salt according to Embodiment

[0449] , wherein Z 1 and Z 2 are independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0648] Embodiment 128. A compound or salt according to Embodiment

[0450] , wherein Z 1 and Z 2 Independently -C(R 2 ) 2 -.

[0649] Embodiment 129. A compound or salt according to Embodiment

[0451] wherein each of a and b is independently selected from 1 and 2.

[0650] Embodiment 130. A compound or salt according to any one of Embodiments

[0449] -

[0452] , wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0651] Embodiment 131. A compound or salt according to Embodiment

[0453] , wherein Y 1 Yes-C(R 2 ) 2 -.

[0652] Embodiment 132. A compound or salt according to any one of Embodiments

[0449] -

[0454] , wherein each R 2 are independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0653] Embodiment 133. A compound or salt according to Embodiment

[0455] , wherein each R 2 are independently selected from hydrogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0654] Embodiment 134. A compound or salt according to Embodiment

[0456] , wherein each R 2 are independently selected from hydrogen, -CN and cyclopropyl.

[0655] Embodiment 135. A compound or salt according to any one of Embodiments

[0449] -

[0457] , wherein R 3 is selected from cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0656] Embodiment 136. A compound or salt according to Embodiment

[0458] , wherein R 3 Selected from cyclopropyl and cyclobutyl.

[0657] Embodiment 137. A compound or salt according to Embodiment

[0459] , wherein R 3 It is cyclopropyl.

[0658] Embodiment 138. A compound according to Embodiment 1 or

[0449] , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IBB):

[0659]

[0660] in,

[0661] R 10is optionally substituted heterocycloalkyl;

[0662] R 11 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0663] p is selected from 0 to 4;

[0664] 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(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0665] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0666] Embodiment 139. A compound or salt according to Embodiment

[0461] , wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0667] Embodiment 140. A compound or salt according to Embodiment

[0462] , wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0668] Embodiment 141. A compound or salt according to any one of Embodiments

[0461] -

[0463] , wherein each R 2 are independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0669] Embodiment 142. A compound or salt according to Embodiment

[0464] , wherein each R 2 are independently selected from hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted oxetane, and optionally substituted azetidine.

[0670] Embodiment 143. A compound or salt according to Embodiment

[0465] , wherein each R 2 are independently selected from hydrogen, fluoro, -CN and cyclopropyl.

[0671] Embodiment 144. A compound or salt according to any one of Embodiments

[0461] -

[0466] , wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

[0672] Embodiment 145. A compound or salt according to Embodiment

[0467] , wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl and propyl.

[0673] Embodiment 146. The compound according to embodiment

[0468] , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It's methyl.

[0674] Embodiment 147. A compound or salt according to any one of Embodiments

[0461] -

[0469] , wherein each a, b, c and d is independently selected from 1 and 2.

[0675] Embodiment 148. A compound or salt according to any one of Embodiments

[0449] -

[0470] , wherein the compound is selected from:

[0676]

[0677] Embodiment 149. The compound according to Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IC):

[0678]

[0679] in,

[0680] R 12is selected from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl; or R 12 and R 13 taken together to form an optionally substituted heterocyclic ring;

[0681] R 13 is selected from halogen, -CN and optionally substituted C 1-4 Alkyl; and

[0682] q is selected from 0 to 2.

[0683] Embodiment 150. A compound or salt according to Embodiment

[0472] , wherein Z 1 and Z 2 Independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0684] Embodiment 151. A compound or salt according to Embodiment

[0473] , wherein Z 1 and Z 2 Independently -C(R 2 ) 2 -.

[0685] Embodiment 152. A compound or salt according to Embodiment

[0474] , wherein each of a and b is independently selected from 1 and 2.

[0686] Embodiment 153. A compound or salt according to any one of Embodiments

[0472] -

[0475] , wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -、-NS(O 2 )R 2 , -O-, and -S-.

[0687] Embodiment 154. A compound or salt according to Embodiment

[0476] , wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 and -NS(O 2 )R 2 .

[0688] Embodiment 155. A compound or salt according to any one of Embodiments

[0472] -

[0477] , wherein each R 2 are independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0689] Embodiment 156. A compound or salt according to Embodiment

[0478] , wherein each R 2 is selected from the group consisting of hydrogen, fluorine, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0690] Embodiment 157. A compound or salt according to Embodiment

[0479] , wherein each R 2 is selected from hydrogen, fluorine, -CN and cyclopropyl.

[0691] Embodiment 158. A compound or salt according to any one of Embodiments

[0472] -

[0480] , wherein R 3 is selected from optionally substituted alkyl.

[0692] Embodiment 159. A compound or salt according to Embodiment

[0481] , wherein R 3 It's methyl.

[0693] Embodiment 160. A pharmaceutically acceptable salt or solvate thereof having the structure of formula (ICC):

[0694]

[0695] in,

[0696] R 12 is optionally substituted heterocycloalkyl; or R 12 and R 13 taken together to form an optionally substituted heterocyclic ring;

[0697] R 13 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0698] q is selected from 0 to 2; and

[0699] 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(O 2 )R 2 , -O-, -S-, -S(O)- and -S(O) 2 -, where Z 5 additionally selected from bonds; and

[0700] Each of a, b, c and d is independently selected from 1, 2, 3 and 4.

[0701] Embodiment 161. A compound or salt according to Embodiment

[0483] , wherein 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(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0702] Embodiment 162. A compound or salt according to Embodiment

[0484] , wherein 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(O 2 )R 3 , where Z 5 Additionally selected from keys.

[0703] Embodiment 163. A compound or salt according to any one of Embodiments

[0483] -

[0485] , wherein each R 2 are independently selected from hydrogen, halogen, -CN, -OH, and optionally substituted alkyl.

[0704] Embodiment 164. The compound according to embodiment

[0486] , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 are independently selected from hydrogen, fluorine and -OH.

[0705] Embodiment 165. A compound or salt according to any one of Embodiments

[0483] -

[0487] , wherein R 3 are independently selected from hydrogen and optionally substituted alkyl.

[0706] Embodiment 166. A compound or salt according to Embodiment

[0488] , wherein R 3 independently selected from hydrogen, methyl, ethyl and propyl

[0707] Embodiment 167. A compound or salt according to Embodiment

[0489] , wherein R 3 It's methyl.

[0708] Embodiment 168. A compound or salt according to any one of Embodiments

[0472] -

[0490] , wherein R 12 is an optionally substituted 5- to 6-membered heterocyclic ring, or R 12 and R 13 are taken together to form an optionally substituted heterocyclic ring or an optionally substituted carbocyclic ring.

[0709] Embodiment 169. A compound or salt according to Embodiment

[0491] , wherein R 12 is optionally substituted piperidine, optionally substituted azaspiro[3.3]heptane, or R 12 and R 13 are taken together to form an optionally substituted heterocyclic ring.

[0710] Embodiment 170. A compound or salt according to any one of Embodiments

[0472] -

[0492] , wherein R 13 and R 12 are taken together to form an optionally substituted heterocyclic ring.

[0711] Embodiment 171. A compound or salt according to any one of Embodiments

[0472] -

[0493] , wherein the compound is selected from:

[0712]

[0713] Embodiment 172. A compound or salt according to Embodiment 1, which has the structure of Formula (ID):

[0714]

[0715] in,

[0716] R 14 Selected from -SOR 16 - and optionally substituted heterocycloalkyl;

[0717] R 15 is selected from hydrogen, halogen, -CN and optionally substituted C 1-4 Alkyl; and

[0718] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0719] Embodiment 173. A compound according to Embodiment 1 or

[0495] , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IDD):

[0720]

[0721] in,

[0722] R 16 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0723] Embodiment 174. A pharmaceutically acceptable salt or solvate thereof having the structure of Formula (IE):

[0724]

[0725] in,

[0726] R 17 Selected from -SOR 19 -, optionally substituted alkyl, optionally substituted carbocycle and optionally substituted heterocycloalkyl;

[0727] R 18 is selected from halogen, -CN and optionally substituted C 1-4 alkyl;

[0728] R 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl; and

[0729] r is selected from 0 to 5.

[0730] Embodiment 175. A compound or salt according to Embodiment

[0497] , wherein Z 1 and Z 2 are independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0731] Embodiment 176. A compound or salt according to Embodiment

[0498] , wherein Z 1 and Z 2 Independently -C(R 2 ) 2 -.

[0732] Embodiment 177. A compound or salt according to Embodiment

[0499] , wherein each of a and b is independently selected from 1 and 2.

[0733] Embodiment 178. A compound or salt according to any one of Embodiments

[0497] -

[0500] , wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -、-NS(O 2 )R 2 , -O- and -S(O) 2 -.

[0734] Embodiment 179. A compound or salt according to any one of Embodiments

[0497] -

[0501] , wherein each R 2 are independently selected from hydrogen, halogen, -CN, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

[0735] Embodiment 180. A compound or salt according to any one of Embodiments

[0497] -

[0502] , R 3 is selected from optionally substituted alkyl.

[0736] Embodiment 181. A compound or salt according to any one of embodiments

[0497] -

[0503] , wherein r is 0.

[0737] Embodiment 182. A compound or salt according to any one of Embodiments

[0497] -

[0504] , wherein R 17 Selected from -SOR 19 -, optionally substituted alkyl, and optionally substituted 3- to 5-membered heterocycloalkyl.

[0738] Embodiment 183. A compound or salt according to Embodiment

[0505] , wherein R 17 Selected from -SOR 19 -, methyl and optionally substituted 4-membered heterocycloalkyl.

[0739] Embodiment 184. A compound according to Embodiment

[0497] , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IEE):

[0740]

[0741] in,

[0742] R 19 Selected from optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 carbocyclic and optionally substituted 3- to 6-membered heterocycloalkyl.

[0743] Embodiment 185. A compound or salt according to Embodiment

[0507] , wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-NS(O 2 )R 3 , -O- and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0744] Embodiment 186. A compound or salt according to Embodiment

[0508] , wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of which is independently selected from -C(R 2 ) 2 -、-NR 3 -、-NS(O 2 )R 3 and -S(O) 2 -, where Z 5 Additionally selected from keys.

[0745] Embodiment 187. A compound or salt according to any one of Embodiments

[0507] -

[0509] , wherein each R 2 are independently selected from hydrogen, halogen, -CN, -OH and optionally substituted alkyl.

[0746] Embodiment 188. A compound or salt according to Embodiment

[0510] , wherein each R 2 are independently selected from hydrogen and fluorine.

[0747] Embodiment 189. A compound or salt according to any one of Embodiments

[0507] -

[0511] , wherein R 3 is an optionally substituted alkyl group.

[0748] Embodiment 190. A compound or salt according to Embodiment

[0512] , wherein R 3 It is methyl, ethyl or propyl.

[0749] Embodiment 191. A compound or salt according to Embodiment

[0513] , wherein R 3 It's methyl.

[0750] Embodiment 192. A compound or salt according to any one of Embodiments

[0507] -

[0504] , wherein R 19 is an optionally substituted alkyl group.

[0751] Embodiment 193. A compound or salt according to Embodiment

[0515] , wherein R 19 It's methyl.

[0752] Embodiment 194. A compound or salt according to any one of Embodiments

[0497] -

[0516] , wherein the compound is selected from:

[0753]

[0754] Embodiment 195. The compound or salt of Embodiment 1, wherein A is selected from optionally substituted pyridine, optionally substituted azabicyclo[3.1.0]hexane, optionally substituted azetidine, and optionally substituted tetrahydroisoquinoline.

[0755] Embodiment 196. A compound or salt according to Embodiment 33, wherein A is -SO 2 Me replaced.

[0756] Embodiment 197. The compound or salt of Embodiment 33 or 35, wherein m is selected from 0 to 1.

[0757] Embodiment 198. A compound or salt according to any one of Embodiments 33-36, wherein each R 1 are independently selected from optionally substituted alkyl, optionally substituted carbocycle, and optionally substituted heterocycle.

[0758] Embodiment 199. The compound or salt according to Embodiment 37, wherein each R 1 are independently selected from optionally substituted alkyl and optionally substituted heterocycle.

[0759] Embodiment 200. A compound or salt according to Embodiment 37, wherein each R 1 independently selected from methyl, ethyl and optionally substituted diazaspiro[3.3]heptane.

[0760] Embodiment 201. A compound or salt according to any one of Embodiments 1-19,

[0449] -

[0460] ,

[0472] -

[0482] ,

[0495] ,

[0497] -

[0506] and 33-38, wherein Z 1 and Z 2 Independently selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0761] Embodiment 202. A compound or salt according to Embodiment 40, wherein Z 1 and Z 2 Independently -C(R 2 ) 2 -.

[0762] Embodiment 203. A compound or salt according to Embodiment 40 or 41, wherein each of a and b is independently selected from 1 and 2.

[0763] Embodiment 204. A compound or salt according to any one of Embodiments 1-19,

[0449] -

[0460] ,

[0472] -

[0482] ,

[0495] ,

[0497] -

[0506] and 33-42, wherein Y 1 Selected from -C(R 2 ) 2 -、-NR 3 -, -O-, and -S-.

[0764] Embodiment 205. A compound or salt according to Embodiment 43, wherein Y 1 Selected from -C(R 2 ) 2 -and-NR 3 -.

[0765] Embodiment 206. A compound or salt according to Embodiment 44, wherein Y 1 Yes-C(R 2 ) 2 - and two R 2 The substituents are taken together to form a ring selected from optionally substituted heterocycle and optionally substituted carbocycle.

[0766] Embodiment 207. A compound or salt according to Embodiment 45, wherein Y 1 Yes-C(R 2 ) 2 - and two R 2 The substituents are taken together to form a ring selected from an optionally substituted heterocycle.

[0767] Embodiment 208. A compound or salt according to any one of Embodiments 1-19,

[0449] -

[0460] ,

[0472] -

[0482] ,

[0495] ,

[0497] -

[0506] and 33-43, wherein the compound or salt is depicted as in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocycle 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 indoline.

[0768] Embodiment 209. The compound or salt according to Embodiment 47, wherein the compound or salt is depicted as in Formula (I), (IB), (IC), (ID) and (IE) The N-containing heterocyclic ring is selected from

[0769] Embodiment 210. The compound or salt according to any one of Embodiments 33-39, wherein the compound is selected from:

[0770]

[0771] Embodiment 211. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] or 33-109, wherein R 4 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0772] Embodiment 212. A compound or salt according to Embodiment 49, wherein R 4 is selected from hydrogen and optionally substituted C 1 alkyl.

[0773] Embodiment 213. A compound or salt according to Embodiment 50, wherein R 4 Selected from hydrogen, methyl and -CHF 2 .

[0774] Embodiment 214. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] or 33-48, wherein R 4 is selected from hydrogen, halogen and -CN.

[0775] Embodiment 215. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] or 33-48, wherein R 4 Selected from hydrogen.

[0776] Embodiment 216. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] or 33-48, wherein R 4 It is not optionally substituted phenyl.

[0777] Embodiment 217. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] or 33-48, wherein R 4 It is not an optionally substituted alkyl group.

[0778] Embodiment 218. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] , 33-39 or 49- to 117, wherein R 5 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0779] Embodiment 219. A compound or salt according to Embodiment 56, wherein R 5 is selected from hydrogen, halogen and optionally substituted C 1-2 alkyl.

[0780] Embodiment 220. A compound or salt according to Embodiment 57, wherein R 5 Selected from hydrogen and fluorine.

[0781] Embodiment 221. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] , 33-39 or 49-58, wherein R 6 is selected from hydrogen, halogen, optionally substituted C 1-2 Alkyl, optionally substituted C 3-4 Carbocyclic and optionally substituted 3- to 4-membered heterocycloalkyl.

[0782] Embodiment 222. A compound or salt according to Embodiment 59, wherein R 6 is selected from hydrogen, halogen and optionally substituted C 1-2 alkyl.

[0783] Embodiment 223. A compound or salt according to Embodiment 60, wherein R 6 It's hydrogen.

[0784] Embodiment 224. A compound or salt according to any one of Embodiments 1-32,

[0449] -

[0470] ,

[0472] -

[0493] ,

[0495] -

[0516] , 33-39 or 49-61, wherein R 7 It's hydrogen.

[0785] Embodiment 225. A pharmaceutical composition comprising a compound or salt according to any one of Embodiments 1 to 62 and a pharmaceutically acceptable excipient.

[0786] Embodiment 226. A method of treating cancer, comprising administering the pharmaceutical composition according to Embodiment 68 to a subject in need thereof.

[0787] Embodiment 227. A method according to Embodiment 69, wherein the cancer is a solid tumor.

[0788] Embodiment 228. The method of Embodiment 69 or 70, wherein the cancer is selected from ovarian cancer, breast cancer, colon cancer, and brain cancer.

[0789] Embodiment 229. The method of Embodiment 71, wherein the cancer is ovarian cancer or breast cancer.

[0790] Embodiment 230. A method of inhibiting cyclin-dependent kinases (CDKs) in a cell using a compound or salt according to any one of Embodiments 1 to 62 or a pharmaceutical composition according to Embodiment 68.

[0791] Embodiment 231. A method according to Embodiment 73, wherein the CDK is selected from CDK 2, CDK 4, CD6 or any combination thereof.

[0792] Embodiment 232. A method according to Embodiment 74, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6 and CDK 2 / 4 / 6.

[0793] Embodiment 233. A method according to Embodiment 75, wherein the CDK is CDK 2 / 4 / 6.

[0794] Example

[0795] Having now generally described the invention, it will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0796] The following synthetic schemes are provided for illustrative purposes, not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art may be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that by using appropriate starting materials and modifying the synthetic routes as needed, those skilled in the art will be able to prepare in a manner similar to that described below. In general, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art, or prepared as described herein.

[0797] General Synthesis Scheme 1-3

[0798] Solution 1

[0799]

[0800] Solution 2

[0801]

[0802] Solution 3

[0803]

[0804] Intermediates

[0805] Intermediate 1: 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine

[0806]

[0807] Step 1: Methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate

[0808]

[0809] To a stirred mixture of methyl 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylate (7.8 g, 29.64 mmol) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.45 g, 44.46 mmol) in tetrahydrofuran (60 mL) under nitrogen atmosphere was added sodium carbonate (4.71 g, 44.46 mmol) and Pd(dppf)Cl in water (20 mL). 2To the 4-thiazolyl-2-yl)-4-nitro-2-yl-2-nitro-4-ol (1.08g, 1.48mmol). The resulting mixture was heated to 65 ° C and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (200mL) and extracted with ethyl acetate (3x200mL). The combined organic layer was washed with brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide a crude product. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 85:15) to provide (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylic acid methyl ester (5.30g, 70.3% yield).

[0810] LCMS (ESI) m / z = 255 [M + H] + .

[0811] Step 2: (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide

[0812]

[0813] To a stirred mixture of (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylic acid methyl ester (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 provide the crude title product (4.2 g). The crude product was used directly in the next step without further purification.

[0814] LCMS (ESI) m / z = 240 [M+H] + .

[0815] Step 3: 2-(Methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

[0816]

[0817] 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 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to provide a crude product. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide a 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] + .

[0818] Step 4: 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine

[0819]

[0820] A mixture of 2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one (4.2g, 21.73mmol) in phosphorus oxychloride (150mL) 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 adding saturated aqueous sodium bicarbonate (500mL) and extracted with ethyl acetate (3x500mL). The combined organic layer was washed with brine (1000mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide a crude product. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2:1) to provide 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (3.70g, 92.4% yield).

[0821] LCMS (ESI) m / z = 212 [M+H] + .

[0822] Intermediate 2: 6-Methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

[0823] Reaction scheme

[0824]

[0825] Detailed procedures

[0826] Step 1: 5-Bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide

[0827]

[0828] Oxalyl chloride (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. One drop of DMF was added and the resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in DCM (800 mL) and aniline (11.96 g, 128.5 mmol) and Et 3 To the bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26g crude product) of 5- is added 4-bromo-2-(methylthio)-N (17.06g, 168.6mmol). The resulting mixture was stirred at room temperature for 24h. The reaction was quenched by adding aqueous HCl (0.5N, 500mL) and extracted with DCM (2x500mL). The combined organic layer was washed with water (2x500mL) and brine (500mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a crude product 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26g crude product). The crude product was used in the next step as it is.

[0829] LCMS(ESI-MS)m / z=324.0,326.0[M+H] + .

[0830] Step 2: 6-Methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

[0831]

[0832] To a solution of 5-bromo-2-(methylthio)-N-phenylpyrimidine-4-carboxamide (26 g, 80.2 mmol) in ACN (270 mL) was added pentane-2,4-dione (16.06 g, 160.4 mmol), CuI (1.53 g, 8.02 mmol) and Cs 2 CO 3 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 evaporated. The residue was then added saturated aqueous NaOH (about 500 mL) at 0 ° C and then saturated aqueous NaHCO 3The product of 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one (5.8 g, 35% yield in 3 steps) was purified by flash column chromatography using 20% ​​to 80% ethyl acetate in petroleum ether and then 0% to 10% MeOH in DCM.

[0833] 1 H NMR (400 MHz, DMSO-d 6 )δ11.9(s,1H),9.07(s,1H),6.31(s,1H),2.58(s,3H),2.22(s,3H).

[0834] LCMS (ESI-MS) m / z = 208.0 [M+H] + .

[0835] Intermediate 3: 8-Chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine thio)pyrido[3,4-d]pyrimidine

[0836]

[0837] 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) was added POCl 3 The product was concentrated to 80 ° C for 2 h. The mixture was stirred at 80 ° C for 2 h. The resulting mixture was concentrated under reduced pressure, quenched with water (200 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (0-20%) to provide 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.01 g, 46.4% yield).

[0838] 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(s,1H),7.79(d,J=0.6Hz,1H),2.66(s,3H),2.60(s,3H).

[0839] LCMS (ESI-MS) m / z = 226.0 [M+H] + .

[0840] 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

[0841]

[0842] 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 h. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL). The resulting mixture was extracted with dichloromethane (3x200 mL). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA in PE, 0% to 100%) to afford 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, 30.4% yield).

[0843] 1 H NMR (400 MHz, DMSO-d 6 )δ9.99(s,1H),8.09-8.06(m,1H),3.54(s,3H),2.81-2.66(m,3H).

[0844] LCMS (ESI-MS) m / z = 257.9 [M+H] + .

[0845] Intermediate 5: 8-Bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0846] Reaction scheme

[0847]

[0848] Detailed procedures

[0849] Step 1: 8-Bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine

[0850]

[0851] POBr3 (50mL, 174.4mmol) was added to 6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine-8(7H)-one (5g, 24.12mmol) in MeCN (50mL). The mixture was stirred at 70°C for 3h and concentrated under reduced pressure. The residue was quenched with aqueous sodium bicarbonate at 0°C and extracted with EA (3x200mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-20%) to provide 8-bromo-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine (2.2g, 33.8% yield).

[0852] LCMS(ESI-MS)m / z=270.0,272.0[M+H] + .

[0853] Step 2: 8-Bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

[0854]

[0855] 3-Chloroperoxybenzoic acid (2.81 g, 16.28 mmol) was added to 8-bromo-6-methyl-2-(methylsulfanyl)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 minutes, then warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL). The resulting mixture was extracted with DCM (3x200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA in PE, 0% to 100%) to provide crude 8-bromo-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1.3 g, 52.8% yield).

[0856] LCMS(ESI-MS)m / z=302.0,304.0[M+H] + .

[0857] Step 3: 8-Bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0858]

[0859] 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) were added 1-(methylsulfonyl)piperidin-4-amine (0.77 g, 4.30 mmol), K 2 CO 3 The product was added into 4-nitro-2-nitropropene (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 (3x50 mL). The combined organic layer was washed with brine (2x40 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 provide 8-bromo-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidine-2-amine (206.1 mg, 10.8% yield).

[0860] 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(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).

[0861] LCMS(ESI-MS)m / z=400.0,402.0[M+H] + .

[0862] Intermediate 6: 8-Chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine

[0863]

[0864] 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 washed with CH 2 Cl 2 (3x100 mL) extraction. The combined organic layers were washed with anhydrous Na 2 SO 4The product was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 1:1) to provide 8-chloro-6-methyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (505.8 mg, 33.3% yield).

[0865] LCMS (ESI-MS) m / z = 356.0 [M+H] + .

[0866] Intermediate 7: 8-Chloro-6-cyclopropyl-2-methylsulfonylpyrido[3,4-d]pyrimidine

[0867] Step 1: 5-Bromo-2-(methylsulfanyl)-N-phenylpyrimidine-4-carboxamide

[0868]

[0869] A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (15.0g, 60.222mmol) in anhydrous dichloromethane (225.0ml) was cooled to 0 ° C. Oxalyl chloride (6.624ml, 78.288mmol) and a 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 (225.0ml) and cooled to 0 ° C. Aniline (9.329ml, 102.377mmol) and triethylamine (18.467ml, 132.488mmol) were slowly added and the reaction mixture was stirred at room temperature for additional 18 hours. The reaction mixture was quenched with 0.5MHCl aqueous solution and each layer was separated. The aqueous layer was extracted with dichloromethane (3x200ml) and the combined organic layer was purified by anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure.The crude material was purified by automated flash column chromatography on silica gel (from hexanes to hexanes / EtOAc 4:1) to afford the title compound (17.34 g, 89% yield).

[0870] 1 H NMR (300 MHz, chloroform-d) δ9.63 (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).

[0871] Step 2: 6-Cyclopropyl-2-(methylsulfanyl)-7H,8H-pyrido[3,4-d]pyrimidin-8-one

[0872]

[0873] 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 hours. 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 hours. The reaction mixture was concentrated under reduced pressure to remove acetonitrile, and the mixture containing acetic acid was diluted with water (100 ml) and extracted with dichloromethane (3 x 100 ml). The combined organic layers were purified by anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure.The crude material was purified by automated flash column chromatography on silica gel (from hexanes / EtOAc 3:2 to EtOAc) to afford the title compound (4.76 g, 66% yield).

[0874] 1 H NMR (300 MHz, DMSO-d 6 )δ12.01(bs,1H),9.06(s,1H),6.21(s,1H),2.58(s,3H),1.88(tt,J=8.3,5.1Hz,1H),1.04–0.92(m,2H),0.89–0.77(m,2H).

[0875] UPLC(ESI)[M+H] + =233.90.

[0876] Step 3: 8-Chloro-6-cyclopropyl-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine

[0877]

[0878] 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 treated with NaHCO 3The saturated aqueous solution was quenched. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure.The crude material was purified by automated flash column chromatography on silica gel (from hexanes to hexanes / EtOAc 7:3) to afford the title compound (4.58 g, 89% yield).

[0879] 1 H NMR (300 MHz, DMSO-d 6 )δ9.48(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=7.2,5.1,2.9Hz,2H).

[0880] UPLC(ESI)[M+H] + =251.85.

[0881] Step 4: 8-Chloro-6-cyclopropyl-2-methylsulfonylpyrido[3,4-d]pyrimidine

[0882]

[0883] 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 3-chloroperbenzoic acid (8.569 g, 49.656 mmol) portionwise and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was stirred by slowly adding 10% Na 2 S 2 O 3 The aqueous solution (50 ml) was quenched and extracted with dichloromethane (3 x 70 ml). The combined organic layers were washed with NaHCO 3 The mixture was washed with saturated aqueous solution and then with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure.The crude material was purified by automated flash column chromatography on silica gel (from hexanes / EtOAc 4:1 to hexanes / EtOAc 2:3) to afford the title compound (2.54 g, 89% yield).

[0884] 1 H NMR (300 MHz, DMSO-d 6 )δ9.94(s,1H),8.12(s,1H),3.52(s,3H),2.42(dq,J=8.4,4.7,4.1Hz,1H),1.17(dt,J=7.9,3.0Hz,2H),1.09–1.02(m,2H).

[0885] UPLC(ESI)[M+H] + =283.80.

[0886] Intermediate 8: 8-Chloro-6-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidine-2-yl amine

[0887]

[0888] 1-(Methylsulfonyl)piperidin-4-amine (69.1 mg, 388 μmol), cesium fluoride (161 mg, 1.06 mmol) and N-ethyl-N-isopropylpropane-2-amine (137 mg, 184 μL, 1.06 mmol) were loaded into 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). The reaction vial was capped and stirred at 30 ° C for 72 hours. Afterwards, the crude mixture was diluted with water (50.0 mL) and extracted with dichloromethane (3x20.0 mL). The combined organic fractions were washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. The crude material was purified by flash chromatography on silica gel (heptane / EtOAc 1 :1) to afford the title compound (62.0 mg, 46% yield).

[0889] LCMS(ESI)[M+H] + =382.10

[0890] Intermediate 9: 8-Chloro-6-(difluoromethyl)-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine

[0891] Reaction scheme

[0892]

[0893] Detailed procedures

[0894] Step 1: Methyl 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylate

[0895]

[0896] 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 hours. Then, the reaction mixture was poured into ice water and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with NaHCO 3 The mixture was washed with saturated aqueous solution and then with anhydrous MgSO 4Dry, filter and concentrate under reduced pressure to afford the title compound (15.02 g, 95% yield). The crude material was used directly in the next step without further purification.

[0897] 1 H NMR (300 MHz, chloroform-d) δ8.73 (s, 1H), 4.02 (s, 3H), 2.59 (s, 3H). UPLC (ESI) [M+H] + = 262.70 and 264.65 (Br isotope pattern).

[0898] Step 2: Methyl 5-(3-methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxylate

[0899]

[0900] 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 min. Next, 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylic acid methyl ester (5.0 g, 19.003 mmol) and 3-methoxyprop-1-yne (4.814 ml, 57.01 mmol) were slowly added and the reaction mixture was stirred overnight at 40 ° C. The reaction mixture was cooled to room temperature, filtered through a celite pad 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 hexanes to hexanes / EtOAc 7:3) to provide the title compound (2.47 g, 52% yield).

[0901] 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).

[0902] UPLC(ESI)[M+H] + =252.80.

[0903] Step 3: 5-(3-methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxamide

[0904]

[0905] A solution of methyl 5-(3-methoxyprop-1-yn-1-yl)-2-(methylsulfanyl)pyrimidine-4-carboxylate (2.47 g, 9.79 mmol) in aqueous ammonia (7.0 N solution in methanol, 34.965 ml, 244.758 mmol) was stirred at 40° C. for 2 hours. The mixture was concentrated under reduced pressure to afford the crude title compound (2.28 g, 98% yield). The crude product was used in the next step without further purification.

[0906] 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).

[0907] UPLC(ESI)[M+H] + =237.85.

[0908] Step 4: 6-(Methoxymethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one

[0909]

[0910] 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 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel (from hexane / EtOAc 7:3 to hexane / EtOAc 3:7) to provide the title compound (0.685 g, 43% yield).

[0911] 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).

[0912] Step 5: 6-(Hydroxymethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one

[0913]

[0914] 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. Boron tribromide (1.0 M solution in dichloromethane, 32.247 ml, 32.247 mmol) was then added dropwise via an addition funnel and the reaction mixture was stirred at the same temperature for 20 minutes. Next, the reaction mixture was warmed to -20 °C and stirred for an additional 2 hours and 30 minutes. The reaction mixture was heated to -20 °C and stirred for an additional 2 hours and 30 minutes. The reaction mixture was heated to -20 °C and then NaHCO 3 The mixture was quenched with saturated aqueous solution (until gas evolution ceased). The mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with anhydrous MgSO 4 Dried, filtered, concentrated under reduced pressure and purified by flash column chromatography on silica gel (from hexanes / EtOAc 7:3 to hexanes / EtOAc 1:9) to provide the title compound (0.787 g, 59% yield).

[0915] 1 H NMR (300 MHz, DMSO-d 6 )δ9.19(s,1H),6.74(d,J=1.2Hz,1H),5.74(t,J=6.0Hz,1H),4.30(dd,J=6.0,1.2Hz,2H),2.61(s,3H).

[0916] Step 6: 2-(Methylsulfanyl)-8-oxo-8H-pyrano[3,4-d]pyrimidine-6-carbaldehyde

[0917]

[0918] 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 in portions. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The solid was filtered off and the filtrate was washed with 0.5 M NaOH aqueous solution and washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure.The crude material was purified by flash column chromatography on silica gel (from hexanes / EtOAc 8:2 to hexanes / EtOAc 4:6) to afford the title compound (0.738 g, 100% yield).

[0919] 1 H NMR (300 MHz, DMSO-d6 )δ9.58(s,1H),9.35(s,1H),7.78(s,1H),2.65(s,3H).

[0920] Step 7: 6-(Difluoromethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one

[0921]

[0922] 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 allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was stirred by adding 10% Na 2 S 2 O 3 The aqueous solution was quenched with 10 mL. The layers were separated and the aqueous layer was extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure to afford the title compound (0.784 g, 92% yield).The crude material was used in the next step without further purification.

[0923] 1 H NMR (300 MHz, DMSO-d 6 )δ9.24(s,1H),7.25(d,J=1.6Hz,1H),6.94(t,J=52.7Hz,1H),2.63(s,3H).

[0924] UPLC(ESI)[M+H] + =244.85.

[0925] Step 8: 6-(Difluoromethyl)-2-(methylsulfanyl)-7H,8H-pyrido[3,4-d]pyrimidin-8-one

[0926]

[0927] A solution of 6-(difluoromethyl)-2-(methylsulfanyl)-8H-pyrano[3,4-d]pyrimidin-8-one (0.734 g, 2.703 mmol) in aqueous ammonia (7.0 N solution in methanol, 21.242 ml, 148.691 mmol) was stirred at 80 ° C for 16 hours. The volatile components were removed under reduced pressure to provide a crude title compound (0.704 g, 96% yield) as a dark solid. The crude product was used in the next step without further purification.

[0928] 1 H NMR (300 MHz, DMSO-d 6 )δ9.28(s,1H),6.95(d,J=1.6Hz,1H),6.88(t,J=53.8Hz,1H),2.62(s,3H).

[0929] UPLC(ESI)[M+H] + =243.75.

[0930] Step 9: 8-Chloro-6-(difluoromethyl)-2-(methylsulfanyl)pyrido[3,4-d]pyrimidine

[0931]

[0932] 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 NaHCO 3 The aqueous layer was extracted with ethyl acetate (15 mL x 3) and the combined organic layers were washed with anhydrous MgSO 4 Dry, filter and concentrate under reduced pressure.The crude material was purified by flash column chromatography on silica gel (from hexanes to hexanes / EtOAc 7:3) to afford the title compound (0.277 g, 41% yield).

[0933] 1 H NMR (300 MHz, DMSO-d 6 )δ9.69(s,1H),8.37(s,1H),7.17(t,J=54.5Hz,1H),2.71(s,3H).

[0934] UPLC(ESI)[M+H] + =261.80.

[0935] Intermediate 10: N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-2-yl)carboxamide

[0936] Reaction scheme

[0937]

[0938] Detailed procedures

[0939] Step 1: tert-Butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0940]

[0941] To 2,6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (5g, 25.21mmol) and 5-fluoro-2-nitropyridine (5.37g, 37.82mmol) in a stirred mixture of dimethyl sulfoxide (30mL) N, N-diisopropylethylamine (9.78g, 75.65mmol). The resulting mixture was heated to 80 ° C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (500mL) and extracted with ethyl acetate (3x500mL). The combined organic layer was washed with brine (500mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to provide a crude product. The residue was purified by trituration with petroleum ether / ethyl acetate (5:1, 100 mL) to afford tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (6.78 g, 83.7% yield).

[0942] LCMS (ESI) m / z = 321 [M+H] + .

[0943] Step 2: 2-(6-Nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0944]

[0945] Trifluoroacetic acid (16 mL) was added to a stirred mixture of 6-(6-nitropyridine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6.78 g, 21.16 mmol) in dichloromethane (80 mL). The resulting mixture was stirred for 1 hour at room temperature and concentrated under vacuum. The residue was diluted with dichloromethane (100 mL) and concentrated under vacuum again to provide a crude product 2-(6-nitropyridine-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g). The crude product was used directly in the next step without further purification.

[0946] LCMS (ESI) m / z = 221 [M+H] + .

[0947] Step 3: 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0948]

[0949] A solution of 2-(6-nitropyridine-3-yl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (6 g, 18.9 mmol) in methanol (100 mL) was treated with triethylamine (5.73 g, 56.7 mmol) for 10 minutes, followed by the addition of acetaldehyde (4.16 g, 94.5 mmol), acetic acid (0.23 mL, 4.08 mmol) and sodium cyanoborohydride (2.51 g, 39.8 mmol). The resulting mixture was stirred at room temperature for 3 hours and concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layer was washed with brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide a crude product. The residue was purified by trituration with dichloromethane (100 mL) to afford 2-ethyl-6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 58.9% yield) as an orange solid. LCMS (ESI) m / z=249 [M+H] + .

[0950] Step 4: 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine

[0951]

[0952] A solution of 2-ethyl-6-(6-nitropyridine-3-yl)-2,6-diazaspiro[3.3]heptane (4 g, 16.11 mmol), ammonium chloride (4.31 g, 80.55 mmol), iron powder (9.00 g, 161.100 mmol) and water (20 mL) in ethanol (60 mL) was stirred at 80 ° C for 1 hour. The resulting mixture was filtered and the filter cake was washed with ethanol (100 mL). The filtrate was concentrated under vacuum to provide a crude product. The residue was purified by reverse phase flash chromatography (C18 silica gel, acetonitrile / water (containing 10 mmol / LNH 4 HCO 3 ) gradient) to afford 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-amine (2 g, 56.6% yield).

[0953] LCMS (ESI) m / z = 219 [M+H] + .

[0954] Step 5: N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)formamide

[0955]

[0956] A solution of acetic anhydride (2mL) in formic acid (4mL) was stirred at room temperature for 1 hour, followed by addition of 5-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)pyridine-2-amine (400mg, 1.83mmol) in batches at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized to PH=7 with saturated aqueous sodium bicarbonate (200mL) and extracted with ethyl acetate (3x100mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative reverse phase HPLC (acetonitrile / water (containing 10mM NH 4 HCO 3 and 0.1% NH 3 .H 2 (0) gradient) purification to afford the title compound (70 mg, 15.3% yield).

[0957] LCMS (ESI) m / z = 247 [M+H] + .

[0958] Intermediate 12: 1-(Cyclopropylsulfonyl)piperidin-4-amine

[0959] Reaction scheme

[0960]

[0961] Detailed procedures

[0962] Step 1: tert-Butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate

[0963]

[0964] To a solution of cyclopropanesulfonyl chloride (7.02 g, 49.93 mmol) and DIEA (19.36 g, 149.79 mmol) in DCM (100 mL) was added tert-butyl N-(piperidin-4-yl)carbamate (10 g, 49.93 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (500 mL). The aqueous solution was washed with CH 2 Cl 2 (3x500 mL) extraction. The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EA (100 mL) to afford tert-butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, 59.2% yield).

[0965] LCMS(ESI-MS)m / z=249.1[M+H-56]+ .

[0966] Step 2: 1-(Cyclopropylsulfonyl)piperidin-4-amine

[0967]

[0968] A solution of tert-butyl (1-(cyclopropylsulfonyl)piperidin-4-yl)carbamate (10 g, 32.87 mmol) in TFA (15 mL) and DCM (45 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to provide 1-(cyclopropylsulfonyl)piperidin-4-amine (8 g). LCMS (ESI-MS) m / z=205.1 [M+H] + .

[0969] Intermediate 13: 8-Chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidine- 2-Amine

[0970]

[0971] A solution of 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (1 g, 3.88 mmol), 1-(cyclopropanesulfonyl)piperidin-4-amine (1.59 g, 7.76 mmol), DIEA (1.50 g, 11.64 mmol) and CsF (1.77 g, 11.64 mmol) in DMSO (10 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 The product was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 1:1) to provide 8-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (505.8 mg, 33.3% yield).

[0972] 1 H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 8.08 (d, J = 7.4Hz, 1H), 7.56 (s, 1H), 4.03 (s, 1H), 3.69-3.57 (m, 2H), 3.09-2.92 (m, 2H), 2.69 -2.55(m,1H),2.17-1.89(m,2H),1.71-1.55(m,2H),1.42-1.30(m,1H),1.29-1.13(m,2H),1.05-0.97(m,2H),0.97-0.91(m,2H).

[0973] LCMS (ESI-MS) m / z = 382.2 [M+H] + .

[0974] Intermediate 14: 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

[0975] Reaction scheme

[0976]

[0977] Step 1: tert-Butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate

[0978]

[0979] To a stirred mixture of 1-methyl-1H-pyrazole-4-sulfonyl chloride (7 g, 38.75 mmol) and DIEA (15.03 g, 116.27 mmol) in DCM (70 mL) was added tert-butyl piperidin-4-ylcarbamate (7.76 g, 38.75 mmol) dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 h. The resulting mixture was diluted with water (500 mL). The aqueous solution was washed with CH 2 Cl 2 (3x500mL) extraction. The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH, 99:1) to afford tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (9 g, 64.1% yield).

[0980] LCMS(ESI-MS)m / z=289.2[M+H-56] + .

[0981] Step 2: 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

[0982]

[0983] A solution of tert-butyl (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (6 g, 17.42 mmol) in TFA (12 mL) and DCM (36 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford 1-(1-methylpyrazol-4-ylsulfonyl)piperidin-4-amine (6.5 g crude).

[0984] LCMS (ESI-MS) m / z = 245.2 [M+H] + .

[0985] Intermediate 15: 8-Chloro-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyridine 2-[3,4-d]pyrimidin-2-amine

[0986]

[0987] A solution of 1-(1-methylpyrazol-4-ylsulfonyl)piperidin-4-amine (6.07 g, 24.83 mmol), 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (4 g, 15.52 mmol), DIEA (6.02 g, 46.56 mmol) and CsF (7.07 g, 46.56 mmol) in DMSO (20 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (500 mL) and then extracted with EA (3 x 500 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA, 1:4) to provide 8-chloro-6-methyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-2-amine (2.5 g, 37.4% yield). LCMS (ESI-MS) m / z=422.0 [M+H] + .

[0988] Intermediate 16: 8-Chloro-N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methylpyrido[3,4- d]pyrimidin-2-amine

[0989] Reaction scheme

[0990]

[0991] Detailed procedures

[0992] Step 1: 5-Fluoroisoindoline-1,3-dione

[0993]

[0994] To a solution of 5-fluoro-2-benzofuran-1,3-dione (10 g, 60.20 mmol) in toluene (30 mL) was added urea (4.34 g, 72.24 mmol) in portions at 110 °C. The resulting mixture was stirred at 110 °C for 18 h. The mixture was cooled to room temperature. The residue was purified by purifying with H 2 0 (100 mL) and triturated to purify. This yielded 5-fluoroisoindoline-1,3-dione (9 g, 38.9% yield).

[0995] LCMS (ESI-MS) m / z = 166.0 [M+H] + .

[0996] Step 2: 5-Fluoro-6-nitroisoindoline-1,3-dione

[0997]

[0998] At 0 °C, 5-fluoroisoindoline-1,3-dione (9 g, 54.50 mmol) was added in H 2 SO 4 HNO was added in portions to the solution (90 mL) 3 (9 mL). The resulting mixture was stirred at 80 °C for an additional 30 min. The mixture was cooled to 0 °C. The reaction was quenched with cold water at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. The precipitated solid was collected by filtration and washed with H 2 O (3 x 500 mL) to afford the desired product, 5-fluoro-6-nitroisoindoline-1,3-dione (4 g, 34.9% yield).

[0999] LCMS (ESI-MS) m / z = 211.0 [M+H] + .

[1000] Step 3: 5-Fluoro-6-nitroisoindoline

[1001]

[1002] To a solution of 5-fluoro-6-nitroisoindoline-1,3-dione (5 g, 23.79 mmol) in THF (217.5 mL) was added NaBH in portions at -10 °C. 4 (0.87 g, 22.99 mmol) and BF3-Et2O (35.56 g, 250.57 mmol). The resulting mixture was stirred at 70°C under nitrogen atmosphere for 18 h and concentrated under vacuum to provide crude 5-fluoro-6-nitroisoindoline (1.5 g crude).

[1003] LCMS (ESI-MS) m / z = 183.0 [M+H] + .

[1004] Step 4: 5-Fluoro-2-(methylsulfonyl)-6-nitroisoindoline

[1005]

[1006] To a solution of 5-fluoro-6-nitroisoindoline (1.5 g, 8.23 ​​mmol) in DCM (10 mL) was added Et 3 N (4.50mL, 32.36mmol) for 3min. MsCl (1.71g, 14.90mmol) was then added in portions at 0°C. The resulting mixture was stirred at room temperature overnight. The aqueous layer was extracted with EtOAc (2x200mL). The resulting mixture was washed with saturated aqueous sodium chloride solution (2x200mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under vacuum. The residue was purified by elution with PE / EA and CH 2 Cl 2 Purification by silica gel column chromatography eluted with 5-fluoro-2-(methylsulfonyl)-6-nitroisoindoline (500 mg, 23.3% yield). LCMS (ESI-MS) m / z=261.0 [M+H] + .

[1007] Step 5: 6-Fluoro-2-(methylsulfonyl)isoindolin-5-amine

[1008]

[1009] To 5-fluoro-2-(methylsulfonyl)-6-nitroisoindoline (500 mg, 1.92 mmol) in EtOH (12 mL) and H 2 Fe (1.07 g, 19.21 mmol) and NH 4 Cl (411.08 mg, 7.68 mmol). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to provide 6-fluoro-2-(methylsulfonyl)isoindolin-5-amine (280 mg, 63.3% yield).

[1010] LCMS (ESI-MS) m / z = 231.0 [M+H] + .

[1011] Step 6: N-(6-Fluoro-2-(methylsulfonyl)isoindolin-5-yl)formamide

[1012]

[1013] To a solution of 6-fluoro-2-(methylsulfonyl)isoindolin-5-amine (110 mg, 0.47 mmol) in THF (2 mL) was added 1,2,3-benzotriazole-1-carbaldehyde (70.29 mg, 0.47 mmol). The resulting mixture was stirred overnight at 65 °C under a nitrogen atmosphere and allowed to cool to room temperature. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EA (1:1) to provide N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)formamide (60 mg, 48.6% yield).

[1014] LCMS (ESI-MS) m / z = 259.0 [M+H] + .

[1015] Step 7: 8-Chloro-N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

[1016]

[1017] To a solution of N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)formamide (55 mg, 0.21 mmol) in dimethylformamide (2 mL) was added sodium hydride (25.55 mg, 1.06 mmol, 60% in mineral oil). The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. 8-Chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (54.88 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched at room temperature by adding saturated aqueous NH 4 Cl solution (60 mL), diluted with EtOAc (500 mL) and washed with saturated aqueous sodium chloride solution (3 x 500 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to afford 8-chloro-N-(6-fluoro-2-(methylsulfonyl)isoindolin-5-yl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (60 mg, 69.1% yield).

[1018] LCMS (ESI-MS) m / z = 408.1 [M+H] + .

[1019] Intermediate 17: 1-(2-Methyl-2-azaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-amine

[1020] Reaction scheme

[1021]

[1022] Detailed procedures

[1023] Step 1: tert-Butyl 6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[1024]

[1025] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 46.88 mmol) in THF (100 mL) were added 4-nitropyrazole (5.30 g, 46.88 mmol), DIAD (9.48 g, 46.88 mmol) and PPh 3 (12.30 g, 46.88 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and purified by silica gel column eluting with DCM / MeOH=10:1 to provide the title product (8 g, 49.8% yield).

[1026] LCMS (ESI-MS) m / z = 309.1 [M+H] + .

[1027] Step 2: 6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane

[1028]

[1029] A mixture of tert-butyl 6-(4-nitropyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (8 g, 25.94 mmol), TFA (3 mL) and DCM (6 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to provide 6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (5 g, 83.3% yield).

[1030] LCMS (ESI-MS) m / z = 209.1 [M+H] + .

[1031] Step 3: 2-Methyl-6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane

[1032]

[1033] A mixture of 6-(4-nitropyrazol-1-yl)-2-azaspiro[3.3]heptane (4.5 g, 21.61 mmol) and HCHO (1.95 g, 64.83 mmol) in MeOH (50 mL) was stirred at room temperature for 2 h. NaBH 3CN (2.72 g, 43.22 mmol) and the resulting mixture was stirred at room temperature for 16 h. The mixture was purified by silica gel column chromatography eluting with DCM / MeOH=10:1 to provide 2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (3.5 g, 58.3% yield).

[1034] LCMS (ESI-MS) m / z = 223.1 [M+H] + .

[1035] Step 4: 1-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-amine

[1036]

[1037] Pd / C (350 mg, 10% on carbon) was added to a solution of 2-methyl-6-(4-nitropyrazole-1-yl)-2-azaspiro[3.3]heptane (3.5 g, 15.74 mmol) in MeOH (50 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude 1-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1H-pyrazole-4-amine (3 g, 99.1% yield).

[1038] LCMS (ESI-MS) m / z = 193.1 [M+H] + .

[1039] Intermediate 18: 2-(Methylsulfonyl)isoindolin-5-amine

[1040] Reaction scheme

[1041]

[1042] Detailed procedures

[1043] Step 1: 2-(Methylsulfonyl)-5-nitroisoindoline

[1044]

[1045] Mesyl mesylate (1326.39 mg, 7.61 mmol) was added to 5-nitro-2,3-dihydro-1H-isoindole (500 mg, 3.04 mmol) and Et 3 In a stirred solution of N (462.31 mg, 4.56 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (100 mL) at 0 °C. The mixture was washed with CH 2Cl 2 (3x150mL) extraction. The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to afford crude 2-(methylsulfonyl)-5-nitroisoindoline (500 mg, 67.7% yield).

[1046] No quality signal.

[1047] Step 2: 2-(Methylsulfonyl)isoindolin-5-amine

[1048]

[1049] Pd / C (219.6 mg, 2.06 mmol, 10% on carbon) was added to a solution of 2-(methylsulfonyl)-5-nitroisoindoline (500 mg, 2.06 mmol) in MeOH (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered. The filter cake was washed with MeOH (4x100 mL) and the combined filtrate was concentrated under reduced pressure to provide crude 2-(methylsulfonyl)isoindoline-5-amine (400 mg, 91.3% yield).

[1050] LCMS (ESI-MS) m / z = 213.1 [M+H] + .

[1051] Intermediate 19: 2-(1-(Methylsulfonyl)azetidin-3-yl)-5-nitroisoindoline

[1052] Reaction scheme

[1053]

[1054] Detailed procedures

[1055] Step 1: tert-Butyl 3-(5-nitroisoindolin-2-yl)azetidine-1-carboxylate

[1056]

[1057] A mixture of 5-nitro-2,3-dihydro-1H-isoindole hydrochloride (1.8 g, 8.97 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (1.54 g, 8.97 mmol) in MeOH (40 mL) was stirred at room temperature for 1 h. NaBH 3 CN (1.13g, 17.94mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and quenched with water (100mL). The mixture was extracted with EA (3x100mL). The combined organic layers were washed with anhydrous Na2 SO 4 Dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EA / PE (30%) to afford tert-butyl 3-(5-nitroisoindolin-2-yl)azetidine-1-carboxylate (2.4 g, 80.8% yield).

[1058] LCMS (ESI-MS) m / z = 320.2 [M+H] + .

[1059] Step 2: 2-(Azetidin-3-yl)-5-nitroisoindoline

[1060]

[1061] A mixture of tert-butyl 3-(5-nitroisoindolin-2-yl)azetidine-1-carboxylate (2.4 g, 7.51 mmol) in TFA (4 mL) and DCM (12 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated and washed with DCM (0.5% Et 3 The obtained product was purified by silica gel column chromatography eluted with 2-(azetidin-3-yl)-5-nitroisoindoline (850 mg, 51.6% yield).

[1062] LCMS (ESI-MS) m / z = 220.1 [M+H] + .

[1063] Step 3: 2-(1-(Methylsulfonyl)azetidin-3-yl)-5-nitroisoindoline

[1064]

[1065] Methanesulfonic anhydride (699.16 mg, 4.01 mmol) was added to 2-(azetidin-3-yl)-5-nitroisoindoline (800 mg, 3.64 mmol) and Et 3 In a mixture of N (1107 mg, 10.94 mmol) in DCM (12 mL). The reaction mixture was stirred overnight at room temperature and quenched with water (60 mL). The resulting mixture was extracted with DCM (3x60 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EA (61%) to afford 2-(1-(methylsulfonyl)azetidin-3-yl)-5-nitroisoindoline (850 mg, 66.6% yield).

[1066] LCMS (ESI-MS) m / z = 298.1 [M+H] + .

[1067] Step 4: 2-(1-(Methylsulfonyl)azetidin-3-yl)isoindolin-5-amine

[1068]

[1069] Pd / C (143.17 mg, 1.34 mmol) was added to a mixture of 2-(1-(methylsulfonyl)azetidin-3-yl)-5-nitroisoindoline (800 mg, 2.69 mmol) in MeOH (15 mL) under nitrogen atmosphere, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 1 h. The mixture was filtered and the filter cake was washed with MeOH (2x50 mL). The filtrate was concentrated under reduced pressure to provide crude 2-(1-(methylsulfonyl)azetidin-3-yl)isoindoline-5-amine (600 mg, 65.3% yield).

[1070] LCMS (ESI-MS) m / z = 268.1 [M+H] + .

[1071] Intermediate 20: 2-(3-(4-amino-1H-pyrazol-1-yl)azetidin-1-yl)acetonitrile

[1072] Reaction scheme

[1073]

[1074] Detailed procedures

[1075] Step 1: tert-Butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate

[1076]

[1077] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol) and 4-nitropyrazole (1.96 g, 17.32 mmol) in THF (20 mL) was added PPh 3 (6.81 g, 25.98 mmol) and DIAD (5.25 g, 25.98 mmol) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography (PE / EA, 5: 1) to provide tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5 g).

[1078] LCMS (ESI-MS) m / z = 269.1 [M+H] +.

[1079] Step 2: 1-(azetidin-3-yl)-4-nitro-1H-pyrazole

[1080]

[1081] A mixture of tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (6 g, 22.36 mmol) and TFA (20 mL) in DCM (60 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to provide crude 1-(azetidine-3-yl)-4-nitro-1H-pyrazole (4 g).

[1082] LCMS (ESI-MS) m / z = 169.1 [M+H] + .

[1083] Step 3: 2-(3-(4-nitro-1H-pyrazol-1-yl)azetidin-1-yl)acetonitrile

[1084]

[1085] 2-bromoacetonitrile (1.60 g, 13.38 mmol) and N, N-diisopropylethylamine (3.46 g, 26.76 mmol) were added to a solution of 1- (azetidine -3- bases) -4- nitro -1H- pyrazole (1.5 g, 8.92 mmol) in MeCN (50 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA, 1: 1) to provide the desired product 2- (3- (4- nitro -1H- pyrazole -1- bases) azetidine -1- bases) acetonitrile (300 mg, 16.23%).

[1086] LCMS (ESI-MS) m / z = 208.1 [M+H] + .

[1087] Step 4: 2-(3-(4-amino-1H-pyrazol-1-yl)azetidin-1-yl)acetonitrile

[1088]

[1089] At 80°C, 2-(3-(4-nitro-1H-pyrazol-1-yl)azetidin-1-yl)acetonitrile (200 mg, 0.96 mmol) and NH 4To a solution of Cl (206.53 mg, 3.86 mmol) in water (3 mL) and EtOH (9 mL) was added Fe (539.06 mg, 9.65 mmol) in portions. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated, diluted with water (30 mL) and extracted with EA (3x30 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum to provide crude 2-(3-(4-amino-1H-pyrazol-1-yl)azetidin-1-yl)acetonitrile (120 mg, 70.2% yield). LCMS (ESI-MS) m / z=178.1 [M+H] + .

[1090] Intermediate 21: 1-((1-(Dimethylamino)cyclopropyl)methyl)-1H-pyrazol-4-amine

[1091] Reaction scheme

[1092]

[1093] Detailed procedures

[1094] Step 1: (1-(Dimethylamino)cyclopropyl)methanol

[1095]

[1096] NaBH 3 CN (2.89g, 45.9mmol) is added to (1-aminocyclopropyl) methanol (2g, 22.9mmol) and paraformaldehyde (6.20g, 68.8mmol) in MeOH (20mL). Gained mixture is stirred overnight at room temperature. The reaction mixture is concentrated under vacuum and purified by silica gel column chromatography eluted with MeOH (0% to 20%) in DCM. The fractions with the desired mass signal are merged and concentrated under vacuum to provide the desired product (1-(dimethylamino) cyclopropyl) methanol (600mg, 22.7% yield).

[1097] LCMS (ESI-MS) m / z = 116.1 [M+H] + .

[1098] Step 2: N,N-dimethyl-1-((4-nitro-1H-pyrazol-1-yl)methyl)cyclopropane-1-amine

[1099]

[1100] DIAD (1.4 g, 7.16 mmol) was added to (1-(dimethylamino)cyclopropyl)methanol (550 mg, 4.77 mmol), 4-nitropyrazole (648 mg, 5.73 mmol) and PPh under nitrogen atmosphere. 3 (1.8g, 7.16mmol) in a solution in THF (6mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography eluted with EA (0% to 30%) in PE. The fractions with the desired mass signal were combined and concentrated under vacuum to provide the desired product N, N-dimethyl-1-((4-nitro-1H-pyrazol-1-yl)methyl)cyclopropane-1-amine (400mg, 39.8% yield). LCMS (ESI-MS) m / z=211.1[M+H] + .

[1101] Step 3: 1-((1-(dimethylamino)cyclopropyl)methyl)-1H-pyrazol-4-amine

[1102]

[1103] Fe (1.0 g, 19.0 mmol) was added to N,N-dimethyl-1-((4-nitro-1H-pyrazol-1-yl)methyl)cyclopropane-1-amine (400 mg, 1.90 mmol) and NH 4 Cl (407 mg, 7.61 mmol) in EtOH (3 mL) and H 2 O (1mL) in a mixture of. The resulting mixture is heated to 80 ° C and stirred for 2h. After cooling to room temperature, the resulting mixture is filtered and the filter cake is washed with ethanol (2x10mL). The filtrate is concentrated under reduced pressure to provide crude 1-((1-(dimethylamino)cyclopropyl)methyl)-1H-pyrazole-4-amine (300mg, 87.5% yield).

[1104] LCMS (ESI-MS) m / z = 181.1 [M+H] + .

[1105] Intermediate 22: 2-Cyclopropylisoindolin-5-amine

[1106] Reaction scheme

[1107]

[1108] Detailed procedures

[1109] Step 1: 2-Cyclopropyl-5-nitroisoindoline

[1110]

[1111] To a solution of 5-nitro-2,3-dihydro-1H-isoindole (2.6 g, 15.8 mmol), AcOH (1.90 g, 31.6 mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (11.04 g, 63.3 mmol) in THF (100 mL) and MeOH (10 mL) was added NaBH 3 CN (1.49 g, 23.7 mmol). The resulting mixture was stirred at 60 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with 1N HCl and extracted with EtOAc. The aqueous layer was washed with solid K 2 CO 3 The solution was basified to pH = 10 and extracted with DCM. The combined organic phases were washed with water and brine and purified by Na 2 SO 4 Drying and concentration afforded 2-cyclopropyl-5-nitroisoindoline (2 g, 49.47%).

[1112] LCMS (ESI-MS) m / z = 205.1 [M+H] + .

[1113] Step 2: 2-Cyclopropylisoindolin-5-amine

[1114]

[1115] Pd / C (14.59 mg, 0.14 mmol) was added to a solution of 2-cyclopropyl-5-nitroisoindoline (350 mg, 1.7 mmol) in MeOH (5 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with MeOH (4 x 10 mL). The combined filtrate was concentrated under reduced pressure to provide the crude product 2-cyclopropylisoindoline-5-amine (270 mg, 88.6% yield).

[1116] LCMS (ESI-MS) m / z = 175.1 [M+H] + .

[1117] Intermediate 23: 1-((Cyclopentylmethyl)sulfonyl)piperidin-4-amine

[1118]

[1119] Step 1: tert-Butyl (1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)carbamate

[1120]

[1121] To a solution of cyclopentylmethanesulfonyl chloride (470 mg, 2.57 mmol) and DIEA (831.41 mg, 6.43 mmol) in DCM (10 mL) was added tert-butyl N-(piperidin-4-yl)carbamate (429.45 mg, 2.14 mmol) dropwise at 0°C. The resultin...

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (I0): Wherein, A is a ring selected from an optionally substituted carbocycle, an optionally substituted 4- to 8-membered heterocycle, an optionally substituted tetrahydrotriazolopyrazine, and an optionally substituted isoindoline; Z 0 is –C(H)- or nitrogen; Z 1 、Z 2 and Y 1 each independently selected from -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 -; Each of a and b is independently selected from 1, 2, 3, and 4; Each R 1 is independently selected from halogen, -CN, -NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle and optionally substituted heterocycle; m is selected from 0 to 5; Each R 2 is 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 combine to form an optionally substituted heterocycle or an optionally substituted carbocycle, or R 2 and R 3 substituents combine to form an optionally substituted heterocycle; Each 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; R 4 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; R 5 、R 6 each 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 selected from hydrogen and optionally substituted C 1-4 alkyl, and wherein if A is an optionally substituted phenyl, m is from 1 to 5 and at least one R 1 is a heterocycloalkyl, wherein if A is optionally substituted pyridine, optionally substituted pyridazine or optionally substituted pyrimidine, R 4 is selected from hydrogen, halogen and -CN, wherein if A is an optionally substituted piperidine sulfonamide, then (i) Y 1 is -C(R 2 ) 2 - and the two R 2 substituents together form a ring selected from optionally substituted heterocycles and optionally substituted carbocycles, or (ii) R 4 is selected from hydrogen, halogen, methyl and -CN, and Wherein if A-R 1 is and Z 0 is CH, then R 4 is methyl or cyclopropyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (I): Wherein, A is a ring selected from an optionally substituted carbocycle, an optionally substituted 4- to 6-membered heterocycle, and an optionally substituted isoindoline; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, having one or more of the structures of formula (IA), (IB), (IC), (ID), or (IE): Wherein, R 8 selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 9 selected from optionally substituted C 3-6 carbocycle, optionally substituted C 5-6 heteroaryl, and 3- to 6-membered heterocycloalkyl; R 10 is an optionally substituted alkyl or an optionally substituted heterocycloalkyl; R 11 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 combine together to form an optionally substituted heterocycle; R 13 selected from halogen, -CN and optionally substituted C 1-4 alkyl; n is selected from 0 to 9; R 14 selected from -SOR 16 - and optionally substituted heterocycloalkyl; R 15 selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl; R 16 selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocycloalkyl; R 17 selected from -SOR 19 - optionally substituted alkyl, optionally substituted carbocyclic and optionally substituted heterocycloalkyl; R 18 Selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 19 selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle and 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 Wherein 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 optionally substituted heterocycles and optionally substituted carbocycles, or (ii) R 4 is selected from hydrogen, halogen and -CN.

4. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IA).

5. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IB).

6. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IC).

7. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IE).

8. The compound or pharmaceutically acceptable salt according to any one of claims 1-7, wherein Z 1 and Z 2 are independently selected from -C(R 2 ) 2 -, -NR 3 -, -O- and -S-.

9. The compound or pharmaceutically acceptable salt according to claim 8, wherein Z 1 and Z 2 are independently -C(R 2 ) 2 -.

10. The compound or pharmaceutically acceptable salt according to claim 9, wherein each of a and b is independently selected from 1 and 2.

11. The compound or pharmaceutically acceptable salt according to any one of claims 1-10, wherein Y 1 is selected from -C(R 2 ) 2 -, -NR 3 -, -NS(O 2 )R 2 , -O-, -S(O) 2 - and -S-.

12. The compound or pharmaceutically acceptable salt according to claim 11, wherein Y 1 is selected from -C(R 2 ) 2 - and -NR 3 .

13. The compound or pharmaceutically acceptable salt according to any one of claims 1-12, wherein each R 2 is independently selected from hydrogen, OH, halogen, -CN, optionally substituted alkyl, optionally substituted -O-alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

14. The compound or pharmaceutically acceptable salt according to claim 13, wherein each R 2 is independently selected from hydrogen, halogen, -CN, cyclopropyl, cyclobutyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.

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

16. The compound or pharmaceutically acceptable salt according to any one of claims 1-15, wherein the two R 2 substituents are joined together to form an optionally substituted heterocycle or an optionally substituted carbocycle.

17. The compound or pharmaceutically acceptable salt according to any one of claims 1-15, wherein each R 3 is selected from hydrogen, optionally substituted alkyl, cyclopropyl, cyclobutyl, optionally substituted oxetane and optionally substituted azetidine.

18. The compound or pharmaceutically acceptable salt according to claim 17, wherein each R 3 is selected from methyl, methoxyethylene, CD 3 , cyclopropyl and cyclobutyl.

19. The compound or pharmaceutically acceptable salt according to claim 18, wherein R 3 is cyclopropyl.

20. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, having one or more of the structures of formula (IAA), (IBB), (ICC), (IDD), or (IEE): Wherein, R 8 selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 9 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 Selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 12 is an optionally substituted heterocycloalkyl; or R 12 and R 13 together form an optionally substituted heterocycle; R 13 selected from halogen, -CN and optionally substituted C 1-4 alkyl; R 15 selected from hydrogen, halogen, -CN and optionally substituted C 1-4 alkyl; R 16 selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocyclic ring and optionally substituted 3- to 6-membered heterocycloalkyl; R 19 selected from optionally substituted C 1-4 alkyl, optionally substituted C 3-6 carbocycle and optionally substituted 3- to 6-membered heterocycloalkyl; n is selected from 0 to 9; p is selected from 0 to 4; q is selected from 0 to 2; 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(O 2 )R 3 , -O-, -S-, -S(O)- and -S(O) 2 -, wherein Z 5 is additionally selected from a bond; and Each of a, b, c, and d is independently selected from 1, 2, 3, and 4.

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

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

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

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

25. The compound or pharmaceutically acceptable salt according to any one of claims 20-24, wherein 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(O 2 )R 3 , -O- and -S(O) 2 -, wherein Z 5 is additionally selected from a bond.

26. The compound or pharmaceutically acceptable salt according to claim 25, wherein Z 1 、Z 2 、Z 3 、Z 4 and Z 5 each independently selected from -C(R 2 ) 2 -, -NR 3 -, -O- and -S(O) 2 -, wherein Z 5 is additionally selected from a bond.

27. The compound or pharmaceutically acceptable salt according to any one of claims 20-26, wherein each R 2 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 heterocycle or an optionally substituted carbocycle.

28. The compound or pharmaceutically acceptable salt according to claim 27, wherein each R 2 is selected from hydrogen, fluorine, 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, optionally substituted oxetane, and optionally substituted azetidine.

29. A compound or a pharmaceutically acceptable salt according to any one of claims 20-28, wherein 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, optionally substituted oxetane and optionally substituted azetidine.

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

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

32. The compound or pharmaceutically acceptable salt according to any one of claims 20-31, wherein each of a, b, c, and d is independently selected from 1 and 2.

33. The compound or pharmaceutically acceptable salt according to claim 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.

34. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein A is optionally substituted piperidine.

35. The compound or pharmaceutically acceptable salt according to claim 34, wherein A is substituted by SO 2 R 9 wherein R 9 is selected from optionally substituted C 3-6 carbocycles, optionally substituted C 5-6 heteroaryl groups, and 3- to 6-membered heterocycloalkyl groups.

36. The compound or pharmaceutically acceptable salt according to claim 34 or 35, wherein m is selected from 0 to 1.

37. A compound or a pharmaceutically acceptable salt according to any one of claims 34 - 36, wherein each R 1 is independently selected from an optionally substituted alkyl group, an optionally substituted carbocyclic ring, and an optionally substituted heterocyclic ring.

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

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

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

41. The compound or pharmaceutically acceptable salt according to claim 40, wherein Z 1 and Z 2 are each -C(R 2 ) 2 -.

42. The compound or pharmaceutically acceptable salt according to claim 40 or 41, wherein each of a and b is independently selected from 1 and 2.

43. A compound or a pharmaceutically acceptable salt according to any one of claims 1-13 and 34-42, wherein Y 1 is selected from -C(R 2 ) 2 -, -NR 3 -, -O- and -S-.

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

45. The compound or pharmaceutically acceptable salt according to claim 44, wherein Y 1 is -C(R 2 ) 2 - and the two R 2 substituents together form a ring selected from optionally substituted heterocycles and optionally substituted carbocycles.

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

47. A compound or a pharmaceutically acceptable salt according to any one of claims 1-19 and 34-46, wherein the N-containing heterocycle depicted as in Formula (IA), (IB), (IC), (ID) and (IE) 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.

48. A compound or a pharmaceutically acceptable salt according to any one of claims 1-19 and 34-46, wherein the N-containing heterocycle depicted as in Formula (IA), (IB), (IC), (ID) and (IE) is selected from is 49. A compound or a pharmaceutically acceptable salt according to any one of claims 1 - 32 or 34 - 48, wherein 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.

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

51. The compound or pharmaceutically acceptable salt according to claim 50, wherein R 4 is selected from hydrogen, methyl, and -CHF 2 .

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

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

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

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

56. A compound or a pharmaceutically acceptable salt according to any one of claims 1 - 32, 34 - 39 or 50 - 55, wherein 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.

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

58. The compound or pharmaceutically acceptable salt according to claim 57, wherein R 5 is selected from hydrogen and fluorine.

59. A compound or a pharmaceutically acceptable salt according to any one of claims 1 - 32, 34 - 39 or 50 - 58, wherein 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.

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

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

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

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

64. The compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from Table 1.

65. The compound or its pharmaceutically acceptable salt according to claim 2, wherein the compound is selected from Table 1.

66. The compound or its pharmaceutically acceptable salt according to claim 3, wherein the compound is selected from Table 1.

67. The compound or its pharmaceutically acceptable salt according to claim 20, wherein the compound is selected from Table 1.

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

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

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 cancer.

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 or its pharmaceutically acceptable salt according to any one of claims 1 to 67 or the pharmaceutical composition according to claim 68.

74. The method according to claim 73, wherein the CDK is selected from CDK 2, CDK 4, CD6, or any combination thereof.

75. The method according to claim 74, wherein the CDK is selected from CDK 2 / 4, CDK 2 / 6, CDK 4 / 6, and CDK2 / 4 / 6.

76. The method according to claim 75, wherein the CDK is CDK 2 / 4 / 6.

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