Substituted thiazole compounds as CDK2 / 4 / 6 inhibitors and methods of use thereof

Abstract

The present disclosure provides small molecule inhibitory compounds of CDK2 / 4 / 6 and compositions comprising the same. The present disclosure also provides methods of targeting CDK2 / 4 / 6 and methods of treating diseases or disorders associated with CDK2 / 4 / 6, such as cancer.

Description

[0001] Cross-referencing

[0002] This patent application claims the benefit of International Application No. PCT / CN2023 / 105592, filed on July 3, 2023, which is incorporated herein by reference in its entirety.

[0003] background

[0004] Cyclin-dependent kinases (CDKs) are crucial enzymes that play key roles in the regulation of eukaryotic cell division and proliferation. The regulatory subunit (cyclin) activates the catalytic unit of CDKs and is also an important regulator of cell cycle progression. Furthermore, the cyclin / CDK heterodyne circuit regulates transcription, DNA repair, differentiation, and apoptosis. CDK2 overexpression is associated with aberrant cell cycle regulation. Cyclin E, a regulatory cyclin of CDK2, is frequently overexpressed in cancer, and its amplification / overexpression is associated with breast cancer.

[0005] Overview

[0006] This disclosure addresses the aforementioned needs and also provides additional advantages.

[0007] In one respect, this paper describes compounds having the structure of formula (I) or salts thereof.

[0008]

[0009] Formula (I).

[0010] In some embodiments, the compound has the structure of formula (II), or a pharmaceutically acceptable salt thereof.

[0011]

[0012] Equation (II).

[0013] In some embodiments, the compound has the structure of formula (III), or a pharmaceutically acceptable salt thereof.

[0014]

[0015] Formula (III).

[0016] In one respect, this article describes compounds having the structure of formula (IIa) or pharmaceutically acceptable salts thereof.

[0017]

[0018] Equation (IIa).

[0019] In an aspect, described herein is a compound having the structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof,

[0020]

[0021] Formula (IIIa).

[0022] In an aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0023] In an aspect, described herein is a method of treating cancer in an individual, comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

[0024] In an aspect, described herein is a method of modulating the activity of a cyclin-dependent kinase (CDK) in an individual, comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

[0025] In an aspect, described herein is a method of inhibiting the activity of a cyclin-dependent kinase (CDK) in an individual, comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.

[0026] In an aspect, described herein is a method of treating a disease or disorder associated with a cyclin-dependent kinase (CDK) in an individual, comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the disease or disorder is cancer.

[0027] In some embodiments, the cancer is a cancer of the bladder, breast, colon, kidney, skin, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; a thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; a melanoma; a seminoma; a teratocarcinoma; an osteosarcoma; xeroderma pigmentosa; keratocanthoma; thyroid follicular cancer; or Kaposi's sarcoma. In some embodiments, the cancer is a pRb+ breast cancer or a hormone receptor (HR)-positive (e.g., estrogen receptor positive (ER+), progesterone receptor positive (PR+), or ER+ PR+), HER2 / neu-negative cancer. In some embodiments, the cancer is an advanced or metastatic or recurrent breast cancer.

[0028] INCORPORATION BY REFERENCE

[0029] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the present specification, the present specification is intended to supersede and / or take precedence over any such contradictory disclosure.

[0030] DETAILED DESCRIPTION

[0031] While the different embodiments of the disclosure have been shown and described herein, it will be apparent to those skilled in the art that many changes, modifications, and substitutions can be made thereto without departing from the disclosure. It is to be understood that different alternatives to the embodiments of the disclosure described herein can be employed and that the present disclosure is not limited to the particular embodiments described.

[0032] A. DEFINITIONS

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0034] In the following description, certain specific details are set forth in order to provide a thorough understanding of different implementations. However, one skilled in the relevant art will recognize that the technology disclosed can be practiced without one or more of the specific details, or with perhaps additional details, In other instances, well-known structures or functions have not been described in detail in order to avoid obscuring aspects of the description. Unless otherwise noted, the use of the term "including" in the specification or the like does not constitute a departure from the scope of the present disclosure, including the claims. Additionally, the use of "including" and "comprising" and variations thereof are intended to be equivalent in this disclosure. Furthermore, the headings provided herein are for convenience only and are not to be construed as limiting the disclosure in any way.

[0035] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic being described is included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Additionally, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" as used in the context of this specification is generally used in the sense that it is used in the field of patent law, i.e., the term "or" is not used in the sense of "either / or" unless the context clearly indicates otherwise.

[0036] As used herein, the following terms have the following meanings, unless indicated otherwise:

[0037] "Oxycarbonyl" means -C(O)O-.

[0038] "Carboxyl" means -COOH.

[0039] "Cyano" means -CN.

[0040] "Alkyl" means a straight or branched chain saturated hydrocarbon monovalent radical of from 1 to about 10 carbon atoms, more preferably 1-6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl- 1 -butyl, 3-methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl- 1 -propyl, 2-methyl- 1 -pentyl, 3-methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl- 1 -butyl, 2-ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, and hexyl, and longer alkyl groups such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as "C1-C6 alkyl," or "C1-Cn alkyl," means that the alkyl group can contain from 1 to n carbon atoms.1-6 "Alkyl" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkyl" without a specified number of carbon atoms. In some embodiments, alkyl is C1-C6alkyl. 1-10 "Alkyl" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkyl" without a specified number of carbon atoms. In some embodiments, alkyl is C1-C6alkyl. 1-6 "Alkyl" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkyl" without a specified number of carbon atoms. In some embodiments, alkyl is C1-C6alkyl. 1-5 "Alkyl" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkyl" without a specified number of carbon atoms. In some embodiments, alkyl is C1-C6alkyl. 1-4 "Alkyl" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkyl" without a specified number of carbon atoms. In some embodiments, alkyl is C1-C6alkyl. 1-3 "Alkyl" refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkyl" without a specified number of carbon atoms. In some embodiments, alkyl is C1-C6alkyl. Unless otherwise expressly specified herein, alkyl can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0041] "Alkenyl" refers to a straight or branched chain hydrocarbon monradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The radical can be in the cis or trans configuration with respect to the double bond(s) and it is understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3- butadienyl, and the like. Whenever it appears in the description herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkenyl" without a specified number of carbon atoms. Unless otherwise expressly specified herein, alkenyl can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0042] "Alkynyl" refers to a straight-chain or branched hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl, and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of alkenyl also covers the occurrence of the term "alkynyl" alone without a specified numerical range. Unless otherwise expressly specified herein, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0043] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise expressly specified herein, alkylene groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0044] "Aryloxy" refers to a radical of the formula -OR a where R a is aryl as defined herein. Unless otherwise expressly specified herein, aryl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0045] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, aryl is a 6- to 10-membered aryl group. In some embodiments, aryl is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, aryl groups derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, benzvalene, chrysene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise expressly stated herein, an aryl group can be optionally substituted, e.g., with halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halo. As used herein, "arylene" refers to a divalent aryl group as described herein. An arylene group can be bonded through the aryl group at any suitable position. In some embodiments, when arylene includes an aryl group fused to a cycloalkyl or heterocycloalkyl ring, the arylene is bonded at the aryl and cycloalkyl or aryl and heterocycloalkyl. In some embodiments, when arylene includes an aryl group fused to a cycloalkyl or heterocycloalkyl ring, the arylene is bonded only at the aryl.

[0046] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, those with 3-15 carbon atoms (e.g., C3-C 15 fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3-10 carbon atoms (e.g., C3-C 10 fully saturated cycloalkyl or C3-C 10cycloalkyl of 3 to 10 members fully saturated or 3 to 10 members partially saturated. In some embodiments, the cycloalkyl is a 3 to 6 membered fully saturated cycloalkyl or 3 to 6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6 membered fully saturated cycloalkyl or 5 to 6 membered cycloalkenyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly specified herein, a cycloalkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a cycloalkyl group is optionally substituted with halogen. As used herein, “cycloalkylene” refers to a divalent cycloalkyl group as described herein. In some embodiments, when a cycloalkylene group comprises a cycloalkyl fused to an aryl or heteroaryl ring, the cycloalkylene is bonded at the cycloalkyl and aryl or cycloalkyl and heteroaryl. In some embodiments, when a cycloalkylene group comprises a cycloalkyl fused to an aryl or heteroaryl ring, the cycloalkylene is bonded only at the cycloalkyl.

[0047] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0048] "Halogenated alkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0049] "Hydroxyalkyl" refers to an alkyl group as defined above, which is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0050] "Aminoalkyl" refers to an alkyl group as defined above, which is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0051] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0052] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2-23 carbon atoms and 1-8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl contains 1-3 nitrogen atoms. In some embodiments, the heterocyclic alkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl contains 1 nitrogen atom. In some embodiments, the heterocyclic alkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise expressly stated in this specification, heterocyclic alkyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl group is bonded by non-aromatic ring atoms), spirocyclic, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms on the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having 2-15 carbon atoms (C2-C4). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups), 2-10 carbon atoms (C2-C4) 10 Fully saturated heterocyclic alkyl or C2-C 10heterocycloalkyl of 2-8 carbon atoms (C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), 2-7 carbon atoms (C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), 2-6 carbon atoms (C2-C6fully saturated heterocycloalkyl or C2-C6heterocycloalkenyl), 2-5 carbon atoms (C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or 2-4 carbon atoms (C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl, [1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzenefuran-1-yl, 3-oxo-1,3-dihydroisobenzenefuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl group has 2-10 carbons in the ring. It will be appreciated that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (which includes heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl group is a 3 to 8 membered fully saturated heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 3 to 7 membered fully saturated heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 3 to 6 membered fully saturated heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 4 to 6 membered fully saturated heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 5 to 6 membered fully saturated heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 3 to 8 membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 3 to 7 membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 3 to 6 membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 4 to 6 membered heterocycloalkenyl group. In some embodiments, the heterocycloalkyl group is a 5 to 6 membered heterocycloalkenyl group. Unless specifically set forth herein, a heterocycloalkyl group can be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heteroaryl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0053] As used herein, "heteroaryloxy" refers to a heteroaryl-O- group, wherein the heteroaryl group is as described herein. In some embodiments, heteroaryloxy is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryloxy is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryloxy is optionally substituted with halogen.

[0054] “Heteroaryl” refers to a 5- to 14-membered ring system radical that includes 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group includes 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group includes 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group includes 1-3 nitrogens. In some embodiments, the heteroaryl group includes 1 or 2 nitrogens. In some embodiments, the heteroaryl group includes 1 nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can optionally be oxidized; the nitrogen atoms can optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzo dioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzo furanyl, dibenzo thiophenyl, furanyl, furanonyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl (i.e., thiophenyl). Unless otherwise explicitly indicated herein, the heteroaryl group can be optionally substituted, e.g., with halo, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen. As used herein, "heteroarylene" refers to a divalent heteroaryl group as described herein. In some embodiments, when heteroarylene comprises a heteroaryl group fused to a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded at the heteroaryl and cycloalkyl or heteroaryl and heterocycloalkyl. In some embodiments, when heteroarylene comprises a heteroaryl group fused to a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded only at the heteroaryl.

[0055] The term "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, that description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Further, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, such group is not intended to

[0056] As used in this specification and claim, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0057] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which 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 salts 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, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, propylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium, and magnesium salts.

[0058] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that 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 problem or complication, commensurate with a reasonable benefit / risk ratio.

[0059] In certain embodiments, the term "preventing" in connection with a disease or disorder can mean a compound that reduces the occurrence of a disease or disorder, or delays the onset of, or reduces the severity of one or more symptoms of a disease or disorder, in a statistical sample relative to an untreated control sample.

[0060] The term "treatment" as used herein can include alleviating, abating or ameliorating a disease or condition symptom, preventing the symptoms from occurring, improving the disease or condition symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing the disease or condition to regress, diminishing the disease or condition, or stopping the disease or condition symptoms.

[0061] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein being administered, which relieves to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief of symptoms of the disease. In some embodiments, an appropriate "effective" amount in any individual case is determined using such techniques as a dose escalation study.

[0062] The term "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Further, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), singly substituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and singly substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0063] As used herein, the term "individual" can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the individual of the methods disclosed herein can be a human, a non-human primate, a horse, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The term does not denote a particular age or gender. Thus, adult and newborn individuals, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the individual is a mammal.

[0064] The ranges provided herein are to be understood to be shorthand for all values within the range. For example, a range of 1 to 50 is to be understood as including any number, combination of numbers, or sub-range selected from the set of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, particular attention is directed to “nested sub-ranges” extending from either end of the range. For example, exemplary nested sub-ranges of a range of 1 to 50 can include 1-10, 1-20, 1-30, and 1-40 in one direction or 50-40, 50-30, 50-20, and 50-10 in the other direction.

[0065] B. Compounds of the Disclosure

[0066] In one aspect, disclosed herein are CDK2 / 4 / 6 or CDK2 / 4 or CDK2 or CDK4 selective inhibitor compounds. The compounds of Formula (I) can have a kinase selectivity for CDK2 or CDK4 or CDK2 and CDK4 and CDK6 over other cell cycle dependent protein kinases.

[0067] In one aspect, the disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

[0068]

[0069] Formula (I)

[0070] wherein

[0071] is or ;

[0072] R 1 is hydrogen, halogen, -NR c R d , C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with one or more R;

[0073] Y is a bond, -S-, -O-, -NR YN , or -C(R Y )2-;

[0074] R YN is hydrogen, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;

[0075] R Y is each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R Y together form oxo;

[0076] is a single or double bond;

[0077] X 1 is N or C;

[0078] X 2 is N or CR 2 ;

[0079] X 3 is N or CR 3 ;

[0080] X 4 is N or CR 4 ;

[0081] X 5 is N or C;

[0082] X 6 is N or C;

[0083] X 7 is O, S, N, NR 7N , CR 7 , or CR 7’ R 7 ;

[0084] X 8 is NR 8N , CR 8 , or CR 8’ R 8 ;

[0085] X 9 is O, S, N, NR 9N, CR 9 or CR 9’ R 9 ;

[0086] R 2 , R 3 and R 4 are each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;

[0087] R 7N and R 9N are each independently hydrogen, -CN, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;

[0088] R 7 and R 7’ are each independently hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or

[0089] R 7 and R 7’ together form oxo; or R 7 and R 7’ , together with the atoms to which they are attached, form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;

[0090] R 9 and R 9’ are each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, C 1-6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or

[0091] R 9 and R 9’ together form oxo; or R 9 and R 9’ together with the atoms to which they are attached form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R;

[0092] R 8 is selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1-6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 heteroalkylene-aryl and -C 1-6 heteroalkylene-heteroaryl, wherein alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R 8a substituents;

[0093] R 8N selected from -CN, -NO2, -OC(=O)R a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1-6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 heteroalkylene-aryl and -C 1-6 heteroalkylene-heteroaryl, wherein alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R 8a substituents;

[0094] R 8’ are independently hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 8a substituents;

[0095] R 8a each independently selected from halogen, -CN, -NO2, -OH, oxo, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R substituents;

[0096] Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0097] R 10 each independently selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a, -OC(=0)OR b , -OC(=0)NR c R d , -P(=0)R c R d , -SF5, -SH, -SR a , -S(=0)R a , -S(=0)2R a , -S(=0)2NR c R d , -S(=0)(=NR b )R b , -NR c R d , -NR b C(=0)NR c R d , -NR b C(=0)R a , -NR b C(=0)OR b , -NR b S(=0)2R a , -N=S(=0)(R b )2, -C(=0)R a , -C(=0)OR b , -C(=0)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ; or two R 10 are taken together to form an oxo;

[0098] R 10a is each independently selected from halogen, -CN, -NO2, -OH, oxo, -OR a , -OC(=0)R a , -OC(=0)OR b , -OC(=0)NR c R d , -SF5, -SH, -SR a , -S(=0)R a , -S(=0)2R a , -S(=0)2NR c R d , -S(=0)(=NR b )Rb -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -N=S(=O)(R b )2 a -C(=O)R b -C(=O)OR c -C(=O)NR d -P(=O)R c R d C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

[0099] n is 0, 1, 2, 3, 4, 5, or 6;

[0100] R a each instance of R is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R;

[0101] R b each instance of R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R;

[0102] Rc and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R;

[0103] or R c and R d together with the atoms to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more R; and

[0104] each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;

[0105] or two R on the same atom form oxo.

[0106] In some embodiments, the compound of Formula (I) has the structure of Formula (II), or a pharmaceutically acceptable salt thereof,

[0107]

[0108] Formula (II).

[0109] In some embodiments, the compound of Formula (I) has the structure of Formula (III), or a pharmaceutically acceptable salt thereof,

[0110]

[0111] Formula (III).

[0112] In some embodiments of the compound of Formula (III), or a pharmaceutically acceptable salt thereof,

[0113] wherein

[0114] Ring A is heterocycloalkyl, aryl, heteroaryl, or C 4-12 cycloalkyl;

[0115] Y is a bond, -S-, -O-, -NR YN - or -C(R Y )2-;

[0116] R YN is hydrogen, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;

[0117] R Y is each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl.

[0118] In some embodiments of the compound of Formula (I), (II), or (III), Y is a bond, -S-, -O-, -NR YN - or -C(R Y )2-. In some embodiments, Y is a bond. In some embodiments, Y is -S- or -O-. In some embodiments, Y is -S-. In some embodiments, Y is -O-. In some embodiments, Y is -NR YN -. In some embodiments, Y is -C(R Y )2-. In some embodiments, Y is -C(R Y )2-, wherein R Y is each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C 1-6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or heterocycloalkyl. In some embodiments, R 2-6 alkenyl, C 2-6 alkynyl, C3-C6cycloalkyl, or heterocycloalkyl. In some embodiments, two R

[0119] In some embodiments of the compound of Formula (I), (II), or (III), R YN is hydrogen, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or heterocycloalkyl. In some embodiments, R Y is hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or heterocycloalkyl. In some embodiments, R 2-6 alkenyl, C 2-6 alkynyl, C3-C6cycloalkyl, or heterocycloalkyl. In some embodiments, two R Y are taken together to form an oxo.

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

[0121]

[0122] Formula (IIa).

[0123] In some embodiments, the compound of Formula (I) has the structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof,

[0124]

[0125] Formula (IIIa).

[0126] In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (IIIa), X 1 is N or C. In some embodiments, X 1 is N. In some embodiments, X 1 is C. In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (IIIa), X 2 is N or CR 2 . In some embodiments, X 2is N. In some embodiments, X 2 is CR 2 In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 3 is N or CR 3 In some embodiments, X 3 is N. In some embodiments, X 3 is CR 3 In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 4 is N or CR 4 In some embodiments, X 4 is N. In some embodiments, X 4 is CR 4 In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 5 is N or C. In some embodiments, X 5 is N. In some embodiments, X 5 is C. In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 6 is N or C. In some embodiments, X 6 is N. In some embodiments, X 6 is C. In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 7 is O, S, N, NR 7N , CR 7 , or CR 7’ R 7 In some embodiments, X 7 is O. In some embodiments, X 7 is S. In some embodiments, X 7 is N. In some embodiments, X 7 is NR 7N In some embodiments, X 7 is CR 7 In some embodiments, X 7 is CR 7’ R 7 In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 8 is NR 8N , CR 8 , or CR 8’ R8 In some embodiments, X 8 is NR 8N In some embodiments, X 8 is CR 8 In some embodiments, X 8 is CR 8’ R 8 In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), X 9 is O, S, N, NR 9N , CR 9 , or CR 9’ R 9 In some embodiments, X 9 is O. In some embodiments, X 9 is S. In some embodiments, X 9 is N. In some embodiments, X 9 is NR 9N In some embodiments, X 9 is CR 9 In some embodiments, X 9 is CR 9’ R 9 .

[0127] In some embodiments of the compound of Formula (I), (II), or (Ila), is , , , , or In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is .

[0128] In some embodiments of the compound of Formula (I), (II), or (Ila), is , , , , , 、 、 、 or In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is .

[0129] In some embodiments of the compound of Formula (I), (III), or (Ilia), is 、 、 、 、 or In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is .

[0130] In some embodiments of the compound of Formula (I), (III), or (Ilia), is 、 、 、 、 、 or .

[0131] In some embodiments of the compound of Formula (I), (III), or (Ilia), , , , , , , , .

[0132] In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , In some embodiments, , .

[0133] In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (Ilia), R 1 is hydrogen, halogen, -NR c R d , C 1-6 1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with one or more R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -NR c R d . In some embodiments, R 1 is C 1-6 1-C6 alkyl. In some embodiments, R 1It is a C1-C6 haloalkyl group. In some embodiments, R 1 It is a C1-C6 hydroxyalkyl group. In some embodiments, R 1 It is a C1-C6 aminoalkyl group. In some embodiments, R 1 It is a C1-C6 heteroalkyl group.

[0134] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 2 Hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d -NO2, -OR a -SR a C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C 2-6 alkenyl, C 2-6 The alkyl, cycloalkyl, or heterocycloalkyl group may be optionally substituted with one or more R groups. In some embodiments, R groups are... 2 Hydrogen, halogen, -CN, C 1-6 Alkyl, C1-C6 haloalkyl, C 2-6 Alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl group is optionally substituted with one or more R groups. In some embodiments, R groups are... 2 It can be H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH. In some implementations, R 2 For H. In some implementations, R 2 For F. In some implementations, R 2 For -CN. In some implementations, R 2 For Cl. In some implementations, R 2 For -CH3. In some implementations, R 2 For -CHF2. In some implementations, R 2 It is -C≡CH.

[0135] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 3 Hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d -NO2, -OR a -SR a C 1-6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 3 is hydrogen, halogen, -CN, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 3 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 3 is H, F, -CN, Cl, -CH3, -CHF2, or -CºCH. In some embodiments, R 3 is H. In some embodiments, R 3 is F. In some embodiments, R 3 is -CN. In some embodiments, R 3 is Cl. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CHF2. In some embodiments, R 4 is -CºCH.

[0136] In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (IIIa), R c is hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR d , a , -NO2, -OR a , -SR 1-6 , C 2-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 4 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 1-6 is hydrogen, halogen, -CN, C 2-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 4 alkenyl, C 4 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, RH. In some embodiments, R 4 F. In some embodiments, R 4 -CN. In some embodiments, R 4 Cl. In some embodiments, R 4 -CH3. In some embodiments, R 4 -CHF2. In some embodiments, R 4 -CºCH.

[0137] In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (IIIa), R 7 is hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 7 is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R 7 H, F, -CH3, or . In some embodiments, R 7 is H. In some embodiments, R 7 is F. In some embodiments, R 7 is -CH3. In some embodiments, R 7 .

[0138] In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (IIIa), R 7’ is hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 7’ is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R 7’ H, F, -CH3, or​ In some embodiments, R 7’ is H. In some embodiments, R 7’ is F. In some embodiments, R 7’ is -CH3. In some embodiments, R 7’ is .

[0139] In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), R 7 and R 7’ together form oxo. In some embodiments, R 7 and R 7’ together with the atom to which they are attached form a cycloalkyl, which is optionally substituted with one or more R.

[0140] In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), R 7N is hydrogen, -CN, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 7N is hydrogen or C 1-6 alkyl, and wherein alkyl is optionally substituted with one or more R. In some embodiments, R 7N is hydrogen. In some embodiments, R 7N is C 1-6 alkyl. In some embodiments, R 7N is C 1-6 alkyl, and wherein alkyl is optionally substituted with one or more R.

[0141] In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), R 9 is hydrogen, halogen, -CN, -OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 9 is hydrogen, halogen, C 1-6alkyl or cycloalkyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R 9 is H, F, -CH3, or In some embodiments, R 9 is H. In some embodiments, R 9 is F. In some embodiments, R 9 is -CH3. In some embodiments, R 9 is .

[0142] In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), R 9’ is hydrogen, halogen, -CN, -OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R 9’ is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R 9’ is H, F, -CH3, or In some embodiments, R 9’ is H. In some embodiments, R 9’ is F. In some embodiments, R 9’ is -CH3. In some embodiments, R 9’ is .

[0143] In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), R 9 and R 9’ together form oxo. In some embodiments, R 9 and R 9’ together with the atoms to which they are attached form a cycloalkyl, optionally substituted with one or more R.

[0144] In some embodiments of the compound of Formula (I), (II), (III), (Ila), or (Ilia), R 9N is hydrogen, -CN, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 2-6 In some embodiments, R 9N is hydrogen or C 1-6 alkyl, and wherein alkyl is optionally substituted with one or more R 9N In some embodiments, R 9N is hydrogen. In some embodiments, R 1-6 is C 9N alkyl. In some embodiments, R 1-6 is C 8 In some embodiments, R a is selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R b , -OC(=O)OR c , -OC(=O)NR d R a , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R c , -S(=O)2NR d R b , -S(=O)(=NR b )R c , -NR d R b , -NR c C(=O)NR d R b , -NR a C(=O)R b , -NR b C(=O)OR b , -NR a S(=O)2R b , -N=S(=O)(R a )2, -C(=O)R b , -C(=O)OR c , -C(=O)NR d R c , -P(=O)R d R

[0145] In some embodiments of the compound of Formula (I), (II), (III), (IIa), or (IIIa), R 8 is selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl and -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 8a Replacement. In some implementations, R 8 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl or -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 8a Replacement. In some implementations, R 8 It is a C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl or -C 1-6 Alkylene-heterocyclic alkyl, wherein the alkyl, alkylene, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each independently and optionally surrounded by one or more (e.g., 1-6) R 8a Replacement. In some implementations, R 8 for In some implementations, R 8 It is a heterocyclic alkyl or cycloalkyl group, wherein the cycloalkyl and heterocyclic alkyl groups are each independently and optionally surrounded by one or more (e.g., 1-6) R. 8a Replacement. In some implementations, R 8 It is a cycloalkyl group, which is optionally surrounded by one or more R8a Replacement. In some implementations, R 8 It is a bicyclic cycloalkyl group, which is optionally separated by one or more R 8a Replacement. In some implementations, R 8 for In some implementations, R 8 It is a 4-6 member monocyclic cycloalkyl group, optionally separated by one or more R 8a Replacement. In some implementations, R 8 for , , , , , , , , , , , or In some implementations, R 8 It is a heterocyclic alkyl group, which is optionally surrounded by one or more R 8a Replacement. In some implementations, R 8 It is a heterocyclic alkyl group, which is optionally surrounded by one or more R 8a Replacement. In some implementations, R 8 It is a bicyclic heterocyclic alkyl group, which is optionally separated by one or more R 8a Replacement. In some implementations, R 8 It is a saturated ring. In some implementations, R 8 It is a partially saturated ring. In some implementations, R 8 for , , , , , or In some implementations, R 8 It is a 4-6 membered monocyclic heterocyclic alkyl group, optionally surrounded by one or more R 8a Replacement. In some implementations, R 8 for , , , , , , , , , , , , , , , , , , , or In some implementations, R 8 -C 1-6 alkylene-heterocyclic alkyl or -C 1-6 Alkylene-cycloalkylene, wherein the alkylene, cycloalkyl, and heterocycloalkyl groups are each independently and optionally separated by one or more R groups. 8a Replacement. In some implementations, R 8 for , , or .

[0146] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 8’ Independently hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl group is optionally each influenced by one or more R groups. 8a Replacement. In some implementations, R 8’ Hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein the alkyl and heteroalkyl are each optionally marked with one or more R 8a replace.

[0147] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 8N Selected from -CN, -NO2, -OC(=O)R a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c Rd -P(=O)R c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl and -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 8a Replacement. In some implementations, R 8N C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl or -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more (e.g., 1-6) R groups. 8a Replacement. In some implementations, R 8N It is a C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl or -C 1-6 Alkylene-heterocyclic alkyl, wherein the alkyl, alkylene, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each independently and optionally formed by one or more (e.g., 1-6) R. 8a Replacement. In some implementations, R 8N for In some implementations, R 8N It is a heterocyclic alkyl or cycloalkyl group, wherein the cycloalkyl and heterocyclic alkyl groups are each independently and optionally formed by one or more R groups. 8aReplacement. In some implementations, R 8N It is a cycloalkyl group, which is optionally surrounded by one or more R 8a Replacement. In some implementations, R 8N It is a bicyclic cycloalkyl group, which is optionally separated by one or more R 8a Replacement. In some implementations, R 8N for In some implementations, R 8N It is a 4-6 member monocyclic cycloalkyl group, optionally separated by one or more R 8a Replacement. In some implementations, R 8N for , , , , , , , , , , , or .

[0148] In some implementation schemes, R 8N It is a heterocyclic alkyl group, which is optionally surrounded by one or more R 8a Replacement. In some implementations, R 8N It is a bicyclic heterocyclic alkyl group, which is optionally separated by one or more R 8a Replacement. In some implementations, R 8N for , , , , , or In some implementations, R 8N It is a 4-6 bicyclic heterocyclic alkyl group, which is optionally divided by one or more R 8a Replacement. In some implementations, R 8N for , , , , , , , , , , , , , , , or In some implementations, R 8N -C 1-6 alkylene-heterocyclic alkyl or -C 1-6 Alkylene-cycloalkylene, wherein the alkylene, cycloalkyl, and heterocycloalkyl groups are each independently and optionally separated by one or more R groups. 8a Replacement. In some implementations, R 8N for , , or .

[0149] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 8a Selected from halogens, -CN, -NO2, -OH, oxo, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) b )R b -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -N=S(=O)(R b )2、-C(=O)R a -C(=O)OR b -C(=O)NR c R d -P(=O)R c R dThe group comprises C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is optionally and independently substituted by one or more R. In some embodiments, R... 8a Independently selected from halogens, -OH, -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R.

[0150] In some embodiments of compounds of formula (I), (II), (III), (IIa), or (IIIa), ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, ring A is cycloalkyl. In some embodiments, ring A is heterocycloalkyl. In some embodiments, ring A is aryl. In some embodiments, ring A is heteroaryl. In some embodiments, ring A is bicyclic. In some embodiments, ring A is a 5-6 membered ring. In some embodiments, ring A is a 6-membered ring. In some embodiments, ring A is substituted at least at the para position.

[0151] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), for ;

[0152] Y 1 For N, C or CR Y1 ;

[0153] Y 2 For O, S, N, NR Y2N CR Y2 or CR Y2 R Y2’ ;

[0154] Y 3 For O, S, N, NR Y3N CR Y3 or CR Y3 R Y3’ ;

[0155] Y 4 For O, NR Y4N CR Y4 or CR Y4 R Y4’ ;

[0156] Y 5 For O, S, N, NR Y5N CR Y5 or CR Y5 R Y5’ ;

[0157] Y 6 For O, S, N, NR Y6N CR Y6 or CR Y6 R Y6’ ;

[0158] R Y1 R Y2 R Y2’ R Y3 R Y3’ R Y4 R Y4’ R Y5 R Y5’ R Y6 and R Y6’ Each is independently selected from hydrogen and R 10 ;

[0159] R Y2N R Y3N R Y4N R Y5N and R Y6N Each is independently selected from -CN, -NO2, and -OC(=O)R. a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d -P(=O)R c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C1-6 Heteroalkyl-aryl and -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 10a replace.

[0160] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), Y 1 For N, C or CR Y1 In some implementation schemes, Y 1 For N. In some implementations, Y 1 For C or CR Y1 In some implementation schemes, Y 1 For C. In some implementations, Y 1 For CR Y1 .

[0161] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), Y 2 For O, S, N, NR Y2N CR Y2 or CR Y2 R Y2’ In some implementation schemes, Y 2 For N or NR Y2N In some implementation schemes, Y 2 For CR Y2 or CR Y2 R Y2’ In some implementation schemes, Y 2 For O. In some implementations, Y 2 For S. In some implementations, Y 2 For N. In some implementations, Y 2 For NR Y2N In some implementation schemes, Y 2 For CR Y2 In some implementation schemes, Y 2 For CR Y2 R Y2’ .

[0162] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), Y 3 For O, S, N, NR Y3N CR Y3 or CR Y3 R Y3’ In some implementation schemes, Y 3For N or NR Y3N In some implementation schemes, Y 3 For CR Y3 or CR Y3 R Y3’ In some implementation schemes, Y 3 For O. In some implementations, Y 3 For S. In some implementations, Y 3 For N. In some implementations, Y 3 For NR Y3N In some implementation schemes, Y 3 For CR Y3 In some implementation schemes, Y 3 For CR Y3 R Y3’ .

[0163] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), Y 4 For O, NR Y4N CR Y4 or CR Y4 R Y4’ In some implementation schemes, Y 4 For O. In some implementations, Y 4 For NR Y4N In some implementation schemes, Y 4 For CR Y4 or CR Y4 R Y4’ In some implementation schemes, Y 4 For CR Y4 In some implementation schemes, Y 4 For CR Y4 R Y4’ .

[0164] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), Y 5 For O, S, N, NR Y5N CR Y5 or CR Y5 R Y5’ In some implementation schemes, Y 5 For N or NR Y5N In some implementation schemes, Y 5 For CR Y5 or CR Y5 R Y5’ In some implementation schemes, Y 5 For O. In some implementations, Y 5For S. In some implementations, Y 5 For N. In some implementations, Y 5 For NR Y5N In some implementation schemes, Y 5 For CR Y5 In some implementation schemes, Y 5 For CR Y5 R Y5’ .

[0165] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), Y 6 For O, S, N, NR Y6N CR Y6 or CR Y6 R Y6’ In some implementation schemes, Y 6 For N or NR Y6N In some implementation schemes, Y 6 For CR Y6 or CR Y6 R Y6’ In some implementation schemes, Y 6 For O. In some implementations, Y 6 For S. In some implementations, Y 6 For N. In some implementations, Y 6 For NR Y6N In some implementation schemes, Y 6 For CR Y6 In some implementation schemes, Y 6 For CR Y6 R Y6’ .

[0166] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R Y1 R Y2 R Y2’ R Y3 R Y3’ R Y4 R Y4’ R Y5 R Y5’ R Y6 and R Y6’ Each is independently selected from hydrogen and R 10 .

[0167] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R Y1 R Y2 RY2’ R Y3 R Y3’ R Y5 R Y5’ R Y6 and R Y6 Each is hydrogen. In some implementations, each R... Y1 R Y2 R Y2’ R Y3 R Y3’ R Y4 R Y4’ R Y5 R Y5’ R Y6 and R Y6’ Each is R 10 In some implementations, R Y1 R Y2 R Y2’ R Y3 R Y3’ R Y5 R Y5’ R Y6 and R Y6’ Each can be hydrogen, OH, or halogen independently.

[0168] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R Y4 and R Y4’ Each is independently hydrogen, -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) b )R b -C(=O)R a C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally and independently bound by one or more R groups. 10a Replacement. In some implementations, R Y4’ It is hydrogen. In some implementations, R Y4 is -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) b )R b -C(=O)R a C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently and optionally formed by one or more R10a Replacement. In some implementations, R Y4N is -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) b )R b -C(=O)R a C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each optionally and independently bound by one or more R groups. 10a replace.

[0169] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), for , , , , , or Where n is 1, 2, 3, 4, 5, or 6. In some implementations, for , , , , , , , , , , or .

[0170] In some implementation schemes, for , or In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for .

[0171] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R Y2N R Y3N R Y4N R Y5N and R Y6NIndependently selected from -CN, -NO2, -OC(=O)R a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d -P(=O)R c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl and -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 10a Replacement. In some implementations, R Y2N R Y3N R Y4N R Y5N and R Y6N Independently selected from -S(=O)R a or -S(=O)2R a In some implementations, R Y4N -S(=O)R a or -S(=O)2R a In some implementations, R Y4N -S(=O)R a In some implementations, R Y4N is -S(=O)2R a In some implementations, R Y4N -S(=O)2NR c R d .

[0172] In some implementation schemes, R Y4NIt is -S(=O)2CH3, -CH2CH2S(=O)2CH3, -S(=O)2CHF2, -S(=O)2CH(CH3)2, -S(=O)2CH2CH2OH, -S(=O)(=NH)CH3 or -S(=O)2NHCH3, , , , , , , , , , , , , , , , , , , , , , or .

[0173] In some implementation schemes, R Y4N For -S(=O)2CH3, -S(=O)2CHF2, -S(=O)2CH(CH3)2, , , , , or In some implementations, R Y4N For -S(=O)2CH3 or .

[0174] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 10 Independently selected from halogens, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -P(=O)R c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR)b )R b -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -N=S(=O)(R b )2、-C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently and optionally formed by one or more R groups. 10a Replacement. In some implementations, the two Rs 10 Together they form an oxygen atom. In some implementations, R 10 Independently selected from halogens, -OH, -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) b )R b -C(=O)R a C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally formed by one or more R 10a Replacement. In some implementations, R 10 It is a halogen. In some implementations, R 10 For F. In some implementations, R 10 For F or OH. In some embodiments, R 10 For -OH. In some implementations, R 10 is -S(=O)2R a -S(=O)2NR c R d or -S(=O)(=NR) b )R b In some implementations, at least one R 10 is -S(=O)2Ra -S(=O)2NR c R d or -S(=O)(=NR) b )R b In some implementations, R 10 is -S(=O)2R a In some implementations, R 10 -S(=O)2NR c R d In some implementations, R 10 -S(=O)(=NR) b )R b In some implementations, R 10 It is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally separated by one or more R 10a Replacement. In some implementations, R 10 It is a heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally surrounded by one or more R 10a Replacement. In some implementations, at least one R 10 For -S(=O)2CH3, -S(=O)2CH(CH3)2, , , -S(=O)2NH2 or -S(=O)2NHCH3. In some embodiments, at least one R 10 for , or In some implementations, R 10 For -S(=O)2CH3. In some implementations, R 10 It is -S(=O)2CH(CH3)2.

[0175] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R 10a Selected from halogens, -CN, -NO2, -OH, oxo, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) b )R b-NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -N=S(=O)(R b )2、-C(=O)R a -C(=O)OR b -C(=O)NR c R d -P(=O)R c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted by one or more R.

[0176] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R a The alkyl group is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a C1-C6 alkylene group (cycloalkyl), a C1-C6 alkylene group (heterocycloalkyl), a C1-C6 alkylene group (aryl), or a C1-C6 alkylene group (heteroaryl), wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally substituted by one or more R. In some embodiments, R is... a It is a C1-C6 alkyl group.

[0177] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R bIndependently, R is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted by one or more R. In some embodiments, R b It is a C1-C6 alkyl group. In some embodiments, R b It is hydrogen.

[0178] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R c The R is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted by one or more R. In some embodiments, R c It is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more R. In some embodiments, R c It is hydrogen. In some implementations, R c It is a C1-C6 alkyl group.

[0179] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with one or more R. In some embodiments, R cThe R is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted by one or more R. In some embodiments, R d It is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more R. In some embodiments, R d It is hydrogen. In some implementations, R d It is a C1-C6 alkyl group.

[0180] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups, which are optionally substituted with one or more R atoms.

[0181] In some embodiments of compounds of formula (I), (II), (III), (IIa) or (IIIa), R is a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2 -N=S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R is a halogen. In some embodiments, R is a C1-C3 alkyl. In some embodiments, R is a C3-C6 cycloalkyl. In some embodiments, two Rs on the same atom form an oxo group.

[0182] In some embodiments of compounds of formula (I), (II), (III), (IIa), or (IIIa), n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0183] Non-limiting examples of the compounds described herein are the compounds shown in Table 1 and their pharmaceutically acceptable salts. In some embodiments, the compounds are selected from Table 1.

[0184] Table 1. Exemplary Compounds of this Disclosure

[0185]

[0186]

[0187]

[0188]

[0189]

[0190] Unless otherwise stated, in this disclosure, the solid wedge line ( ) and virtual wedge line ( The bond, represented by a solid line, is used to indicate the absolute configuration of the chiral center; ) and dashed lines ( The bond indicated by ) is used to indicate the relative configuration of the chiral center; the bond at the chiral center ( This indicates that the corresponding compound is racemic at the chiral center; the bond at the chiral center ( () indicates that the corresponding compound is chiral pure, but its absolute configuration has not yet been determined.

[0191] Other non-limiting examples of the compounds described herein are the compounds listed in Table 2 and their pharmaceutically acceptable salts. In some embodiments, the compounds are selected from Table 2.

[0192] Table 2. Exemplary Compounds of this Disclosure

[0193]

[0194]

[0195]

[0196]

[0197]

[0198] Unless otherwise stated, in this disclosure, the solid wedge line ( ) and virtual wedge line ( The bond, represented by a solid line, is used to indicate the absolute configuration of the chiral center; ) and dashed lines ( The bond represented by ) is used to indicate the relative configuration of the chiral center; the bond on the chiral center ( This indicates that the corresponding compound is racemic at the chiral center; the bond at the chiral center ( () indicates that the corresponding compound is chiral pure, but its absolute configuration has not yet been determined.

[0199] Other forms of the compounds disclosed herein

[0200] isomers / stereoisomers

[0201] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis, syn, zusammen(Z)), trans (trans, anti, entgegen(E)) isomers and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, and corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as separate stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers possess different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized for separation. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are subsequently recovered by any practical method that does not lead to racemization.

[0202] isotopically enriched compounds

[0203] Unless otherwise indicated, the compounds described herein may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium may provide some therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds for studying in vivo drug elimination and metabolic pathways.

[0204] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes selected from deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from 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, 131 I, and 125I. In some embodiments, the abundance of enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0205] In some embodiments, the compound is deuterated at at least one position. In some embodiments, some or all of the compounds disclosed herein are used. 1 H atoms are 2 H atom substitution.

[0206] Methods for synthesizing deuterium-containing compounds are known in the art, and by way of non-limiting example only, include the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997 and the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using various methods, as described in the following literature: Dean, Dennis C.; Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0207] pharmaceutically acceptable salts

[0208] In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0209] In some embodiments, the compounds described herein have acidic or basic groups, and thus can react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final separation and purification of the compounds disclosed herein, or by reacting the purified compounds in their free form with a suitable acid or base and separating the resulting salts.

[0210] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases, including acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconate, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-heptanoates, glycerophosphates, glycolates, hemisulfates, heptasulfates, heptasulfates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0211] Furthermore, the compounds described herein can be prepared into pharmaceutically acceptable salts by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, etc. Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (e.g., oxalic acid), while not pharmaceutically acceptable on their own, may be used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0212] In some embodiments, the compounds comprising free acid groups described herein react with suitable bases, such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations, or with ammonia or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include bases or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4, etc.

[0213] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization yields products soluble or dispersible in water or oil.

[0214] tautomers

[0215] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0216] Dosage

[0217] In some embodiments, a composition comprising the compounds described herein is administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or disorder in an amount sufficient to cure or at least partially alleviate at least one symptom of the disease or disorder. The effective amount for this purpose depends on the severity and course of the disease or condition, prior treatments, the patient's health status, weight, and response to medication, as well as the judgment of the attending physician.

[0218] Application route

[0219] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0220] Pharmaceutical Compositions / Formulations

[0221] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to an individual in need. In some embodiments, the compounds described herein are administered to animals.

[0222] On the other hand, this document provides pharmaceutical compositions comprising the compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, the following references: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the contents of which are incorporated herein by reference.

[0223] Treatment

[0224] Cyclin-dependent kinases (CDKs) play a crucial role in regulating cell division and proliferation. CDKs are heterodimers of serine / threonine protein kinases involved in cell cycle and transcription (cell cycle CDKs and transcription CDKs). The functionality of CDKs is determined by their specific interactions with regulatory proteins (cyclins), which form heterodimerized complexes that act as regulators of cellular processes such as cell cycle progression and proliferation. Uncontrolled proliferation is synonymous with cancer stemming from problems in cell cycle regulation.

[0225] It is estimated that there are 20 CDKs and 29 cyclins in the human proteome. CDKs commonly associated with cell cycle regulation include CDK1, CDK2, CDK4, and CDK6. CDKs involved in transcriptional regulation include CDK7, CDK8, CDK9, and CDK10. Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, and cyclin D / CDK6 are important regulators of cell cycle progression. Overexpression of CDK2 is associated with abnormal cell cycle regulation. CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib have emerged as candidates in clinical trials for breast cancer and other cancers; palbociclib and abemaciclib have been approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. The cyclin E / CDK2 complex has been studied to play a crucial role in the regulation of G1 / S transition, histone biosynthesis, and centrosome replication. Cyclin E (a regulatory cyclin of CDK2) is commonly amplified in cancer, and overexpression of cyclin E2 (CCNE2) is associated with endocrine resistance in breast cancer cells. Inhibition of CDK2 has been shown to restore tamoxifen-resistant and CCNE2-overexpressing cells' sensitivity to tamoxifen / CDK4 inhibitors. Furthermore, cyclin E overexpression contributes to trastuzumab resistance in HER2+ breast cancer and is known to play a role in basal-like and triple-negative breast cancer (TNBC), in addition to inflammatory breast cancer.

[0226] The compounds described herein can be used to prepare medicaments for the prevention or treatment of diseases or conditions. In some embodiments, the compounds described herein are used in methods of modulating an individual's cell cycle-dependent protein kinase (CDK). In some embodiments, the compounds described herein are used in methods of inhibiting an individual's cell cycle-dependent protein kinase (CDK). In some embodiments, the compounds described herein are used in methods of treating an individual with a disease or disorder related to cell cycle-dependent protein kinase (CDK). In some embodiments, the compounds described herein are used in methods of treating an individual with a disease or disorder related to the regulation of cell cycle-dependent protein kinase (CDK). Furthermore, methods for modulating, inhibiting, or treating the diseases or conditions described herein in an individual requiring such treatment involve administering a pharmaceutical composition of a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0227] In some implementations, the CDK is CDK2. In some implementations, the CDK is CDK4. In some implementations, the CDK is CDK6.

[0228] If the patient’s condition does not improve, the compound may be administered long-term, i.e., for an extended period of time (including the entire duration of the patient’s life), in accordance with the doctor’s judgment, to improve or otherwise control or limit the symptoms of the patient’s disease or ailment.

[0229] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the dose or frequency, or both, may be reduced based on symptoms until the improved disease, disorder, or condition is maintained at a level that allows for better management. However, patients may require long-term intermittent treatment due to any recurrence of symptoms.

[0230] The amount of the specified active agent corresponding to this quantity will vary depending on factors such as the specific compound, the disease or condition and its severity, and the identity of the individual or subject requiring treatment (e.g., weight). However, it can still be determined in a manner recognized in the art based on the specific circumstances surrounding the case, including, for example, the specific active agent applied, the route of administration, the condition being treated, and the individual or subject being treated. Generally, however, the dosage for adult treatment will typically range from about 0.01 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day.

[0231] In one aspect, this disclosure provides a method for modulating cell cycle-dependent kinases (CDKs) in an individual, comprising administering to the individual a compound described herein or a pharmaceutically acceptable salt thereof.

[0232] In one aspect, this disclosure provides a method for inhibiting the activity of cell cycle-dependent kinases (CDKs) in an individual, comprising administering to the individual a compound described herein or a pharmaceutically acceptable salt thereof.

[0233] In one aspect, this disclosure provides a method for treating an individual in need of a disease or disorder related to cyclin-dependent kinases (CDKs), comprising administering to the individual a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the individual has cancer.

[0234] In one aspect, this disclosure provides a method for treating an individual with a disease or disorder related to CDK regulation, comprising administering to the individual a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the disease or disorder is cancer.

[0235] In one aspect, this disclosure provides a method of treating cancer in an individual, comprising administering to the individual in need an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0236] In one aspect, this disclosure provides a method of treating cancer in an individual, comprising administering to the individual in need a quantity of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloid leukemia (MM).

[0237] In some embodiments, the cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, or skin cancer; lymphoblastic hematologic malignancies; myeloid hematologic malignancies; follicular thyroid carcinoma; mesenchymal tumors; central or peripheral nervous system tumors; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; follicular thyroid carcinoma; or Kaposi's sarcoma. In some embodiments, the cancer treated by the methods of this disclosure is breast cancer. In some embodiments, the cancer treated by the methods of this disclosure is triple-negative breast cancer (TNBC). In some embodiments, the cancer is pRb+ breast cancer or hormone receptor (HR)-positive (e.g., estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or ER+PR+), HER2 / neu-negative cancer. In some embodiments, the cancer is advanced, metastatic, or recurrent breast cancer.

[0238] In some embodiments, the patient or patient group treated with the pharmaceutical composition of this disclosure has a solid tumor. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, the solid tumor is breast cancer.

[0239] Specific examples of cancers that this disclosure can prevent and / or treat include, but are not limited to, the following: kidney cancer, renal cell carcinoma, glioblastoma multiforme, metastatic breast cancer; breast cancer; breast sarcoma; neurofibroma; neurofibromatosis; pediatric oncology; neuroblastoma; malignant melanoma; epidermal cancer; leukemia including but not limited to acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia such as myeloid, promyelocytic, myelomonocytic, monocytic, erythroleukemia, and myelodysplastic syndrome; chronic leukemia such as, but not limited to, chronic myeloid (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; polycythemia vera; lymphoma such as, but not limited to, Hodgkin's disease and non-Hodgkin's disease; and multiple myeloma such as, but not limited to, smoldering multiple myeloma. Myeloma, non-secretory myeloma, osteosclerosing myeloma, plasmacytosis, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcoma such as, but not limited to, osteosarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced osteosarcoma, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma. (e.g., periosteal sarcoma, soft tissue sarcoma, angiosarcoma, fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, schwannoma; rhabdomyosarcoma and synovial sarcoma; brain tumors such as, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, oligodendroglioma, non-glioma, acoustic neuroma, craniopharyngioma, medulloblastoma, meningioma, pineal cell tumor, pinealoblastoma and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, ductal carcinoma, medullary carcinoma, mucinous carcinoma, tubular breast cancer.) Papillary breast cancer, Paget's disease (including juvenile Paget's disease), and inflammatory breast cancer; adrenal cancer, such as, but not limited to, pheochromocytoma and adrenocortical tumor; thyroid cancer, such as, but not limited to, papillary or follicular thyroid cancer, medullary thyroid carcinoma, and anaplastic thyroid cancer; pancreatic cancer, such as, but not limited to, insulinoma, gastrinoma, glucagonoma, VIP tumor, somatostatin-secreting tumors, and carcinoid or islet cell tumors;Pituitary cancers such as, but not limited to, Cushing's disease, prolactin-secreting tumors, acromegaly, and diabetes insipidus. Insipidus); eye cancers such as, but not limited to, ocular melanomas such as iris melanoma, choroidal melanoma, ciliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancers such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as, but not limited to, squamous cell carcinoma and adenocarcinoma; uterine cancers such as, but not limited to, endometrial cancer and uterine sarcoma; ovarian cancers such as, but not limited to, ovarian epithelial carcinoma, junctional tumor, germ cell tumor, and stromal tumor; esophageal cancers such as, but not limited to, squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; gastric cancers such as, but not limited to, adenocarcinoma, mycosis fungoides, ulcerative gastrointestinal cancer, etc. Superficial, diffuse, and malignant lymphomas, liposarcomas, fibrosarcomas, and carcinosarcomas; colon cancer; colorectal cancer, KRAS-mutant colon cancer; colon cancer; rectal cancer; liver cancer, including but not limited to hepatocellular carcinoma and hepatoblastoma; gallbladder cancer, including adenocarcinoma; bile duct cancer, including but not limited to papillary, nodular, and diffuse types; lung cancer, including KRAS-mutant non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; lung cancer; testicular cancer, including but not limited to germ cell tumors, seminoma, anaplastic, classic (typical), spermatoma, non-seminomatous carcinoma, embryonal carcinoma, teratoma, choriocarcinoma (yolk sac tumor); prostate cancer, including but not limited to non-androgen-dependent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penile cancer. Cancers include: oral cancers such as, but not limited to, squamous cell carcinoma; basal carcinoma; salivary gland cancers such as, but not limited to, adenocarcinoma, mucoepidermoid adenocarcinoma, and adenoid cystic carcinoma; pharyngeal cancers such as, but not limited to, squamous cell carcinoma and verrucous carcinoma; skin cancers such as, but not limited to, basal cell carcinoma, squamous cell carcinoma, melanoma, superficial diffuse melanoma, nodular melanoma, lentigines malignant melanoma, acral lentigines melanoma; renal cancers such as, but not limited to, renal cell carcinoma, adenocarcinoma, adrenal adenoid tumor, fibrosarcoma, transitional cell carcinoma (renal pelvis and / or ureter); renal cancer; nephroblastoma; bladder cancers such as, but not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, and carcinosarcoma. In addition, cancers include myxosarcoma, osteoblastic sarcoma, endothelial sarcoma, lymphangioendothelial sarcoma, mesothelioma, synovial malformation, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchial protocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma. ;

[0240] In one aspect, this disclosure provides a method of treating an individual with cancer, comprising administering to the individual in need an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0241] Example

[0242] The following examples are provided for illustration, but do not limit the scope of the claimed disclosure. The following examples further illustrate the disclosure, but should not be construed as limiting its scope in any way.

[0243] The following synthetic schemes are provided for illustrative purposes and not for limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to them. It should also be understood that those skilled in the art will be able to prepare them by using suitable starting materials and modifying the synthetic route as needed in a similar manner as described below. Generally, starting materials and reagents are available from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0244] The compounds and salts described herein can be synthesized according to one or more exemplary schemes and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods known in the art. These schemes are not limited to the compounds or any specific substituents listed in the examples, which are used for illustrative purposes. Although various steps are described and depicted in the synthetic schemes below, these steps may in some cases be performed in a different order than shown below. Numbers or R groups in each scheme do not necessarily correspond to the claims or other schemes or the tables herein.

[0245] Example

[0246] Example A1: Synthesis of Intermediate 1

[0247]

[0248] Step 1: Preparation of Int 1-1

[0249] To a solution of 1-(methanesulfonyl)piperidin-4-amine (2.98 g, 16.72 mmol) and 2-chlorothiazolium (2.00 g, 16.72 mmol) in dioxane (100 mL), Ruphos (1.56 g, 3.34 mmol), Pd₂(dba)₃ (1.53 g, 1.67 mmol), and Cs₂CO₃ (16.34 g, 50.16 mmol) were added. The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO₂, ethyl acetate / petroleum ether = 100 / 1-3 / 1) to give Int 1-1 (2.4 g, 54.9% yield, 82% purity). LCMS: 262.1 [M+H] + ;

[0250] Step 2: Preparation of Intermediate 1

[0251] Br2 (457 mg, 1.91 mmol) was added to a solution of Int 1-1 (500 mg, 1.91 mmol) in AcOH (10 mL), and the resulting mixture was stirred at 25 °C for 15 min under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to obtain a residue, and the pH was adjusted to 7 with NaHCO3 (aqueous solution). The reaction was then quenched by adding H2O (30 mL). The resulting mixture was extracted with EA (10 mL × 3), and the combined organic layers were concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 50 / 1–10 / 1) to give the title compound (300 mg). LCMS: 340.0 / 342.0 [M+H] + ;

[0252] Example A2: Synthesis of Intermediate 2

[0253]

[0254] Intermediate 2 was synthesized using (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol as a substrate, according to the method in Example A1. LCMS: 279.1 / 281.1 [M+H] + ;

[0255] Example A3: Synthesis of Compound 1

[0256] Step 1: Preparation of Compound 1-1

[0257]

[0258] CDI (17.33 g, 106.92 mmol) was added to a solution of 3-bromophenyl-1,2-diamine (10 g, 53.46 mmol) in DCM (15 mL), and the solution was stirred overnight at 50 °C. Upon completion, the reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product.

[0259] Step 2: Preparation of compounds 1-2

[0260] A solution of compound 1-1 (9 g, 42.25 mmol) in POCl3 (30 mL) was stirred at room temperature for 2 hours. The reaction mixture was quenched with NaHCO3 (aq, 20 mL) and extracted with EA (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 50 / 1–10 / 1) to give compound 1-2 (1.5 g, 15.3% yield). LCMS: 230.9 / 232.9 [M+H] + ;

[0261] Step 3: Preparation of compounds 1-3

[0262] Add ( ) to a solution of compound 1-2 (1 g, 4.31 mmol) in MeSO3H (15 mL) R 3-Fluoropyrrolidine (1.08 g, 8.62 mmol). The resulting mixture was heated at 150 °C. o Stirred at C for 0.5 hours. Quench the reaction mixture with water (20 mL) and extract with EA (20 mL × 3). Wash the combined organic phases with brine, dry with anhydrous Na2SO4, concentrate under reduced pressure, and give the residue, which is purified by silica gel column chromatography (PE / EA = 50 / 1-3 / 1) to give compounds 1-3 (800 mg, 65.3% yield). LCMS: 284.0 / 286.0 [M+H] + ;

[0263] Step 4: Preparation of compounds 1-4

[0264] Pd(dppf)Cl2 (52 mg, 0.07 mmol), KOAc (103 mg, 1.05 mmol), B2PIN2 (1.08 g, 8.62 mmol), and K2CO3 (145 mg, 1.05 mmol) were added to a solution of compounds 1-3 (100 mg, 0.35 mmol) in 1,4-dioxane (10 mL). The solution was then incubated at 100 mL. o Stir overnight. Quench the reaction mixture with water (20 mL) and extract with EA (20 mL × 3). Wash the combined organic phases with brine, dry with anhydrous Na₂SO₄, filter, concentrate under reduced pressure, and give the residue, which is purified by silica gel column chromatography (PE / EA = 50 / 1-1 / 1) to give compounds 1-4. LCMS: 250.1 [M+H] + ;

[0265] Step 5: Preparation of Compound 1

[0266] Intermediate 1 (60 mg, 0.29 mmol), Pd(dppf)Cl2 (42.40 mg, 0.058 mmol), and K2CO3 (120 mg, 0.87 mmol) were added to a solution of compounds 1-4 (87.5 mg, 0.35 mmol) in dioxane / H2O (6 ml / 3 ml). The solution was stirred overnight at 90 °C. The reaction mixture was filtered, quenched with water (20 mL), and extracted with EA (20 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by preparative-HPLC to give compound 1. LCMS: 465.3 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ 7.73 (s, 1H), 7.09 (dd, J = 7.5, 1.3 Hz, 1H), 7.02 (dd, J = 7.7, 1.3 Hz, 1H), 6.99-6.93 (m, 1H), 5.50-5.30 (m, 1H), 3.95-3.61 (m, 7H), 2.93 (td, J = 11.8,2.7 Hz, 2H), 2.83 (s, 3H), 2.39-2.26 (m, 2H), 2.22-2.11 (m, 2H), 1.68-1.53(m, 2H).

[0267] Following a similar method to that used for compound 1, the following compounds were prepared using the corresponding substrates.

[0268]

[0269] Example A4: Synthesis of Compound 3

[0270] Step 1: Preparation of compound 3-1

[0271]

[0272] Compound 3

[0273] Br2 (0.5 mL, 9.105 mmol) was added to a solution of 5-(1-methylpiperidin-4-yl)pyridine-2-amine (400 mg, 2.091 mmol) in HBr (6 mL, 0.136 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. NaNO2 (400 mg, 5.797 mmol) was added to H2O (20 mL), and the mixture was stirred at 0 °C for 20 min. The mixture was adjusted to pH = 9 with an aqueous solution of NaHCO3 to partition it between EtOAc (50 mL) and H2O (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give compound 3-1 (160 mg, 29.99%). LCMS: 255.0 [M+H] + ;

[0274] Step 2: Preparation of compound 3-3

[0275] To a solution of (5-bromothiazol-2-yl)carbamate tert-butyl ester (758.2 mg, 2.72 mmol) and compound 3-2 (850 mg, 2.47 mmol, prepared according to steps 1-4 of the synthesis of compound 1 in Example 1), K2CO3 (682.5 mg, 4.94 mmol) and Pd(dtbpf)Cl2 (161.44 mg, 0.25 mmol) were added. The reaction was stirred at 80 °C for 30 min. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to give compound 3-3 (208 mg, 20.23%). LCMS: 417.2 [M+H] + ;

[0276] Step 3: Preparation of compounds 3-4

[0277] To compound 3-3 TFA (4 mL, 0.744 mmol) was added to a solution of DCM (5 mL), and the reaction was stirred at rt for 2 hours. The mixture was adjusted to pH 9 with an aqueous NaHCO3 solution and extracted with a solvent of DCM / MeOH = 10:1 (100 mL × 5). The combined organic phases were washed with water and saturated NaCl solution, dried over Na2SO4, filtered, and concentrated to give compounds 3-4 (200 mg, 84.93%). LCMS: 317.0 [M+H] + ;

[0278] Step 4: Preparation of Compound 3

[0279] Compounds 3-1 (88.71 mg, 0.348 mmol), Cs₂CO₃ (226.77 mg, 0.696 mmol), Xantphos (40.27 mg, 0.070 mmol), and Pd₂(dba)₃ (31.87 mg, 0.035 mmol) were added to a solution of compound 3-4 (110 mg, 0.348 mmol) in dioxane (3 mL). The reaction was stirred overnight at 90 °C under N₂ atmosphere. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative-HPLC to give the title compound. LCMS: 491.3 [M+H] + ;1 H NMR (400 MHz, DMSO- d 6) δ 11.44 (s, 1H), 9.38 (s, 1H), 8.24 (d, J =2.2 Hz, 1H), 7.96 (s, 1H), 7.64 (dd, J = 8.6, 2.3 Hz, 1H), 7.18-7.14 (m, 3H),7.13-7.09 (m, 1H), 3.83-3.46 (m, 5H), 3.15-3.02 (m, 2H), 2.87-2.78 (m, 4H),2.08-1.94 (m, 5H), 1.90-1.77 (m, 2H), 1.40 (s, 3H).

[0280] Example A5: Synthesis of Compound 4

[0281]

[0282] The title compound was prepared using compounds 3-4 and 4-1 (synthesized according to step 1 in the synthesis of compound 3 in Example A3) as substrates, following a similar method to that used in the synthesis of compound 3 in Example A3. LCMS: 534.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.53 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.97(s, 1H), 7.67 (dd, J = 8.8, 2.6 Hz, 1H), 7.23-7.10 (m, 4H), 5.00 (s, 1H), 3.75 (t, J = 7.0 Hz, 2H), 3.69-3.36 (m, 4H), 2.78-2.43 (m, 1H), 2.43-2.33 (m,2H), 2.23 (s, 6H), 2.11-1.94 (m, 2H), 1.97 (t, J = 7.3 Hz, 2H), 1.39 (s, 3H).

[0283] Example A6: Synthesis of Compound 6

[0284]

[0285] Step 1: Preparation of Compound 6-1

[0286] A solution of TsCl (7.5 g, 39.177 mmol) in DCM (50 mL) was added dropwise to a solution of cyclopentadiol (5 g, 48.972 mmol) in pyridine (25 mL) and DCM (50 mL) at 0 °C. The solution was stirred at 25 °C for 2 hours. The solution was diluted with dichloromethane (100 mL) and water (100 mL). The organic layer was washed with 2 N hydrochloric acid (100 mL × 2) and brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under vacuum to give compound 6-1 (9.5 g, 75.7%). LCMS: 279.1 [M + Na] + ;

[0287] Step 2: Preparation of Compound 6-2

[0288] Compound 6-1 (7.5 g, 29.263 mmol) and 4-bromo-2 H -Indazole (4.8 g, 24.385 mmol) was added to a solution of Cs₂CO₃ (19.1 g, 58.526 mmol) in DMF (50 mL). The mixture was stirred at 90 °C under N₂ for 16 h. The reaction was quenched at 20 °C by adding water (500 mL), and the mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography (ISCO; 80 g SepaFlash silica gel rapid column, eluent: 0-50% ethyl acetate / petroleum ether gradient, 40 mL / min) to give compound 6-2 (1.3 g, 15.8%). LCMS: 281.1 / 283.1 [M+H] + ;

[0289] Step 3: Preparation of compound 6-3

[0290] DMSO (0.49 mL, 6.935 mmol) was added dropwise to a solution of oxaloyl chloride (0.59 mL, 6.935 mmol) in dichloromethane (10 mL) at -78 °C under a nitrogen atmosphere over 10 min. A solution of compound 6-2 (1.3 g, 4.623 mmol) in dichloromethane (20 mL) was then added, and the resulting solution was stirred at -78 °C for 45 min. DIEA (3.83 mL, 23.115 mmol) was then added over 5 min. The resulting mixture was stirred at -78 °C for 25 min, and then at room temperature for another 30 min. The reaction was quenched by adding 100 mL of aqueous NH4Cl solution. The organic layer was separated, washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (ISCO; 40 g SepaFlash silica gel column, eluent: 0-50% ethyl acetate / petroleum ether gradient, 35 mL / min) to give compound 6-3 (816 mg, 63.2%). LCMS: 279.0 / 281.0 [M+H] + ;

[0291] Step 4: Preparation of compound 6-4

[0292] Methylmagnesium bromide (8.77 mL, 8.771 mmol) was added dropwise to a solution of compound 6-3 (816 mg, 2.924 mmol) in THF (20 mL) at -60 °C. The solution was stirred at room temperature under N2 for 2 hours. The reaction mixture was quenched at 0 °C with saturated NH4Cl solution (20 mL) and diluted with EtOAc (100 mL). The organic phase was separated, washed with 100 mL (50 mL × 2) of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase column chromatography to give compound 6-4 (216 mg, 25.0%). LCMS: 295.1 / 297.1 [M+H] + ;

[0293] Step 5: Preparation of Compound 6-5

[0294] Pd(dppf)Cl2 (107 mg, 0.146 mmol) was added to a solution of compounds 6-4 (216 mg, 0.732 mmol), B2Pin2 (438.6 mg, 1.728 mmol), and KOAc (464.5 mg, 1.829 mmol) in DMSO (5 mL). The reaction mixture was stirred at 90 °C under N2 for 18 hours. The resulting mixture was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL × 3) and brine (50 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 6-5. LCMS: 343.2 [M+H] + ;

[0295] Step 6: Preparation of Compound 6

[0296] Compound 6-5 (128 mg, 0.374 mmol) and intermediate 1 were subjected to treatment. K₂CO₃ (103 mg, 0.748 mmol) and Pd(dppf)Cl₂ (54.7 mg, 0.075 mmol) were added to a solution of dioxane (3 mL) and H₂O (1 mL). The reaction mixture was stirred at 85 °C under N₂ for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL). The separated organic layer was washed with water (30 mL) and saturated brine (50 mL), and concentrated under reduced pressure to give the residue. The residue was purified by preparative-HPLC to give the title compound. LCMS: 476.2 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) δ 8.75 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.46(d, J = 8.6 Hz, 1H), 7.20 (dd, J = 8.6, 7.0 Hz, 1H), 6.96 (d, J= 6.9 Hz,1H), 5.18-5.06 (m, 1H), 5.03 (s, 1H), 3.79-3.68 (m, 1H), 3.55-3.47 (m, 2H),2.97-2.90 (m, 2H), 2.89 (s, 3H), 2.34-2.25 (m, 3H), 2.22-2.15 (m, 1H), 2.12-2.03 (m, 2H), 1.93-1.85 (m, 1H), 1.71-1.62 (m, 1H), 1.62-1.51 (m, 2H), 1.32(s, 3H).

[0297] Following a similar method to compound 6, the following compounds were prepared using the corresponding substrates.

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] Example A7: Synthesis of Compound 10

[0304]

[0305] Step 1: Preparation of Compound 10-1

[0306] Compound 10-1 was synthesized using tert-butyl 3-hydroxypyrrolidine-1-carboxylate as the starting substrate according to the aforementioned method. LCMS: 547.3 [M+H] + ;

[0307] Step 2: Preparation of compound 10-2

[0308] To a solution of compound 10⁻¹ (400.0 mg, 0.732 mmol) in dioxane (4 mL), HCl-dioxane (4 mL) was added. The mixture was stirred at rt for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 10⁻²; LCMS: 447.1 [M+H⁺] + ;

[0309] Step 2: Preparation of Compound 10

[0310] STAB (708.4 mg, 3.359 mmol) was added to a solution of compound 10⁻² (300 mg, 0.672 mmol), HCOH (0.04 mL, 1.343 mmol), and AcOH (0.19 mL, 3.359 mmol) in dichloromethane (8 mL) and MeOH (4 mL). The reaction was stirred at rt under N₂ for 1 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was analyzed by preparative HPLC (Waters 2767 / Qda, column: Pursuit XRs C18, 19.5 mm). 250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 20%-30%; retention time: 8-8.8 min (out of 17 min) to further purify the residue, yielding compound 10. LCMS: 461.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.7 (s, 1H), 7.9 (d, J = 7.2 Hz, 1H), 7.6 (s, 1H), 7.5 (d, J = 8.6 Hz, 1H), 7.2 (dd, J = 8.6, 7.0 Hz, 1H), 7.0 (d, J = 6.9 Hz, 1H), 5.3-5.1 (m, 1H), 3.8-3.7 (m, 1H), 3.5-3.5 (m, 2H), 3.0-2.9 (m, 2H), 2.9-2.9 (m, 2H), 2.9 (s,3H), 2.9-2.8 (m, 1H), 2.6-2.6 (m, 1H), 2.5-2.4 (m, 1H), 2.3 (s, 3H), 2.3-2.2(m, 1H), 2.1-2.0 (m, 2H), 1.6-1.5 (m, 2H).

[0311] Following a similar method to compound 10, the following compounds were prepared using the corresponding substrates.

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] Example A8: Synthesis of Compound 17

[0319]

[0320] Step 1: Preparation of Compound 17-1

[0321] DAST (0.85 mL, 6.449 mmol) was added to a solution of compound 6-3 (600 mg, 2.150 mmol) in DCM (15 mL) at 0 °C under N2. The mixture was stirred at rt under N2 for 1 h. The reaction mixture was partitioned between H2O (30 mL) and ethyl acetate (90 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 40 g SepaFlash@ silica gel column, eluent: 0-30% ethyl acetate / petroleum ether gradient@ 50 mL / min) to give compound 17-1. LCMS: 301.0 / 303.0 [M+H] + ; 1 HNMR: (400 MHz, DMSO) δ 8.52 (d, J = 0.8 Hz, 1H), 7.71-7.60 (m, 1H), 7.29(d, J = 7.1 Hz, 1H), 7.18 (dd, J = 8.6, 7.2 Hz, 1H), 5.33 (p, J = 7.5 Hz,1H), 2.93-2.69 (m, 2H), 2.49-2.36 (m, 2H), 2.36-2.14(m, 2H);

[0322] Step 2: Preparation of the title compound

[0323] Following a similar method described above, the title compound was synthesized using compound 17-1 as a substrate. LCMS: 464.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.8 (s, 1H), 8.0 (d, J= 7.2 Hz, 1H), 7.6(s, 1H), 7.5 (d, J = 8.8 Hz, 1H), 7.3-7.2 (m, 1H), 7.0 (d, J = 6.8 Hz, 1H), 5.3 (t, J = 7.7 Hz, 1H), 3.8-3.7 (m, 1H), 3.5-3.5 (m, 2H), 3.2-3.2 (m, 1H), 3.0-2.8 (m, 8H), 2.5-2.4 (m, 2H), 2.1-2.0 (m, 2H), 1.6-1.5 (m, 2H).

[0324] Following a similar method to compound 10, the following compounds were prepared using the corresponding substrates.

[0325]

[0326] Example A9: Synthesis of Compound 19

[0327]

[0328] Step 1: Preparation of Compound 19-1

[0329] Potassium carbonate (6.31 g, 45.7 mmol) and methyl cyclopent-1-ene-1-carboxylate (4.80 g, 38.1 mmol) were added to a solution of 4-bromo-2H-indazole (3.00 g, 15.2 mmol) in DMF (60 mL). The reaction was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 19-1. LCMS: 323.0 / 325.0 [M+H] + ;

[0330] Step 2: Preparation of Compound 19-2

[0331] Magnesium monobromide (13.5 mL, 0.278 mmol) was added dropwise to a solution of compound 19-1 (1.50 g, 4.64 mmol) in tetrahydrofuran (50 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 19-2. LCMS: 323.2 / 325.2 [M+H] + ;

[0332] Step 3: Preparation of the title compound

[0333] Following a similar method described above, the title compound was synthesized using compound 19-2 as a substrate. LCMS: 504.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.76 (s, 1H), 7.94-7.91 (m, 1H), 7.63 (s,1H), 7.46 (d, J = 8.4 Hz, 1H), 7.19-7.15 (m, 1H), 6.94 (d, J = 7.2 Hz, 1H),5.05-5.04 (m, 1H), 3.74-3.73 (m, 1H), 3.51 (d, J = 11.6 Hz, 3H), 2.97-2.89(m, 6H), 2.08 (d, J = 10.8 Hz, 3H), 1.95 (s, 3H), 1.68-1.66 (m, 2H), 1.57-1.55 (m, 2H), 1.05 (s, 3H), 0.94 (s, 3H).

[0334] Example A10: Synthesis of Compound 22

[0335]

[0336] Step 1: Preparation of Compound 22-1

[0337] Cs₂CO₃ (16.5 g, 50.761 mmol) was added to a solution of 4-bromo-2H-indazole (5 g, 25.381 mmol) and 2,2-dimethylethylene oxide (9.1 g, 126.904 mmol) in dioxane (100 mL). The mixture was stirred at 90 °C under N₂ for 2 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 22-1. LCMS: 269.1 / 270.8 [M+H] + ;

[0338] Step 2: Preparation of the title compound

[0339] Following a similar method described above, the title compound was synthesized using compound 22-1 as a substrate. LCMS: 450.1 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.56(s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 8.6, 7.0 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 4.85 (s, 1H), 4.36 (s, 2H), 3.81-3.67 (m, 1H), 3.51 (d, J =12.3 Hz, 2H), 2.94 (dd, J = 16.7, 6.0 Hz, 2H), 2.89 (s, 3H), 2.16-1.97 (m,2H), 1.56 (td, J = 13.8, 4.0 Hz, 2H), 1.12 (s, 6H).

[0340] Following a similar method to compound 22, the following compounds were prepared using the corresponding substrates.

[0341]

[0342] Example A11: Synthesis of Compound 39

[0343]

[0344] To a solution of 39-1 (20 mg, 0.040 mmol, synthesized according to the aforementioned method) and 2-bromoethane-1-ol (7.5 mg, 0.060 mmol) in DMF (1 mL), K₂CO₃ (16.7 mg, 0.121 mmol) and potassium iodide (0.7 mg, 0.004 mmol) were added. The mixture was stirred at 65 °C for 12 hours. The reaction mixture was filtered and analyzed by preparative HPLC (Gilson GX 281, column: Pursuit XRs 10 C18, 19). Purification was performed using a flow rate of 250 mm, 10 μm; mobile phase A: 0.1% FA / H₂O, B: ACN; flow rate: 25 mL / min; gradient: 17%–17%; retention time: 6.8–7.0 min (out of 16 min) to obtain the title compound. LCMS: 505.3 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 8.00 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.32 (d, J =8.5 Hz, 1H), 4.59 (t, J = 14.3 Hz, 1H), 3.87 (t, J = 5.4 Hz, 2H), 3.80-3.66(m, 3H), 3.60 (d, J = 11.9 Hz, 2H), 3.15-2.92 (m, 6H), 2.87 (s, 3H), 2.49(dd, J = 22.2, 11.1 Hz, 2H), 2.19 (s, 4H), 1.73-1.54 (m, 2H).

[0345] Following a similar method to compound 39, the following compounds were prepared using the corresponding substrates.

[0346]

[0347] Example A12: Synthesis of Compound 43

[0348]

[0349] Step 1: Preparation of Compound 43-1

[0350] Add 5-bromo- N -(1-(methanesulfonyl)piperidin-4-yl)thiazolyl-2-amine (767 mg, 2.25 mmol), Pd(dppf)Cl2 (330 mg, 0.451 mmol), and Cs2CO3 (2.20 g, 6.76 mmol). The reaction was stirred at 100 °C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The crude product was purified by rapid silica gel chromatography to give compound 43-1. LCMS: 378.1 [M+H] + ;

[0351] Step 2: Preparation of compound 43-2

[0352] POCl3 (426 mg, 2.78 mmol) was added to a solution of compound 43-1 (350 mg, 0.927 mmol) in DMF (3 mL). The mixture was stirred overnight at room temperature. The mixture was quenched with H2O (0.1 mL). The mixture was purified by reversed-phase HPLC (0.1% TFA) to give compound 43-2. ​​LCMS: 405.9 [M+H] + ;

[0353] Step 3: Preparation of the title compound

[0354] To a solution of compound 43-2 (100 mg, 0.247 mmol) in MeOH / DCE (1 mL / 1 mL), AcOH (6 drops), formaldehyde (75 mg, 0.740 mmol), and TiO(iPr)4 (140 mg, 0.493 mmol) were added. The mixture was stirred overnight at room temperature. Then, STAB (155 mg, 0.740 mmol) was added. The mixture was stirred overnight at room temperature. The analysis was performed by preparative HPLC (Waters 3767 / column: SunFire Sunfire C18, 19). 250 mm, 10 μm; mobile phase A: 0.1% FA / H₂O, B: ACN; flow rate: 20 mL / min; gradient: 30–31%; retention time: 8.5–9.5 min in 20 min) purify the mixture to give the title compound. LCMS: 513.2 [M+Na] + ; 1 H NMR (400 MHz, MeOD) δ8.49 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.21 (d, J = 7.2 Hz, 1H), 4.56-4.54 (m, 2H), 3.82-3.81 (M, 1H), 3.76-3.67 (m, 2H), 3.61-3.60 (m, 1H), 3.43-3.42 (m, 1H), 3.23-3.22 (m, 1H), 3.17-3.16 (m, 1H), 3.01-2.91 (m, 2H), 2.86 (s, 3H), 2.28-2.02 (m, 4H), 1.75-1.56 (m, 2H), 1.43(s, 3H).

[0355] Example A13: Synthesis of Compound 76

[0356]

[0357] Step 1: Preparation of Compound 76-1

[0358] Cs₂CO₃ (70.8 g, 217.297 mmol) was added to a solution of 2-amino-4-bromo-3-methylbenzoic acid (25 g, 108.648 mmol) and iodomethane (46.3 g, 325.945 mmol) in DMF (50 mL). The reaction mixture was stirred at rt under N₂ for 16 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 76-1 (15.7 g, 59.2%). LCMS: 244.09 / 245.9 [M+H] + ;

[0359] Step 2: Preparation of Compound 76-2

[0360] Sodium nitrite (4.9 g, 70.750 mmol) and H₂O (8 mL) were added to a solution of methyl compound 76-1 (15.7 g, 64.318 mmol) in HOAc (80 mL) at 0 °C. The reaction was stirred at rt under N₂ for 1 h. The mixture was adjusted to pH 9 with an aqueous solution of NaHCO₃. The mixture was diluted with water (300 mL) and extracted with ethyl acetate. The crude product was ground with ethyl acetate / petroleum ether = 10% at rt for 20 min to give compound 76-2 (7.6 g, 46.3%). LCMS: 255.0 / 257.0 [M+H] + ;

[0361] Step 3: Preparation of Compound 76-3

[0362] SEMCl (10.29 mL, 58.016 mmol) and DIEA (9.61 mL, 58.016 mmol) were added to a solution of compound 76-2 (7.4 g, 29.008 mmol) in DCM (50 mL). The reaction was stirred at rt under N2 for 16 h. The mixture was diluted with water (200 mL) and extracted with dichloromethane. The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 76-3; LCMS: 384.9 / 386.9 [M+H] + ;

[0363] Step 4: Preparation of compound 76-4

[0364] LiAlH4 (2.30 mL, 5.762 mmol) was added to a solution of compound 76-3 (3.7 g, 9.603 mmol) in THF (15 mL) at 0 °C. The reaction mixture was stirred at 0 °C under a N2 atmosphere for 30 min. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 76-4. LCMS: 357.3 / 359.0 [M + H] + ;

[0365] Step 5: Preparation of compound 76-5

[0366] To a solution of compound 76-4 (2.0 g, 5.598 mmol) in DCM (100 mL), manganese dioxide (4.9 g, 55.980 mmol) was added. The reaction mixture was stirred at rt under N2 for 16 hours. After the reaction was complete, the reaction mixture was filtered. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 76-5. LCMS: 355.3 / 357.0 [M+H] + ;

[0367] Step 6: Preparation of compound 76-6

[0368] DAST (3.12 mL, 23.642 mmol) was added to a solution of compound 76-5 (2 g, 5.629 mmol) in DCM (30 mL) at 0 °C. The reaction mixture was stirred at rt under N2 for 16 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 76-6. LCMS: 377.0 / 379.0 [M+H] + ;

[0369] Step 7: Preparation of Compound 76-7

[0370] TFA (5 mL, 0.318 mmol) was added to a solution of compound 76-6 (1.3 g, 3.446 mmol) in DCM (10 mL). The reaction mixture was stirred at rt for 2 hours. The combined organic layers were concentrated under reduced pressure to give compound 76-7. LCMS: 246.9 / 248.9 [M+H] + ;

[0371] Step 8: Preparation of the title compound

[0372] The title compound was synthesized using compound 76-7 as a substrate according to the aforementioned method. LCMS: 526.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.9 (s, 1H), 8.1 (d, J = 7.2 Hz, 1H), 7.7 (s,1H), 7.5-7.1 (m, 2H), 7.0 (d, J= 7.2 Hz, 1H), 5.2-5.1 (m, 1H), 5.0 (s, 1H), 3.8-3.7 (m, 1H), 3.6-3.5 (m, 2H), 2.9 (t, J = 10.4 Hz, 2H), 2.9 (s, 3H), 2.4-2.2 (m, 3H), 2.2 (dd, J = 13.3, 5.5 Hz, 1H), 2.1-2.0 (m, 2H), 1.9-1.9 (m,1H), 1.7-1.6 (m, 1H), 1.6-1.5 (m, 2H), 1.3 (s, 3H).

[0373] Following a similar method to compound 76, the following compounds were prepared using the corresponding substrates.

[0374]

[0375] Example A14: Synthesis of Compound 108

[0376]

[0377] Step 1: Preparation of Compound 108-1

[0378] LDA (219 ml, 439 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-1-methoxybenzene (60 g, 293 mmol) in THF (500 ml) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at -78 °C for 0.5 h. DMF (45.3 ml, 585 mmol) was added dropwise to the mixture at -78 °C, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was quenched with a saturated aqueous solution of NH4Cl (500 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was ground with PE at 35 °C for 20 min to give compound 108-1 (60 g, 87% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.18 (s, 1H), 7.56 (dd, J = 8.9, 1.8 Hz, 1H), 7.42 (t, J = 8.8 Hz, 1H), 3.89 (s, 3H).

[0379] Step 2: Preparation of Compound 108-2

[0380] A mixture of compound 108-1 (50 g, 213 mmol) in N2H4·H2O (500 mL, 213 mmol) was stirred at 100 °C under N2 for 16 hours. The mixture was diluted with water (1000 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 108-2 (35 g, 72.5% yield). LCMS: 227.0 / 229.0 [M+H] + ;

[0381] Step 3: Preparation of Compound 108-3

[0382] Compound 108-3 was synthesized according to the aforementioned method. LCMS: 311.0 / 313.0 [M+H] + .

[0383] Step 4: Preparation of compound 108-4

[0384] A solution of BBr3 (6.21 ml, 69.4 mmol) was added to a solution of compound 108-3 (2.70 g, 8.68 mmol) in DCM (20 ml) at 0 °C. The reaction mixture was stirred at 0 °C under N2 for 30 min. The mixture was diluted with water (100 mL) and extracted with dichloromethane. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 108-4.

[0385] Step 5: Preparation of compound 108-5

[0386] CF2ClCOONa (924 mg, 6.06 mmol) was added to a solution of compound 108-4 (600 mg, 2.019 mmol) and Cs2CO3 (1974 mg, 6.06 mmol) in DMF (20 mL). The reaction mixture was stirred at 100 °C under N2 for 2 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 108-5. LCMS: 347.16 / 349.0 [M+H] + .

[0387] Step 6: Preparation of the title compound

[0388] The title compound was synthesized according to the aforementioned method. LCMS: 605.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.8 (s, 1H), 8.8 (d, J = 4.0 Hz, 1H), 8.1 (td, J = 7.8, 1.6 Hz, 1H), 7.9 (d, J = 7.9 Hz, 1H), 7.9 (d, J = 7.1 Hz, 1H), 7.8-7.7 (m, 2H), 7.5 (s,1H), 7.5 (t, J = 74.6 Hz, 1H), 7.0-6.8 (m, 2H), 5.1 (p, J = 7.7 Hz, 1H), 5.0(s, 1H), 3.7-3.6 (m, 2H), 2.9 (t, J = 10.4 Hz, 2H), 2.3 (ddt, J = 15.9, 8.1,3.4 Hz, 1H), 2.3-2.3 (m, 2H), 2.2 (dd, J = 13.9, 5.8 Hz, 1H), 2.1-2.0 (m,2H), 1.9-1.9 (m, 1H), 1.7-1.6 (m, 1H), 1.5 (qd, J = 10.7, 3.6 Hz, 2H), 1.3(s, 3H).

[0389] Following a similar method to compound 108, the following compounds were prepared using the corresponding substrates.

[0390]

[0391] Example A15: Synthesis of Compound 116

[0392]

[0393] Step 1: Preparation of Compound 116-1

[0394] To a solution of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (5.0 g, 23.552 mmol), 2-chlorothiazolium (2.8 g, 23.552 mmol), Cs₂CO₃ (15.3 g, 47.103 mmol) in dioxane (50 mL), Pd₂(dba)₃ (1.1 g, 1.178 mmol) and RuPhos (1.1 g, 2.355 mmol) were added. The reaction mixture was stirred at 100 °C under N₂ for 16 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 116-1 (3.9 g, 13.202 mmol, 56.1%). LCMS: 296.1 [M+H] + ;

[0395] Step 2: Preparation of compound 116-2

[0396] TFA (20 mL) was added dropwise to a solution of compound 116-1 (3800 mg, 12.864 mmol) in DCM (30 mL) at 0 °C, and the reaction mixture was stirred at rt for 2 hours. The mixture was concentrated to give compound 116-2 (2.5 g, 12.801 mmol, 99.5%, crude product), which was used for the next reaction step without further purification.

[0397] Step 3: Preparation of compound 116-3

[0398] MsCl (1.6 mL, 20.840 mmol) was added to a solution of compound 116-2 (3700 mg, 18.945 mmol) and TEA (10.5 mL, 75.781 mmol) in DCM (50 mL) at 0 °C under a nitrogen atmosphere over a period of 20 min. The reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with water (100 mL) and extracted with dichloromethane. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 116-3. LCMS: 274.0 [M+H] + ;

[0399] Step 4: Preparation of the title compound

[0400] The title compound was synthesized according to the aforementioned method. LCMS: 488.3 [M+H]+ ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.75 (s, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.60 (s, 1H), 7.46 (d, J = 8.6Hz, 1H), 7.22-7.16 (m, 1H), 6.97 (d, J = 6.9 Hz, 1H), 5.17-5.08 (m, 1H), 5.03(s, 1H), 4.02 (dt, J = 14.6, 7.3 Hz, 1H), 3.94 (s, 2H), 3.83 (d, J = 6.6 Hz, 2H), 2.97 (s, 3H), 2.68-2.60 (m, 2H), 2.31 (ddd, J = 23.1, 11.4, 6.6 Hz, 3H),2.21-2.13 (m, 3H), 1.91 (d, J = 8.7 Hz, 1H), 1.72-1.61 (m, 1H), 1.32 (s, 3H).

[0401] Following a similar method to compound 116, the following compounds were prepared using the corresponding substrates.

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] Example A16: Synthesis of Compound 61

[0412]

[0413] Step 1: Preparation of Compound 61-1

[0414] Add 1 mmol of piperidine-1-carboxylic acid (11.9 g, 51.9 mmol) to a solution of 1-(tert-butoxycarbonyl)piperidine-1-carboxylic acid in DMF (50 mL) H -Benzo[d][1,2,3]triazol-4-ol (5.3 g, 38.904 mmol), 1-{[3-(dimethylamino)propyl]aminoidene}- N -Ethylmethylamine hydrochloride (7.50 g, 38.9 mmol), DIEA (10.0 g, 77.7 mmol), and (5-bromopyridin-2-yl)methylamine (4.85 g, 25.9 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The crude product was purified by rapid silica gel chromatography to give compound 61-1 (6.00 g, 48.4%). LCMS: 398.2 / 400.2 [M+H] + ;

[0415] Step 2: Preparation of compound 61-2

[0416] A solution of compound 61-1 (4.2 g, 10.55 mmol) in POCl3 (50 g) was stirred at 130 °C for 16 hours. The mixture was concentrated under vacuum to give a residue. The residue was purified by reversed-phase chromatography to give compound 61-2 (2.30 g, 50.5%). LCMS: 280.0 / 282.0 [M+H] + ;

[0417] Step 3: Preparation of compound 61-3

[0418] To a solution of compound 61-2 (1.4 g, 5.00 mmol) in DCM (36 mL), 4-(dimethylamino)pyridine (61.1 mg, 0.500 mmol), triethylamine (2 mL, 15.0 mmol), and 2-methylprop-2-yl)oxidanecarboxylic anhydride (1.7 mL, 7.50 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography to give compound 61-3. LCMS: 380.0 / 382.0 [M+H] + ;

[0419] Step 4: Preparation of the title compound

[0420] The title compound was synthesized using compound 61-3 as a substrate according to the aforementioned method. LCMS: 475.3 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ 8.13 (s, 1H), 7.55 (d, J = 9.3 Hz, 1H), 7.43(s, 1H), 7.39 (s, 1H), 7.02 (d, J = 9.3 Hz, 1H), 3.79-3.17 (m, 8H), 3.02-2.92(m, 5H), 2.87 (s, 3H), 2.35-2.10 (m, 6H), 1.75-1.50 (m, 2H).

[0421] Following a similar method to compound 61, the following compounds were prepared using the corresponding positions.

[0422]

[0423] Example A17: Synthesis of Compound 66-1 / 2

[0424]

[0425] Step 1: Preparation of compound 66-A / B

[0426] 5-(1-(2,2-dimethylpiperidin-4-yl)-5-fluoro-1H-indazole-6-yl)-N-(1-(methanesulfonyl)piperidin-4-yl)thiazol-2-amine, a racemic mixture, was synthesized according to the aforementioned method. The racemic mixture was separated by SFC (Waters SFC 150, column name: DAICELCHIRALCEL® AD, column size: 250 × 25 mm 10 μm; mobile phase A: supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / L ammonia in ETOH), A:B = 60:40; 214 nm; flow rate: 120 mL / min) to obtain compound 66-A as the first eluent and compound 66-B as the second eluent.

[0427] Compound 66-A: 1 H NMR (400 MHz, methanol-) d 4) δ 7.96 (s, 1H), 7.72 (d, J = 6.0Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 11.2 Hz, 1H), 5.00-4.91 (m, 1H), 3.83-3.68 (m, 3H), 3.14-2.95 (m, 4H), 2.87 (s, 3H), 2.24-2.14 (m, 2H), 2.07-1.86(m, 4H), 1.70-1.60 (m, 2H), 1.36 (s, 3H), 1.24 (s, 3H).

[0428] Compound 66-B: 1 H NMR (400 MHz, DMSO- d 6) δ 8.03 (s, 1H), 7.83 (d, J = 6.0Hz, 1H), 7.60 (s, 1H), 7.52 (d, J = 11.2 Hz, 1H), 5.30-5.13 (m, 1H), 3.92-3.64 (m, 3H), 3.54-3.38 (m, 2H), 2.98 (t, J = 9.6 Hz, 2H), 2.46-2.15 (m, 6H), 1.72-1.64 (m, 2H), 1.62 (s, 3H), 1.50 (s, 3H).

[0429] Step 2: Preparation of compound 66-1 / 2

[0430] The title compound was synthesized using compounds 66-A and 66-B as substrates, respectively, according to the aforementioned method.

[0431] Compound 66-1: LCMS: 520.9 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.16 (s,1H), 8.03 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.61(s, 1H), 5.07-4.74 (m, 1H), 3.85-3.63 (m, 1H), 3.55-3.49 (m, 2H), 3.00-2.90(m, 2H), 2.89 (s, 3H), 2.82-2.74 (m, 2H), 2.30 (s, 3H), 2.12-2.04 (m, 4H), 1.98-1.88 (m, 1H), 1.83-1.72 (m, 1H), 1.61-1.48 (m, 2H), 1.17 (s, 6H).

[0432] Compound 66-2: LCMS: 520.9 [M+H] + ; 1 H NMR (400 MHz, methanol-) d 4) δ 8.53 (s,1H), 8.00 (s, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 11.2Hz, 1H), 5.11-4.95 (m, 1H), 3.81-3.70 (m, 3H), 3.27-3.12 (m, 2H), 2.97 (t, J= 10.4 Hz, 2H), 2.87 (s, 3H), 2.67 (s, 3H), 2.47-2.33 (m, 2H), 2.22-2.06 (m,4H), 1.70-1.61 (m, 2H), 1.46 (s, 3H), 1.41 (s, 3H).

[0433] Following a similar method to compound 66, the following compounds were prepared using the corresponding substrates.

[0434]

[0435] SFC conditions for compounds 175 & 176: System: Waters SFC 80; Column: DAICELCHIRALPAK® IC, 250 × 25 mm 10 m; Mobile phase A: supercritical CO2, Mobile phase B: MeOH (+0.1% 7.0 mol / L ammonia in MeOH); Flow rate: 70 mL / min; Gradient: 35% isocratic B; Column temperature (RT); Back pressure (bar): 100; Wavelength: 214 nm; RI1 (min): 3.529, RI2 (min): 4.204.

[0436] SFC conditions for compounds 177 & 178: YMC-300; column: DAICELCHIRALPAK® IE, 250 × 30 mm10 m; Mobile phase A: n-hexane, Mobile phase B: EtOH (+0.1% 7.0 mol / L ammonia in MeOH); Flow rate: 100 mL / min; Gradient: 30% isocratic B; Column temperature (RT); Wavelength: 254 nm; RI1 (min): 25.909, RI2 (min): 29.837;

[0437] Example B. Biological assay

[0438] CDK1 / CycA2

[0439] The test compound was diluted with DMSO (Sigma, D4540). 40 nL of the diluted compound was transferred to a 384-well plate (Greiner, 784075) using an Echo 655 (Beckman). A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT). 2 μL of CDK1 / CycA2 (4 nM, promethazine enzyme, 0134-0054-1) solution was transferred to a 384-well plate, followed by centrifugation at 1000 rpm for 60 seconds and incubation at 25°C for 10 minutes. Then, 2 μL of a mixture containing 2× substrate (histone H1: 0.1 mg / mL) and ATP (50 μM) in kinase reaction buffer was added to each well, followed by centrifugation for 60 seconds and incubation at 25°C for 60 minutes. Add 4 μL of ADP-Glo ​​reagent (Promega, V9103) to each well of a 384 reaction plate and incubate at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Add 8 μL of detection reagent (Promega, V9103) to each well of the 384 reaction plate for incubation at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Read the chemiluminescence (luminescence) signal using a multifunctional enzyme marker (BMG, PHERAstar FSX).

[0440] CDK2 / CycE1

[0441] The test compound was diluted with DMSO (Sigma, D4540). 40 nL of the diluted compound was transferred to a 384-well plate (Greiner, 784075) using an Echo 655 (Beckman). A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT). 2 μL of CDK2 / CycE1 (0.33 nM, Carna, O4-165) solution was transferred to a 384-well plate, followed by centrifugation at 1000 rpm for 60 seconds and incubation at 25°C for 10 minutes. Then, 2 μL of a mixture containing 2× substrate (histone H1: 0.1 mg / mL) and ATP (20 μM) in kinase reaction buffer was added to each well, followed by centrifugation for 60 seconds and incubation at 25°C for 60 minutes. Add 4 μL of ADP-Glo ​​reagent (Promega, V9103) to each well of a 384 reaction plate and incubate at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Add 8 μL of detection reagent (Promega, V9103) to each well of the 384 reaction plate for incubation at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Read the chemiluminescence (luminescence) signal using a multifunctional enzyme marker (BMG, PHERAstar FSX).

[0442] CDK4 / CycD3

[0443] The test compound was diluted with DMSO (Sigma, D4540). 40 nL of the diluted compound was transferred to a 384-well plate (Greiner, 784075) using an Echo 655 (Beckman). A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT). 2 μL of CDK4 / CycD3 (31 nM, promethazine enzyme, 0142-0373-1) solution was transferred to a 384-well plate, followed by centrifugation at 1000 rpm for 60 seconds and incubation at 25°C for 10 minutes. Then, 2 μL of a mixture containing 2× substrate (DYRK tide: 0.1 mg / mL) and ATP (100 μM) in kinase reaction buffer was added to each well, followed by centrifugation for 60 seconds and incubation at 25°C for 60 minutes. Add 4 μL of ADP-Glo ​​reagent (Promega, V9103) to each well of a 384 reaction plate and incubate at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Add 8 μL of detection reagent (Promega, V9103) to each well of the 384 reaction plate for incubation at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Read the chemiluminescence (luminescence) signal using a multifunctional enzyme marker (BMG, PHERAstar FSX).

[0444] CDK9 / CycT1

[0445] The test compound was diluted with DMSO (Sigma, D4540). 40 nL of the diluted compound was transferred to a 384-well plate (Greiner, 784075) using an Echo 655 (Beckman). A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 2 mM DTT). 2 μL of CDK9 / CycT1 (7 nM, Carna, O4-110) solution was transferred to a 384-well plate, followed by centrifugation at 1000 rpm for 60 seconds and incubation at 25°C for 10 minutes. Then, 2 μL of a mixture containing 2x substrate (CDK9 / CycT1: 0.1 mg / mL) and ATP (20 μM) in kinase reaction buffer was added to each well, followed by centrifugation for 60 seconds and incubation at 25°C for 60 minutes. Add 4 μL of ADP-Glo ​​reagent (Promega, V9103) to each well of a 384 reaction plate and incubate at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Add 8 μL of detection reagent (Promega, V9103) to each well of the 384 reaction plate for incubation at 25°C. Centrifuge the reagent at 1000 rpm for 60 s and incubate at 25°C for 40 min. Read the chemiluminescence (luminescence) signal using a multifunctional enzyme marker (BMG, PHERAstar FSX).

[0446] Table 3 shows the corresponding biological data for CDK1, CDK2, CDK3 and CDK4 (nM) of the compounds shown in Table 1.

[0447] Table 3:

[0448]

[0449]

[0450]

[0451]

[0452] IC 50 (nM):

[0453] 0 < A ≤ 10 nM;

[0454] 10 < B ≤ 200 nM;

[0455] 200 < C ≤ 1000 nM;

[0456] D > 1000 nM.

[0457] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations thereof will be made by those skilled in the art and are included within the spirit and scope of this application and the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, Formula (I) wherein, for or ; R 1 halogen, -NR c R d , C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with one or more R; Y is a bond, -S-, -O-, -NR YN - or -C(R Y )2-; R YN is hydrogen, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R Y each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R Y together form oxo; is a single or double bond; X 1 is N or C; X 2 is N or CR 2 ; X 3 is N or CR 3 ; X 4 is N or CR 4 ; X 5 is N or C; X 6 is N or C; X 7 is O, S, N, NR 7N , CR 7 or CR 7’ R 7 ; X 8 for NR 8N , CR 8 or CR 8’ R 8 ; X 9 is O, S, N, NR 9N , CR 9 or CR 9’ R 9 ; R 2 , R 3 , and R 4 are each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 2-C6alkenyl, C 2-6 2-C6alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R ; R 7N and R 9N each independently is hydrogen, -CN, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; R 7 and R 7’ each independently is hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or R 7 and R 7’ together form oxo; or R 7 and R 7’ together with the atoms to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R R 9 and R 9’ each independently is hydrogen, halogen, -CN, -OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or R 9 and R 9’ together form oxo; or R 9 and R 9’ together with the atoms to which they are attached form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R R 8 selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1-6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 heteroalkylene-aryl and -C 1-6 heteroalkylene-heteroaryl, wherein alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R 8a ; R 8N Selected from -CN, -NO2, -OC(=O)R a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d -P(=O)R c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl and -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 8a replace; R 8’ independently hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 8a substituents; R 8a each independently is selected from halogen, -CN, -NO2, -OH, oxo, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 10 each independently is selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -P(=O)R c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ; or two R 10 together form oxo; R 10a each independently is selected from halogen, -CN, -NO2, -OH, oxo, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)R c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R n is 0, 1, 2, 3, 4, 5, or 6; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; or R c and R d with the atom to which they are attached to form a heterocycloalkyl group, which is optionally substituted with one or more R; and R is each independently halogen, -CN, -OH, -SF5, -SH, -S(=0)C1-C3 alkyl, -S(=0)2C1-C3 alkyl, -S(=0)2NH2, -S(=0)2NHC1-C3 alkyl, -S(=0)2N(C1-C3 alkyl)2, -S(=0)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=0)(C1-C3 alkyl)2, -C(=0)C1-C3 alkyl, -C(=0)OH, -C(=0)OC1-C3 alkyl, -C(=0)NH2, -C(=0)NHC1-C3 alkyl, -C(=0)N(C1-C3 alkyl)2, -P(=0)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II), Formula (II).

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III), Formula (III) wherein Ring A is heterocycloalkyl, aryl, heteroaryl or C 4-12 cycloalkyl; Y is a bond, -S-, -O-, -NR YN - or -C(R Y )2-; R YN is hydrogen, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; R Y each independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NR c R d , -NO2, -OR a , -SR a , C 1-6 alkyl, C 1-6 haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IIa), Formula (IIa).

5. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IIIa), Formula (IIIa).

6. The compound of any one of claims 1, 2, or 4, or a pharmaceutically acceptable salt thereof, wherein is , , , , or .

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein is , , , , , , , , or .

8. The compound of any one of claims 1, 3, or 5, or a pharmaceutically acceptable salt thereof, wherein is , , , or .

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is , , , , , , or .

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, -CN, Cl, -CH3, -CHF2, or -CºCH.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 3 is H, F, -CN, Cl, -CH3, -CHF2, or -CºCH.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 4 is H, F, -CN, Cl, -CH3, -CHF2, or -CºCH.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R 7 is H, F, -CH3, or .

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R 7’ is H, F, CH3, or .

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R 7’ is hydrogen.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 7’ together form oxo, or R 7 and R 7’ together with the atoms to which they are attached form cycloalkyl optionally substituted with one or more R.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R 7N is hydrogen or C 1-6 alkyl, and wherein alkyl is optionally substituted with one or more R.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R 9 is H, F, -CH3, or .

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R 9’ is H, F, -CH3, or .

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R 9’ is hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 9’ together form oxo, or R 9 and R 9’ together with the atoms to which they are attached form cycloalkyl optionally substituted with one or more R.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R 9N is hydrogen or C 1-6 alkyl, wherein each instance of alkyl is optionally substituted with one or more R.

28. The compound of any one of claims 1-27, wherein R 8 is heterocycloalkyl or cycloalkyl, wherein cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more (e.g. 1-6) R 8a .

29. The compound of any one of claims 1-28, wherein R 8 is , , , , , , , , , , , , or .

30. The compound of any one of claims 1-28, wherein R 8 is , , , , , , or .

31. The compound of any one of claims 1-28, wherein R 8 is , , , , , , , , , , , , , , , , , , , or .

32. The compound of any one of claims 1-27, wherein R 8’ is hydrogen, halogen, -CN, OH, -SF5, -SH, C 1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with one or more R 8a .

33. The compound of any one of claims 1-27, wherein R 8N is heterocycloalkyl or cycloalkyl, wherein each of cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 8a .

34. The compound of any one of claims 1-27, wherein R 8N is 4-6 membered monocyclic cycloalkyl optionally substituted with one or more R 8a substituents.

35. The compound of any one of claims 1-27, wherein R 8N is , , , , , , , , , , , , or .

36. The compound of any one of claims 1-27, wherein R 8N is , , , , , , or .

37. The compound of any one of claims 1-27, wherein R 8N is , , , , , , , , , , , , , , , , or .

38. The compound of any one of claims 1-37, wherein R 8a each is independently selected from halogen, -OH, -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein is ; Y 1 is N, C or CR Y1 ; Y 2 is O, S, N, NR Y2N , CR Y2 or CR Y2 R Y2’ ; Y 3 is O, S, N, NR Y3N , CR Y3 or CR Y3 R Y3’ ; Y 4 is O, NR Y4N , CR Y4 or CR Y4 R Y4’ ; Y 5 is O, S, N, NR Y5N , CR Y5 or CR Y5 R Y5’ ; Y 6 is O, S, N, NR Y6N , CR Y6 or CR Y6 R Y6’ ; R Y1 , R Y2 , R Y2’ , R Y3 , R Y3’ , R Y4 , R Y4’ , R Y5 , R Y5’ , R Y6 and R Y6’ are each independently selected from hydrogen and R 10 ; R Y2N R Y3N R Y4N R Y5N and R Y6N Each is independently selected from -CN, -NO2, and -OC(=O)R. a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d -P(=O)R c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocyclic alkyl, -C 1-6 Heteroalkyl-cycloalkyl, -C 1-6 Heteroalkyl-heterocyclic alkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 Heteroalkyl-aryl and -C 1-6 Heteroalkyl-heteroaryl, wherein the alkyl, alkylene, heteroalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. 10a replace.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is , , , , , , or ; wherein n is 1, 2, 3, 4, 5, or 6.

41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is , , , , , , , , , , or .

42. The compound of any one of claims 1-41 or a pharmaceutically acceptable salt thereof, wherein R 10 each is independently selected from halogen, -OH, -S(=0)2R a , -S(=0)2NR c R d , -S(=0)(=NR b )R b , -C(=0)R a , Ci-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a .

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein one or more R 10 is F or OH.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein at least one R 10 is -S(=0)2R a , -S(=0)2NR c R d or -S(=0)(=NR b )R b .

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein at least one R 10 -S(=0)2CH3, -S(=0)2CH(CH3)2, , , or -S(=0)2NHCH3.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein R Y4N -S(=0)2CH3, -CH2CH2S(=0)2CH3, -S(=0)2CHF2, -S(=0)2CH(CH3)2, -S(=0)2CH2CH2OH, -S(=0)(=NH)CH3, or -S(=0)2NHCH3, , , , , , , , , , , , , , , , , , , , , , or .

47. A compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

49. A method of treating cancer, comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

50. A method of treating a disease or disorder associated with a cyclin-dependent kinase (CDK) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.

51. The method of claim 50, wherein the disease or disorder is cancer.

52. The method of claim 49 or 51, wherein the cancer is a cancer of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a lymphoid lineage hematological tumor; a myeloid lineage hematological tumor; a thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; a melanoma; a seminoma; a teratocarcinoma; an osteosarcoma; xeroderma pigmentosum; keratocanthomas; thyroid follicular cancer; or Kaposi's sarcoma.

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