Amino heteroaryl kinase inhibitors

Abstract

Provided herein are certain aminoheteroaryl compounds having a tricyclic structural moiety, pharmaceutical compositions, and methods of use related to cyclin-dependent kinases (CDKs). The compounds provided herein are typically inhibitors of CDK4, which are useful in the treatment of a variety of diseases or disorders, such as cancer.

Description

Cross-references to related applications

[0001] This application claims priority to International Patent Application No. PCT / CN2024 / 074116, filed January 25, 2024, and PCT / CN2024 / 118474, filed September 12, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] In some embodiments, this document provides certain aminoheteroaryl compounds having a tricyclic structural moiety, compositions comprising such aminoheteroaryl compounds, methods for preparing such aminoheteroaryl compounds, and methods for using such aminoheteroaryl compounds, for example for inhibiting cyclin-dependent kinases and / or for treating or preventing various diseases or disorders provided herein. Background Technology

[0003] Unrestricted cell growth is a hallmark of cancer, and disrupted cell cycle regulation is a common feature in malignant cells. Cyclin-dependent kinases (CDKs) are a family of serine / threonine protein kinases that regulate mammalian cell division and proliferation. At least 20 CDKs and 29 cyclins have been identified in human cells (Cao et al., BMC Evol.Biol [BMC Evolutionary Biology], 2014; 14:10). Besides regulating cell cycle progression, these CDKs and cyclins also play important roles in regulating transcription, DNA repair, differentiation, and apoptosis (Palmer and Kaldis, 2014; 14:10). Semin Cell Dev Biol [Symposium on Cell and Developmental Biology], 2020; 107:54-62).

[0004] CDK4 and CDK6 are key regulators of the G1-S phase transition. D-type cyclin forms a complex with CDK4 / 6 and phosphorylates into retinoblastoma (Rb) protein. This alleviates the inhibition of the Rb-mediated transcription factor E2F and leads to S-phase entry. The CDK4 / 6-cyclin D-Rb pathway is frequently disrupted in human cancers. Amplification of CDK4 / 6 and cyclin D1, overexpression of D-type cyclin, mutations, deletions, or transcriptional silencing of the endogenous CDK4 / 6 inhibitor p16 (CDKN2A) have all been reported as mechanisms leading to pathway activation (Dickson, […]). Molecular Cancer Research 2014;20: 3379-3383). In breast cancer, dysregulation of the CDK4 / 6 pathway is associated with resistance to endocrine therapy (Ding et al., 2014;20: 3379-3383). Int J Mol Sci. [International Journal of Molecular Sciences] 2020; 21:1960).

[0005] In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefits in various tumor types. CDK4 / 6 inhibitors, when used in combination with endocrine therapy, have demonstrated efficacy in treating human epidermal growth factor 2 (HER2)-negative, estrogen receptor (ER)-positive breast cancer. Therefore, various CDK4 / 6 inhibitors, such as palbociclib, ribociclib, and abecilibi, have been approved for use in first- or second-line therapy in combination with endocrine therapy (Cogliati et al., Life [Life], 2022;12:378). Recently, abecilibaly was also approved for adjuvant therapy in early-stage breast cancer.

[0006] Despite the clinical success of CDK4 / 6 inhibitors, treatment-related adverse events, particularly hematological toxicities such as neutropenia, have prevented sustained administration. Currently, palbociclib and ribociclib are administered on a three-week / one-week off schedule. Mouse genetics and other emerging data suggest that the observed hematological toxicities may be related to inhibition of CDK6-cyclin D3 (Sicinska et al., Mol Cell Biol study], 2006; 26: 8052-8060; Cooper et al., Nat Immunol [Natural Immunology], 2006; 5:489-497). On the other hand, CDK6-cyclin D3 expression levels are very low in HR+ / HER2- breast cancer, while CDK4 has been identified as an oncogenic driver in this type of tumor (Zhang 2006; 5:489-497). et al. , Cancer Research 2022; Electronic Publication). Summary of the Invention

[0007] Inhibitors specific to certain CDKs (e.g., CDK4) can offer advantages such as improved safety profiles, improved dosing regimens and higher dosages, and can lead to deeper target inhibition, better efficacy, and potential overcoming of drug resistance. There remains a need for CDK inhibitors, such as selective CDK4 inhibitors, those with improved efficacy and reduced clinical side effects.

[0008] In some embodiments, this document provides certain aminoheteroaryl compounds having a tricyclic structural moiety that can inhibit CDKs, for example, selectively inhibit CDK4. The compounds and compositions provided herein can be used to treat various diseases or disorders associated with abnormal CDK4 activity, such as hormone receptor-positive, HER2-negative breast cancer.

[0009] In some embodiments, compounds having formula (I) are provided herein:

[0010] (I), Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts, wherein L 1 R 1 X, R 3 R 4 J 1 J 2 R 20A M 1 M 2 Rings B and C are as defined herein or elsewhere.

[0011] This document also provides pharmaceutical compositions comprising the compounds provided herein and one or more pharmaceutically acceptable excipients. Pharmaceutical compositions are generally formulated for oral administration.

[0012] This document also provides methods for inhibiting CDK activity (e.g., CDK4 activity) in a subject or biological sample. In some embodiments, the method includes contacting the subject or biological sample with an effective amount of the compound or pharmaceutical composition provided herein.

[0013] This document also provides methods for treating or preventing CDK-mediated diseases or disorders in subjects of need. In some embodiments, the method includes administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.

[0014] This document also provides methods for treating cancer in subjects in need, including administering to the subject an effective amount of the compound or pharmaceutical composition provided herein. This document also provides methods for preventing cancer in subjects in need, including administering to the subject an effective amount of the compound or pharmaceutical composition provided herein. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer, thyroid cancer, and combinations thereof. In some embodiments, the cancer is selected from breast cancer: ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from breast cancer: endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the cancer is advanced or metastatic breast cancer. In some embodiments, the cancer is ovarian cancer.

[0015] The use of the compounds provided herein in the manufacture of medicaments for treating cancer (as described herein) is also provided. The use of the compounds provided herein for treating cancer (as described herein) is also provided. The use of the compounds provided herein in the treatment of cancer (as described herein) is also provided. The use of the compounds provided herein in the treatment of cancer (as described herein) is also provided, wherein the method comprises administering an effective amount of the compounds provided herein to a subject in need. Detailed Implementation

[0016] definition It should be understood that all parts and their combinations maintain appropriate valences.

[0017] It should also be understood that a particular embodiment of the variable section of this document may be the same as or different from another particular embodiment having the same identifier.

[0018] If applicable, suitable groups for each variable in compounds having formula (I) or its subforms are chosen independently. Non-limiting useful groups for each variable in compounds having formula (I) or its subforms (if applicable) include any corresponding group, alone or in any combination, as shown in the examples or in the specific compounds described herein in Table 1 or Table 1A. Using variable R 1 As an example, in some embodiments, a compound having formula (I) may include any R shown in the examples or in Table 1 or Table 1A herein. 1 R of the group 1 The group, without regard to other variables shown in these specific compounds. In some embodiments, a compound having formula (I) may include any R group shown in the examples or in Table 1 or Table 1A herein. 1 R of the group 1 A group, which, together with at least one other variable (e.g., L) of a particular compound described in examples or in Table 1 or Table 1A herein, is a group. 1 ) combination, where R 1 And at least one other variable may be derived from the same compound or different compounds. Any such combinations are considered and are within the scope of this disclosure. Unless otherwise stated, the description of the variables relating to a formula also applies to any other overlapping formulas (e.g., sub-formulas) in which said variables exist.

[0019] The embodiments described herein, if applicable, can be combined. Such combinations are contemplated and are within the scope of this disclosure. For example, it is conceivable that L in formula (I) (or a sub-formula thereof) 1 R 1 X, R3 R 4 J 1 J 2 R 20A M 1 M 2 The definitions of any one or more of rings B and C can be used with (as applicable) L 1 R 1 X, R 3 R 4 J 1 J 2 R 20A M 1 M 2 Combine the definitions of any one or more of rings B and C.

[0020] Titles and subheadings are used for convenience and / or formal compliance only, do not limit the subject matter, and are not associated with the interpretation of the subject matter description. In some embodiments, features described under a title or subheading may be combined with features described under other titles or subheadings. Furthermore, all features under a single title or subheading are not necessarily used together in the embodiments.

[0021] 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. All patents, applications, published applications and other publications are incorporated herein by reference in their entirety. If a term has multiple definitions herein, the definition in this section shall prevail unless otherwise stated.

[0022] As used in this article, the singular forms “a” and “the” include plural references unless explicitly stated or clearly indicated from the context.

[0023] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be construed as specifying the presence of the stated features or components as mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include instances covered by the term “consisting of”. Therefore, the term “consisting of” may be used in place of the terms “comprising” and “including” to provide more specific embodiments.

[0024] As used herein, the term "or" should be interpreted as inclusive "or," meaning either one or any combination. Therefore, "A, B, or C" refers to any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition occur only when the combination of elements, functions, steps, or actions is inherently mutually exclusive in some way.

[0025] The term "and / or" as used herein, such as in phrases such as "A and / or B," is intended to include A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used herein, such as in phrases such as "A, B, and / or C," is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0026] When listing a range of values, the aim is to cover every value within that range and its subranges. For example, "C 1-6 "Intended to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 And C 5-6 .

[0027] It should be noted that if there is a difference between the described structure and its name, the described structure will be given greater weight.

[0028] The following section describes the definitions of specific functional groups and chemical terms in more detail. Chemical elements are defined according to the periodic table, CAS version. Handbook of Chemistry and Physics [Handbook of Chemistry and Physics], 75th edition, inner cover identifies and defines specific functional groups as described herein. Furthermore, the general principles of organic chemistry, as well as descriptions of specific functional groups and reactivity, are given in the following: Thomas Sorrell, Organic Chemistry [Organic Chemistry], University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry [March's Advanced Organic Chemistry], 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations[Comprehensive Organic Transformation], VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis [Some Modern Methods of Organic Synthesis], 3rd Edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way to the exemplary list of substituents provided herein.

[0029] As used herein, and unless otherwise stated, the term "alkyl" used alone or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, an alkyl group may comprise one to twelve carbon atoms (i.e., C64 ... 1-12 Alkyl group (or a specified number of carbon atoms). In some embodiments, the alkyl group is a straight-chain C14 group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-10 Alkyl group. In another embodiment, the alkyl group is a straight-chain C18 group. 1-6 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C18 group. 1-4 Alkyl groups. For example, C 1-4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl. As used herein, and unless otherwise stated, the term "alkylene" used alone or as part of another group refers to a polyvalent (e.g., divalent) group derived from an alkyl group. For example, non-limiting straight-chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc. Unless otherwise stated, the alkyl group is optionally substituted. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is substituted.

[0030] As used herein, and unless otherwise stated, the term "alkenyl" used alone or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-carbon double bonds. In some embodiments, the alkenyl group is C 2-6 An alkenyl group. In another embodiment, the alkenyl group is C. 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl. Unless otherwise stated, alkenyl groups are optionally substituted. In some embodiments, the alkenyl groups are unsubstituted. In some embodiments, the alkenyl groups are substituted.

[0031] As used herein, and unless otherwise stated, the term "alkynyl" used alone or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-carbon triple bonds. In some embodiments, the alkynyl group has one carbon-carbon triple bond. In some embodiments, the alkynyl group is C 2-6 An alkynyl group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentyynyl, and hexynyl groups. Unless otherwise stated, the alkynyl group is optionally substituted. In some embodiments, the alkynyl group is unsubstituted. In some embodiments, the alkynyl group is substituted.

[0032] As used herein, and unless otherwise stated, the term "alkoxy" when used alone or as part of another group refers to -O-(alkyl), wherein the alkyl group is as described herein. As used herein, and unless otherwise stated, the term "cycloalkoxy" when used alone or as part of another group refers to -O-(cycloalkyl), wherein the cycloalkyl group is as described herein.

[0033] As used herein, and unless otherwise stated, the term "haloalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In some embodiments, the haloalkyl group is C10. 1-10 Haloalkyl group. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl group. In some embodiments, the haloalkyl group is C10. 1-4 Halogenated alkyl groups.

[0034] As used herein, and unless otherwise stated, the term "heteroalkyl" used alone or in combination with another term refers to a stable straight-chain or branched alkyl group, for example having 2 to 14 carbons in the chain, such as 2 to 10 carbons, wherein one or more carbons are replaced by heteroatoms selected from S, O, P, and N, and wherein the N, P, and S atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms S, O, P, and N may be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. When a heteroalkyl group is referred to as substituted, one or more substituents may replace one or more hydrogen atoms attached to one or more carbon atoms and / or one or more heteroatoms of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1-4 Heteroalkyl refers to a heteroalkyl group having 1-4 carbon atoms as defined in this paper. C 1-4Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups, such as -CH2-CH2-N(CH3)-CH3; C3 heteroalkyl groups, such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, and -CH2-CH2-S(O)2-CH3; C2 heteroalkyl groups, such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), and -O-CH2-CH3; and C1 heteroalkyl groups, such as -CH2-OH, -CH2-NH2, and -O-CH3. In some embodiments, C 1-4 Heteroalkyl groups have one or two heteroatoms, such as those with one oxygen atom, one oxygen and one nitrogen atom, two oxygen atoms, or two nitrogen atoms. Similarly, the term "heteroalkylene," used alone or as part of another substituent, refers to a polyvalent (e.g., divalent) group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy one or two chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkyl linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. When listing "heteroalkyl," a specific heteroalkyl group is then listed, such as -NR'R. '' When referring to heteroalkyl and -NR'R terms, it should be understood that... '' This is neither redundant nor mutually exclusive. Rather, specific heteroalkyl groups are listed to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R. '' Unless otherwise stated, heteroalkyl groups are optionally substituted. In some embodiments, the heteroalkyl groups are unsubstituted. In some embodiments, the heteroalkyl groups are substituted.

[0035] As used herein, and unless otherwise stated, the term "carbocyclic" or "carbocyclic" used alone or as part of another group refers to having at least 3 carbon atoms (e.g., 3 to 10 cyclic carbon atoms ("C")). 3-10A carbocyclic group is a non-aromatic cyclic hydrocarbon group that has zero heteroatoms in a non-aromatic ring system. The carbocyclic group can be monocyclic (“monocyclic carbocyclic”) or contain a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and can be saturated or partially unsaturated. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, naphthane, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term “carbocyclic”, used alone or as part of another group, refers to a polyvalent (e.g., divalent) group derived from a carbocyclic group as defined herein. Unless otherwise stated, the carbocyclic group is optionally substituted. In some embodiments, the carbocyclic group is unsubstituted. In some embodiments, the carbocyclic group is substituted.

[0036] In some embodiments, the "carbocyclic group" is fully saturated, and is also referred to as a "cycloalkyl group". In some embodiments, the cycloalkyl group may have 3 to 10 cyclic carbon atoms ("C10"). 3-10 cycloalkyl group (“cycloalkylene”). In some embodiments, the cycloalkyl group is monocyclic. As used herein, the term “cycloalkylene”, used alone or as part of another group, refers to a group derived from a cycloalkyl group, such as… or Multivalent (divalent) groups, etc.

[0037] As used herein, and unless otherwise stated, the term "heterocyclic group" or "heterocyclic" used alone or as part of another group refers to a group with a 3-membered or larger (e.g., 3 to 14-membered) non-aromatic ring system having a ring carbon atom and at least one (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, wherein the N, P, and S atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In heterocyclic groups containing one or more nitrogen atoms, the attachment point may be a carbon atom or a nitrogen atom, where the valence allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. Heterocyclic bicyclic systems may contain one or more heteroatoms in one or two rings, and the attachment point may be on any ring. As used herein, and unless otherwise stated, the term "heterocyclic group" used alone or as part of another group refers to a polyvalent (e.g., divalent) group derived from a heterocyclic group as defined herein. The heterocyclic group or heteroalkyl group may optionally be attached to the remainder of the molecule via a carbon or nitrogen atom. Unless otherwise stated, the heterocyclic group is optionally substituted. In some embodiments, the heterocyclic group is unsubstituted. In some embodiments, the heterocyclic group is substituted.

[0038] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, ethylene oxide, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridine, oxadiazolinyl, and thiohexacyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxadiazolinyl, dithiofuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thialkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxecanyl, and thiocanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to: dihydroindolyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0039] As used herein, and unless otherwise stated, the term "aryl" used alone or as part of another group refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic hydrocarbon ring system (e.g., having 6, 10, or 14 π electrons common in a ring array). In some embodiments, the aryl group has 6 to 14 ring carbon atoms ("C..."). 6-14 Aryl group (“C6 aryl”); in some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms ("C"). 14"Aryl" (e.g., anthracene). As used herein, and unless otherwise stated, the term "aryl" used alone or as part of another group refers to a polyvalent (e.g., divalent) group derived from an aryl group as defined herein. Unless otherwise stated, the aryl group is optionally substituted. In some embodiments, the aryl group is unsubstituted. In some embodiments, the aryl group is substituted.

[0040] As used herein, and unless otherwise stated, the term "aralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more aryl groups, for example, substituted with one aryl group. Examples of aralkyl groups include benzyl, phenethyl, etc. Unless otherwise stated, the aralkyl group is optionally substituted. When aralkyl is referred to as optionally substituted, the alkyl or aryl portion of the aralkyl group may be optionally substituted.

[0041] As used herein, and unless otherwise stated, the term "heteroaryl" used alone or as part of another group refers to a group with a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons common in the ring arrangement), the aromatic ring system having a ring carbon atom and at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has 5 to 14 membered ring atoms ("5 to 14 membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, where the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. In a bicyclic heteroaryl group, where one ring does not contain a heteroatom (e.g., indole, quinolinyl, etc.), the attachment point can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indole) or the ring without a heteroatom (e.g., 5-indole). As used herein, and unless otherwise stated, the term "heteroaryl" used alone or as part of another group refers to a polyvalent (e.g., divalent) group derived from a heteroaryl group as defined herein. Unless specified or otherwise contrary to the context, the resulting fused ring system when a heteroaryl group is fused to a non-aromatic ring is referred to as a heterocyclic group. Unless otherwise stated, the heteroaryl group is optionally substituted. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl group is substituted.

[0042] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0043] As used herein, and unless otherwise stated, the term "heteroaryl" used alone or as part of another group refers to an alkyl group substituted with one or more heteroaryl groups, for example, substituted with a single heteroaryl group. Unless otherwise stated, the heteroaryl group is optionally substituted. When a heteroaryl group is referred to as optionally substituted, the alkyl portion or the heteroaryl portion of the heteroaryl group may be optionally substituted.

[0044] As used herein, and unless otherwise stated, the term "amino" refers to -N(R) # (R) # ), where each R # It can be, independently but not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic, each of which is defined herein. When -N(R # (R) # The group has two R groups other than hydrogen. # When combined with a nitrogen atom, it can form a ring. In some embodiments, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, one or more ring atoms are heteroatoms independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. The term "amino" also includes N-oxides (-N... + (R# (R) # )O - In some embodiments, each R # Or by -N(R) # (R) # The ring formed can be either unsubstituted or substituted by one or more substituents.

[0045] As used herein, and unless otherwise stated, "optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the corresponding unsubstituted or substituted group. Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permitted substituent (e.g., a substituent that, upon substitution, produces a stable compound, such as a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions)). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position can be the same or different. In some embodiments, when substituted, the optionally substituted groups provided herein may be substituted by 1 to 5 substituents. The substituents can be carbon, nitrogen, oxygen, or sulfur substituents, and each of them may optionally be isotopically labeled, such as deuterated, if applicable. Two of the optional substituents may connect to form a ring structure, such as an optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom and can form a spirocyclic ring.

[0046] As used herein, and unless otherwise stated, permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, permitted substituents may be one or more and may be the same or different. Heteroatoms (such as nitrogen) may have hydrogen substituents of the organic compounds described herein and / or any permitted substituents that will satisfy the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic esters, or thiocarbamates), alkoxy groups, cycloalkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphonites, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, aryl groups, or heteroaryl groups, each of which may be substituted if applicable.

[0047] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -aryl-alkyl, -alkylene-heteroaryl, -alkenyl-heteroaryl, -alkynyl-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halogenated, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(═N-CN)-NH2, -C(═NH)-NH2, -C(═NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y1)(Y2), -C(O)N(Y1)(Y2) and -S(O)2N(Y1)(Y2), wherein Y1 and Y2 may be the same or different, and are independently selected from the group consisting of: hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0048] Some examples of suitable substituents include, but are not limited to, (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C8) alkyl groups, and (C2-C8) alkyne groups. 10Cycloalkyl groups, halogens (F, Cl, Br, or I), halogenated (C1-C8)alkyl groups (e.g., but not limited to —CF3), —O—(C1-C8)alkyl groups, —OH, —S—(C1-C8)alkyl groups, —SH, —NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)2 groups, —NH2, —C(O)NH2, —C(O)NH(C1-C8)alkyl groups, —C(O)N((C1-C8)alkyl)2, —NHC(O)H, —NHC(O) (C1-C8)alkyl groups, —NHC(O) (C3-C8)cycloalkyl group, —N((C1-C8)alkyl)C(O)H, —N((C1-C8)alkyl)C(O)(C1-C8)alkyl group, —NHC(O)NH2, —NHC(O)NH(C1-C8)alkyl group, —N((C1-C8)alkyl)C(O)NH2 group, —NHC(O)N((C1-C8)alkyl)2 group, —N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 group, —N((C1-C8)alkyl)C(O)NH ... 8) Alkyl groups, —C(O)H, —C(O)(C1-C8)alkyl groups, —CN, —NO2, —S(O)(C1-C8)alkyl groups, —S(O)2(C1-C8)alkyl groups, —S(O)2N((C1-C8)alkyl)2 groups, —S(O)2NH(C1-C8)alkyl groups, —S(O)2NH(C3-C8)cycloalkyl groups, —S(O)2NH2 groups, —NHS(O)2(C1-C8)alkyl groups, —N((C1-C8)alkyl)S(O)2(C1-C8)alkyl groups —(C1-C8)alkyl-O—(C1-C8)alkyl group, —O—(C1-C8)alkyl-O—(C1-C8)alkyl group, —C(O)OH, —C(O)O(C1-C8)alkyl group, NHOH, NHO(C1-C8)alkyl group, —O-halogenated (C1-C8)alkyl group (e.g., but not limited to —OCF3), —S(O)2-halogenated (C1-C8)alkyl group (e.g., but not limited to —S(O)2CF3), —S-halogenated (C1-C8)alkyl group (e.g., but not limited to —SCF3) —(C1-C6) heterocyclic (e.g., but not limited to pyrrolidine, tetrahydrofuran, pyran, or morpholine), —(C1-C6) heteroaryl (e.g., but not limited to tetrazolium, imidazole, furan, pyrazine, or pyrazole), —phenyl, —NHC(O)O—(C1-C6)alkyl group, —N((C1-C6)alkyl)C(O)O—(C1-C6)alkyl group, —C(═NH)—(C1-C6)alkyl group, —C(═NOH)—(C1-C6)alkyl group, or —C(═N—O—(C1-C6)alkyl)-(C1-C6)alkyl group.

[0049] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3-10 carbonyl group, C 6-10 Aryl, 3- to 10-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, etc. For example, exemplary carbon atom substituents may include F, Cl, -CN, -SO2H, -SO3H, -OH, -OC. 1-6 Alkyl, -NH2, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), -SH, -SC 1-6 Alkyl group, -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 Aryl, 3 to 10-membered heterocyclic, 5 to 10-membered heteroaryl; or two gem substituents can be linked to form =O.

[0050] Nitrogen atoms can be substituted or unsubstituted, provided the valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfones, sulfoxides, and C64. 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14-membered heteroaryl groups, or two substituent groups attached to the nitrogen atom, are linked to form a 3-14-membered heterocyclic group or a 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail below: Protective Groups in Organic Synthesis [Protecting Groups in Organic Synthesis], TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form urethane esters, such as benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butyloxycarbonyl (BOC) groups, Troc, 9-fluorenylmethoxycarbonyl (Fmoc) groups, etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfonamides, such as toluenesulfonyl, nitrobenzenesulfonyl, etc.; and others such as p-methoxyphenyl.

[0051] Exemplary oxygen substituents include, but are not limited to, acyl groups, esters, sulfonates, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxyprotecting groups are well known in the art and include those described in detail below: Protective Groups in Organic Synthesis[Protecting Groups in Organic Synthesis], TW Greene and PGMWuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.; those that form silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc.; those that form acetals or ketals, such as tetrahydropyranyl (THP); those that form esters, such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc.; and those that form carbonates or sulfonates, such as methanesulfonate (or mesylate), benzylsulfonate, toluenesulfonate (Ts), etc.

[0052] Unless explicitly stated otherwise, combinations of substituents and / or variables are permitted only if such combinations are chemically permissible and produce stable compounds. A “stable” compound is one whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0053] In some embodiments, the "optionally substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclic, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclic, or heterocyclic groups may each be independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from the following substituents: deuterium, F, Cl, -OH, oxo (if applicable), NH2, NH(C 1-4 Alkyl), N(C) 1-4 Alkyl ((C) 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6Cycloalkoxy, phenyl, a 5- or 6-membered heteroaryl group containing 1, 2, or 3 independently selected cyclic heteroatoms chosen from O, S, and N, and a 3- to 7-membered heterocyclic group containing 1 or 2 independently selected cyclic heteroatoms chosen from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 independently selected substituents chosen from: deuterium, F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl groups (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4 Alkoxy. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl, or heteroarylene groups herein may each be independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected substituents from: deuterium, F, Cl, -OH, -CN, NH2, NH(C 1-4 Alkyl), N(C) 1-4 Alkyl ((C) 1-4 Alkyl), -S(=O)(C 1-4 Alkyl), -SO2(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, a 5- or 6-membered heteroaryl group containing 1, 2, or 3 independently selected cyclic heteroatoms chosen from O, S, and N, and a 3- to 7-membered heterocyclic group containing 1 or 2 independently selected cyclic heteroatoms chosen from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 independently selected substituents chosen from: deuterium, F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy and fluorine-substituted C 1-4 Alkyl group.

[0054] As used herein, and unless otherwise stated, the term “halogen” or “halogen” means fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br) or iodine (iodinated, -I).

[0055] As used herein, and unless otherwise stated, the term "isomer" refers to different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms. "Rotation-blocked isomers" are stereoisomers resulting from blocked rotation of single bonds. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A mixture of any proportion of a pair of enantiomers can be called a "racemic" mixture. "Diadiaomers" are stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry can be determined according to the Cahn-Ingold-Prelog equation. RS The system specifies that when the compound is an enantiomer, the stereochemistry at each chiral carbon can be determined by... R or S The sign of optical rotation is specified. For compounds with unknown absolute configuration, the sign can be (+) or (-) depending on the direction (right-handed or left-handed) in which they rotate plane-polarized light at the wavelength of the sodium D line. However, the sign of optical rotation (+) and (-) is not related to the absolute configuration of the molecule. R and S Irrelevant. Some compounds presented in this article contain one or more asymmetric centers and therefore can produce enantiomers, diastereomers, and other stereoisomers, which can be defined according to the absolute stereochemical definition of each asymmetric atom (…). R )-or( S The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically essentially pure forms, and intermediate mixtures. Optical activity ( R )-and( S )-Isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0056] As used herein, and unless otherwise stated, the term "enantiomer purity" or "enantiomer purity" refers to a qualitative or quantitative measurement of a purified enantiomer. The enantiomer purity of the compounds presented herein can be described by enantiomer excess (ee), which indicates the extent to which one enantiomer is present in a sample in greater quantities than another. The ee for racemic mixtures is 0%, while the ee for a single, completely pure enantiomer is 100%. Examples of enantiomer purity include at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, at least about 26%, at least about 28%, at least about 30%, at least about 32%, at least about 34%, at least about 36%, at least about 38%, at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, and at least about 62%. At least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about or at least about 99% of ee. Similarly, "purity of diastereomers" can be described by diastereomer excess (de), which indicates the extent to which the content of one diastereomer in a sample is greater than the content of other diastereomers.

[0057] As used herein, and unless otherwise stated, the term "substantially pure enantiomer" refers to a compound in which one enantiomer is more enriched than another enantiomer, for example, where the other enantiomer constitutes less than about 20%, less than about 10%, less than about 5%, or less than about 2% of the original enantiomer. In some embodiments, the substantially pure enantiomer has at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%. SAn excess of enantiomers is present. In some embodiments, the substantially pure enantiomers have an enantiomer content of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%. R Enantiomers are in excess.

[0058] "Stereoisomers" may also include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, the compounds provided herein are isolated as either E or Z isomers. In other embodiments, the compounds provided herein are mixtures of E and Z isomers.

[0059] "Tautomers" refer to the equilibrium isomers of a compound. The concentrations of these isomers will depend on the environment in which the compound exists and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomers, which are referred to as tautomers of each other: .

[0060] As used herein, and unless otherwise stated, the term "pharmaceutically acceptable salt" means that salt is suitable for contact with the tissues of humans and lower animals to the extent of reasonable medical judgment without undue toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. As used herein, and unless otherwise stated, the term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.

[0061] Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentianic acid, glucoheponic acid, and glucosamine. Glucuronic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, mesylic acid, mucoacid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

[0062] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared by adding an inorganic or organic base to a free acid compound. Inorganic base-derived salts include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In some embodiments, the inorganic salt is an ammonium, sodium, potassium, calcium, or magnesium salt. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of base ion exchange resins (such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, heparin, choline, betaine, phenethylbenzylamine, benzylamine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). In some embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0063] The compounds described herein may exist in the form of isotopic labeling or isotopic enrichment, containing one or more atoms whose atomic mass or mass number differs from the most abundant atomic mass or mass number found in nature. Isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, those of other atoms. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32P, 35 S, 18 F, 36 Cl, and 125 I. In some embodiments, the compound contains other isotopes of these and / or other atoms.

[0064] As used herein, and unless otherwise stated, the terms “administration of”, “administering”, or other variations thereof refer to the provision of a compound to a subject in need of treatment.

[0065] As used herein, and unless otherwise stated, the term “subject” (which may alternatively be referred to as “patient”) means an animal, such as a mammal, such as a human being who has been used as a subject of treatment, observation or experimentation.

[0066] As used herein, and unless otherwise stated, the terms "treat," "treating," "treatment," etc., refer to the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not necessarily require the complete elimination of said disease, condition, or its associated symptoms. The term "treatment" and its synonyms are intended to refer to the administration of a therapeutically effective amount of the compounds provided herein to a subject in need of such treatment.

[0067] As used herein, and unless otherwise stated, the term “prevent, preventing, prevention, etc.” means reducing the probability of the onset, recurrence, or relapse of a previously controlled disease or condition in a subject who does not have the disease or condition but is at risk or susceptible to or prone to developing or relapsing into the disease or condition, or who is at risk or susceptible to relapse into the disease or condition.

[0068] As used herein, and unless otherwise stated, the term "effective amount" means the amount of a compound or combination of compounds provided herein that is sufficient to achieve the intended application (including, but not limited to, the prevention or treatment of disease). Therapeutic effective amounts can vary depending on the intended administration (in vitro or in vivo), or the subject and the condition of the disease being treated (e.g., the subject's weight, age, and sex), the severity of the disease, the method of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells and / or tissues. This specific dose will vary depending on the specific compound selected, the subsequent dosing regimen (whether or not the compound is combined with other compounds), the time of administration, the tissue to be administered, and the physical delivery system carrying the compound.

[0069] As used herein, and unless otherwise stated, the terms “about” or “approximately” mean an acceptable error in a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In some embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0070] compound In some embodiments, this document provides compounds and compositions that can be used to inhibit CDKs such as CDK4 and / or to treat or prevent various diseases or disorders such as cancer as described herein. In some embodiments, the compounds are aminoheteroaryl (e.g., aminopyridine or aminopyrimidine) compounds having an additional tricyclic structural moiety. The compounds provided herein generally inhibit CDKs, such as CDK4. In some embodiments, the compounds provided herein selectively inhibit CDK4 relative to other CDKs.

[0071] In some embodiments, compounds having formula (I) are provided herein:

[0072] (I), Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts, wherein: L 1 It is a optionally substituted phenylene, an optionally substituted 5- or 6-membered heteroarylene, an optionally substituted 4- to 8-membered heterocyclic group, or an optionally substituted C 3-8 subcarbonyl cyclo group; R 1 It is hydrogen, OH, NH2, NHCH3 or N(CH3)2; X is N or CR 10 ; R 3 It is hydrogen, deuterium, halogen, CN, OR 11 NR 12 R 13 C(O)NR 12 R 13 COOR A COR B C, which is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 alkynyl group, optionally substituted C 1-4 Heteroalkyl groups, optionally substituted C3-8 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, or optionally substituted 5- to 10-membered heteroaryl group; R 4 It is hydrogen, deuterium, halogen, or optionally substituted C. 1-6 Alkyl, or NR 12 R 13 ; R 10 It is hydrogen, halogen, CN, -OH, or optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl groups, optionally substituted C 3-8 Carbocyclic group, or optionally substituted 4- to 10-membered heterocyclic group; R 11 It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted 4- to 10-membered heterocyclic group; R 12 and R 13 Each of them, each time it appears, is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted 4- to 10-membered heterocyclic group; or R 12 and R 13 Together with the nitrogen to which they are attached, they form optionally substituted 4- to 10-membered heterocyclic groups or optionally substituted 5- or 6-membered heteroaryl groups; R A It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted 4- to 10-membered heterocyclic group; R B It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 4- to 10-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl group; J 1 and J 2 Independently N or CR 30 , where R 30 Each time it appears, it is independently hydrogen, halogen, or C optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; R 20A It is a carbon that is hydrogen, deuterium, halogen, CN, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, C substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl, or optionally substituted 3 to 6-membered ring structures; M 1 It is C or N; M 2 It is C or N; Ring B is in M 1 and M 2 The formed bonds are fused to the optionally substituted 5- to 7-membered rings of ring A; Ring C is a 5- to 7-membered ring fused to ring B, which is optionally replaced.

[0073] In some embodiments, the compound is not a compound described in WO 2024 / 022487 (e.g., compounds described in Table 1 and the examples of WO2024 / 022487), the entire contents of which are incorporated herein by reference.

[0074] In some embodiments, the compound is not a compound described in WO 2019 / 207463 (e.g., a compound described in the preparation of an example of WO 2019 / 207463), the entire contents of which are incorporated herein by reference.

[0075] In some embodiments, the compound is not a compound listed in Table X, or a stereoisomer, mixture of stereoisomers, isotope, or pharmaceutically acceptable salt thereof. For example, in some embodiments of formulas (IA), (II), (IJ), (IK), (IV), or (IW), or their subforms, the compound is not a compound listed in Table X, or a stereoisomer, mixture of stereoisomers, isotope, or pharmaceutically acceptable salt thereof.

[0076] Table X. List of Compounds

[0077] In some embodiments, compounds having formula (I) (including any applicable sub-formulas described herein) may contain one or more asymmetric centers and / or axial chirality, and thus can exist in a variety of stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, the compound may exist as a single enantiomer and / or diastereomer (if applicable), or a mixture of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, when applicable, the compound may have an enantiomer excess (“ee”) of greater than 60%, such as greater than 80%, greater than 90%, greater than 95%, greater than 98%, greater than 99%, or other enantiomers in undetectable amounts. In some embodiments, when applicable, the compound may also exist as a mixture of stereoisomers (in any ratio), such as a racemic mixture.

[0078] In some embodiments, compounds having formula (I) (including any applicable sub-formulas as described herein) may exist as isotopically labeled compounds, such as deuterated analogs, wherein one or more hydrogen atoms of the compound are substituted with deuterium atoms of higher abundance than their native abundance, for example, CD3 analogs when the compound has a CH3 group. Without being bound by any particular theory, it is believed that deuteration at certain positions (e.g., those explicitly specified herein) can result in compounds with better pharmacokinetic characteristics when compared to their hydrogen counterparts (i.e., in native abundance), and thus can have better in vivo pharmacodynamic results. Compounds with specific deuteration substitutions can be prepared by using commercially available deuterium enrichment reagents such as deuterium gas, deuterium oxide (D2O), deuterated formic acid (DCOOD), deuterated methyl iodine (CD3I), deuterated methanol (CD3OD), sodium deuterated oxide (NaOD), sodium borodeuteride (NaBD4), lithium aluminum deuteride (LiAlD4), etc.

[0079] It will be apparent to those skilled in the art that, in certain circumstances, compounds having formula (I) can exist as mixtures of tautomers. Unless otherwise stated, such compounds are not limited to any particular tautomer. Rather, any and all such tautomers are covered, whether or not explicitly drawn or mentioned.

[0080] In some embodiments, ring B is a optionally substituted 5-membered ring (e.g., a 5-membered heteroaryl). In some embodiments, ring B is an optionally substituted 6-membered ring (e.g., a 6-membered heteroaryl). In some embodiments, ring B is an optionally substituted 7-membered ring (e.g., a 7-membered heterocyclic group).

[0081] In some embodiments, ring C is an optionally substituted 5-membered ring (e.g., a 5-membered heterocyclic aryl group or a C5-membered carbocyclic aryl group). In some embodiments, ring C is an optionally substituted 6-membered ring (e.g., a 6-membered heterocyclic aryl group or a C6-membered carbocyclic aryl group). In some embodiments, ring C is an optionally substituted 7-membered ring (e.g., a 7-membered heterocyclic aryl group). In some embodiments, ring B is an optionally substituted N-containing heterocyclic aryl group. In some embodiments, ring B is an optionally substituted O-containing heterocyclic aryl group. In some embodiments, ring B is an optionally substituted S-containing heterocyclic aryl group. In some embodiments, ring B is an optionally substituted P-containing heterocyclic aryl group.

[0082] In some embodiments, ring B is a optionally substituted 5-membered heteroaryl group, and ring C is an optionally substituted 6-membered heterocyclic group.

[0083] In some embodiments, ring B is a optionally substituted 6-membered heterocyclic alkyl group, and ring C is an optionally substituted 5-membered heterocyclic alkyl group. In some embodiments, ring B is a optionally substituted 6-membered heterocyclic alkyl group, and ring C is an optionally substituted 6-membered heterocyclic alkyl group. In some embodiments, ring B is a optionally substituted 6-membered heterocyclic alkyl group, and ring C is an optionally substituted 7-membered heterocyclic alkyl group. In some embodiments, ring B is a optionally substituted 6-membered heterocyclic alkyl group, and ring C is an optionally substituted C5 carbocyclic alkyl group. In some embodiments, ring B is a optionally substituted 6-membered heterocyclic alkyl group, and ring C is an optionally substituted C6 carbocyclic alkyl group.

[0084] In some embodiments, ring B is a optionally substituted 7-membered heterocyclic group, and ring C is an optionally substituted 5-membered heterocyclic group. In some embodiments, ring B is an optionally substituted 7-membered heterocyclic group, and ring C is an optionally substituted 6-membered heterocyclic group.

[0085] In some embodiments, yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some embodiments, yes In some embodiments, yes ;in It is M 1 The location, and It is M 2 Location; R 21A It is a carbon that is hydrogen, deuterium, halogen, CN, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, C substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl, or optionally substituted 3 to 6-membered ring structures; X 1 It is O, NR 31 , or CR 32 R 33 ; X 2 It is O, NR 31 , or CR 32 R 33 ; Ring D is a 5- to 7-membered ring that is optionally substituted, except for X. 3 All the ring atoms except X are carbon atoms, and X 3 is -O-, -S(O)-, -S(O)2-, -S(O)2-NR 31 -、-NR 31 -S(O)2-, -S(O)(NH)-, -P(O)(R 34 )-、-P(O)(R 34 )-NR 31 - or -NR 31 -P(O)(R34 )-; M 3 It is C or N; The ring E is a phenyl group that is optionally substituted, or a 5- or 6-membered heteroaryl group that is optionally substituted. R 31 Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, O(C) 1-4 Alkyl), C(O)H, C(O)(C 1-4 Alkyl), C(O)O(C 1-4 Alkyl), C(O)NH2, C(O)NH(C 1-4 Alkyl), C(O)N(C 1-4 Alkyl)2, C(O)(C 3-6 C(O) (phenyl), C(O) (4- to 6-membered heterocyclic group), C(O) (5- or 6-membered heteroaryl group), SO2 (C 1-4 Alkyl), SO2NH2, SO2NH(C 1-4 Alkyl), SO2N(C) 1-4 Alkyl)2, SO2(C 3-6 (Carbocyclic group), SO2 (phenyl), SO2 (4- to 6-membered heterocyclic group), SO2 (5- or 6-membered heteroaryl group), C 3-6 Carbocyclic, phenyl, 4- to 6-membered heterocyclic, or 5- or 6-membered heteroaryl; wherein R 31 The alkyl moiety is optionally and independently substituted with one or more (e.g., 1, 2, or 3) substituents each time it appears, each of which is independently deuterium, halogenated, OH, O(C) 1-4 Alkyl), SO2 (C) 1-4 Alkyl), NH2, NH(C) 1-4 alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), NH(C) 3-6 cycloalkyl), N(C) 1-4 Alkyl)(C 3-6 cycloalkyl), or N(C) 3-6 cycloalkyl)(C 3-6 cycloalkyl); and wherein the R 31 The carbocyclic, phenyl, heterocyclic, and heteroaryl moieties in the C group are each optionally and independently substituted with one or more (e.g., 1, 2, or 3) substituents, each of which is independently oxo, halogenated, OH, NH2, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F groups. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; R32 and R 33 Each of the elements is independent each time it appears: (1) Hydrogen or deuterium; (2) Halogen or cyano; (3) OH, NH2, NH(C) 1-4 Alkyl), or N(C) 1-4 Alkyl)(C 1-4 alkyl); (4) C that is optionally substituted by one or more (e.g., 1, 2 or 3) substituents 1-4 Alkyl groups, each of which is independently deuterium, F, OH, NH2, NH(C) 1-4 alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), NH(C) 3-6 cycloalkyl), N(C) 1-4 Alkyl)(C 3-6 cycloalkyl), or N(C) 3-6 cycloalkyl)(C 3-6 (Cycloalkyl); (In some embodiments, the independent optional substituent option also includes SO2 (C 1-4 alkyl).) (5) C that is optionally replaced by one or more (e.g., 1, 2 or 3) deuterium or F 1-4 alkoxy group, or C group optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; (6) C that can be arbitrarily replaced 3-6 Carbocyclic group, optionally substituted phenyl group, optionally substituted 4- to 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl group; (7)R 32 and R 33 Together with the carbon atoms to which they are attached, they form carbonyl groups (CO); (8)R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 A carbocyclic or 4- to 6-membered heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (e.g., 1, 2, or 3) substituents, each of which is independently oxo, halogenated, OH, NH2, or optionally substituted by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; or (9) Two Rs 32Linked with one or more spacer atoms to form optionally substituted 3- to 7-membered rings; or R 31 and adjacent R 32 It is linked together with one or more spacer atoms to form optionally substituted 3- to 7-membered rings; R 34 Each time it appears, it is independently hydrogen, optionally replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, optionally substituted C 3-6 A carbocyclic group, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl group; or R 34 and R 32 It is linked with one or more spacer atoms to form optionally substituted 3- to 7-membered rings; and L 2 C is arbitrarily replaced 1-3 Alkylene.

[0086] In some embodiments, the compound is a compound having the formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (I-AA), (I-AB), (I-AC), (I-AD), (I-AE), or (I-AF):

[0087] Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts.

[0088] In some embodiments, L 1 It is an optionally substituted phenylene. In some embodiments, L 1 It is a optionally substituted 5- or 6-membered heteroaryl group, such as those having 1 to 3 independently selected cyclic heteroatoms chosen from N, O, and S, for example, a pyridyl group, for example... , which is optionally replaced. In some embodiments, L 1 yes The pyridyl group is optionally substituted with a 5-membered heteroaryl group, such as pyrazole or imidazole. In some embodiments, L1 Selected from: Typically, in such an embodiment, R 1 It is hydrogen (i.e., -L) 1 -R 1 yes , ,or In some embodiments, L 1 It is an optionally substituted 4- to 8-membered subheterocyclic group, such as a monocyclic or bicyclic (e.g., fused, bridged, or spirobicyclic) 4- to 8-membered subheterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S. 1 C is arbitrarily replaced 3-8 Subcarbonyl groups, such as monocyclic or bicyclic (e.g., fused, bridged, or spirobicyclic) subcarbonyl groups.

[0089] In some embodiments, -L 1 -R 1 It has the structure of formula (A):

[0090] Equation (A), in: Q is (1)O; (2)NR 14 , where R 14 It is hydrogen, G A SO2G A SO2NG B G C S(O)(NH)G A COG A COOG A 、or C(O)NG B G C ; (3) CR 15 R 16 , where R 15 and R 16 They are linked together with the carbon atoms to form optionally substituted 4- to 6-membered heterocycles, which have one or two independent cyclic heteroatoms selected from O and N; or (4) Does not exist; r1 is 1, 2, or 3; and r2 is 0, 1, or 2; When valence is allowed, n is 0, 1, 2, 3, or 4; and (i)R 100 Each time it appears, it is independently selected from halogens (e.g., F or Cl), CN, OH, COOH, G.A OG A NG B G C NG B G C SO2G A NG B G C SO2NG B G C NG B G C S(O)(NH)G A NG B G C COG A NG B G C COOG A NG B G C C(O)NG B G C SO2G A SO2NG B G C S(O)(NH)G A COG A COOG A 、or C(O)NG B G C ;or (ii)R 100 Two instances of are linked together with one or more spacer atoms to form optionally substituted rings, such as optionally substituted 3- to 6-membered rings, and any remaining R 100 As defined in (i) each time it occurs; in: G A C is independently and arbitrarily replaced each time it appears. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), or optionally substituted 4- to 10-membered heterocyclic group; and G B and G C Each of them, each time it appears, is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or G B and G CThey can be linked to form optionally substituted 4- to 10-membered heterocyclic groups or 5- or 6-membered heteroaryl groups.

[0091] In some embodiments, the structure having formula (A) has the stereochemistry shown in formula (A-S1) or (A-S2):

[0092] In some embodiments, the compound may exist as a stereoisomer of formula (A-S1), for example having greater than about 60%, greater than about 80%, greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99% ee, or in an amount undetectable by the enantiomer of formula (A-S2).

[0093] In some embodiments, the structure having formula (A) has the stereochemistry shown in formula (A-S3) or (A-S4):

[0094] In some embodiments, Q is absent (i.e., Q is a bond between the two carbon atoms adjacent to Q in the linking formula A). In some embodiments, Q is O. In some embodiments, Q is NR. 14 In some embodiments, Q is CR 15 R 16 .

[0095] In some embodiments, r1 is 1 and r2 is 1. In some embodiments, r1 is 2 and r2 is 1. In some embodiments, r1 is 1 and r2 is 2. In some embodiments, r1 is 2 and r2 is 2. In some embodiments, r1 is 1, r2 is 1, and Q is 0. In some embodiments, r1 is 2, r2 is 1, and Q is 0.

[0096] 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.

[0097] In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes .

[0098] In some embodiments, n is 1 or 2, and R 100 Each time it appears, it is independently selected from F, Cl, CN, OH, and optionally substituted by one or more (e.g., 1, 2, or 3) deuterium, F, or OH. 1-4 Alkyl group, optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F, C 1-4 Alkyl groups, and C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl. In some embodiments, n is 1, and R 100 It is F, Cl, CN, OH, methyl, -CH2OH, fluorine-substituted methyl such as CF3, methoxy, or fluorine-substituted methoxy.

[0099] In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes .

[0100] In some embodiments, n is 2, and the two symmetric Rs are 2. 100 They are linked together with the carbon atoms to which they are attached to form optionally substituted 3- to 6-membered rings. In some embodiments, the ring (consisting of two fused carbon atoms) is further substituted with a carbon atom. 100 (Formed together with the carbon atoms to which they are attached) is C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl). In some embodiments, the ring is a 4- to 6-membered heterocyclic group (e.g., oxetyl). In some embodiments, the ring is unsubstituted. In some embodiments, the ring is separated by one or more (e.g., 1, 2, or 3) deuterium, halogen, CN, OH, or C. 1-3 Alkyl (e.g., methyl) substitution.

[0101] In some embodiments, -L 1 -R1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes .

[0102] In some embodiments, n is 2, and two non-homogeneous R 100 It is linked together with one or more spacer atoms to form an optionally substituted 4- to 6-membered ring. In some embodiments, the ring (consisting of two non-homogeneous R atoms) 100 (Formed together with spacer atoms) is C 4-6 Cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, the ring is a 4- to 6-membered heterocyclic group. In some embodiments, the ring is unsubstituted. In some embodiments, the ring is separated by one or more (e.g., 1, 2, or 3) deuterium, halogen, CN, OH, or C. 1-3 Alkyl (e.g., methyl) substitution.

[0103] In some embodiments, -L 1 -R 1 Having a structure of formula (A-1) or (A-2):

[0104] Equation (A-1), or Equation (A-2), Where Z is C 1-3 Alkylene, wherein the non-terminal CH2 is optionally replaced by O or NH, and wherein Z is optionally replaced by one or more (e.g., 1 or 2) substituents, each of which is independently a halogen, OH, or C optionally replaced by one or more (e.g., 1, 2 or 3) deuterium or F. 1-4 alkyl.

[0105] In some embodiments, Q is O, NH, NHR 17 ,NHC(O)R 17 or NHS(O)2R 17 .

[0106] In some embodiments, Z is -CH2-. In some embodiments, Z is -CH2CH2-. In some embodiments, Z is -CH2CH2CH2-. In some embodiments, Z is -CH2OCH2-. In some embodiments, Z is -CH2NHCH2-.

[0107] In some embodiments, Z is unsubstituted. In some embodiments, Z is substituted by one or more (e.g., 1 or 2) substituents, each of which is independently OH or C. 1-4 Alkyl group. In some embodiments, Z is -CH2C(OH)(CH3)CH2-.

[0108] In some embodiments, -L 1 -R 1 yes , , , , , ,or In some embodiments, -L 1 -R 1 yes , , , , , ,or .

[0109] In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, R 17 C is arbitrarily replaced 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycle, or optionally substituted 5 or 6 membered heteroaryl.

[0110] In some embodiments, R 17 Yes: (1) C 1-4 (1) An alkyl group, optionally substituted with one to three substituents independently selected from deuterium, F, and OH, such as CHF2, CF3, etc.; (2) A phenyl, pyridyl, or pyrimidinyl group, each optionally substituted with one to three substituents independently selected from deuterium, halogen, CN, OH, C, optionally substituted with F. 1-3 Alkyl groups, or C groups optionally substituted with F. 1-3 Alkyl substituent; or (3) a 5-membered heteroaryl group, optionally substituted with 1 to 3 C groups independently selected from deuterium, halogen, CN, OH, optionally substituted with F. 1-3Alkyl groups, or C groups optionally substituted with F. 1-3 Substitution of alkoxy groups.

[0111] In some embodiments, R 17 It is C 1-4 Alkyl, (C 1-4 Alkylene) j -C 3-6 cycloalkyl, (C 1-4 Alkylene) j -(a 4- to 8-membered monocyclic heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S), or (C 1-4 Alkylene) j -(a 5- or 6-membered heteroaryl group having 1 to 3 independent cyclic heteroatoms selected from N, O, and S), Where j is 0 or 1, and the C 1-4 The alkylene group is a straight-chain or branched alkylene chain optionally substituted with F; and Where C 1-4 Alkyl, C 3-6 Each of the cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 8-membered monocyclic heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2, or 3) oxo (where valence permits), halogenated (e.g., F), G 1 OH, OG 1 NH2, NH(G) 1 ) and N(G 1 (G) 1 Substitution of substituents, Among them G 1 Each time it appears independently, it is (1) optionally selected independently from 1 to 3 of F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl group, or (2) optionally composed of one to three independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; When replaced, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 8-membered monocyclic heterocyclic groups, for example, with 1, 2, or 3 C groups, each independently of F, Cl, CN, OH, or optionally substituted with F. 1-4 Alkyl groups, or C groups optionally substituted with F. 1-4 The alkoxy group is substituted, for example, by one, two or three methyl groups that are independently F, OH, methyl, fluorine-substituted (e.g., CF3), methoxy, or fluorine-substituted methoxy groups.

[0112] In some embodiments, j is 0. In some embodiments, j is 1, and the C 1-4 Alkylenes are straight-chain or branched alkylene chains, such as CH2.

[0113] In some embodiments, R 17 It is C 1-4 Alkyl groups, such as methyl, ethyl, isopropyl, etc. In some embodiments, R 17 C is C that is arbitrarily replaced by F. 1-4 Alkyl group. In some embodiments, R 17 It is C 3-6 Cycloalkyl groups, optionally substituted, for example, by the substituents described herein. In some embodiments, R 17 It is a 4- to 8-membered monocyclic heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S, optionally substituted, for example, by the substituents described herein. In some embodiments, R 17 It is a 5-membered heteroaryl group, which is optionally, for example, by C 1-4 Alkyl substitution, for example, R 17 You can choose from: .

[0114] In some embodiments, R 17 It is a phenyl group or a 6-membered heteroaryl group having 1 to 3 cyclic nitrogen atoms, wherein the phenyl or 6-membered heteroaryl group is optionally independently selected by one or more (e.g., 1, 2 or 3) halogenated groups (e.g., F, G). 1 OH, OG 1 NH2, NH(G) 1 ) and N(G 1 (G) 1 Substitution of substituents, Among them G 1 Each time it appears independently, it is (1) optionally selected independently from 1 to 3 of F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl group, or (2) optionally composed of one to three independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl, When substituted, the phenyl or 6-membered heteroaryl group is, for example, replaced by 1, 2, or 3 C groups, each independently of F, Cl, CN, OH, or optionally F-substituted. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 The alkoxy group is substituted, for example, by one or two substituents that are each independently F or methyl.

[0115] In some embodiments, R 17 yes , , , , , , , , ,or .

[0116] In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes In some embodiments, -L 1 -R 1 yes .

[0117] In some embodiments, when ring C is a saturated ring directly substituted with -OH (e.g., formulas (IV), (IM), (IN), (IV), (IW), (IX), (IY), (IZ), or (I-AA), or subformulations thereof), L is also provided herein. 2 Compounds inserted between -OH and the saturated ring. For example, for compounds having formula (IV) or its sub-formulas, corresponding compounds having formula (I-AB) or its sub-formulas are also provided, even if formula (I-AB) is not explicitly shown herein.

[0118] In some embodiments, L 2 Yes - (CR) 32 R 33 ) 1-3 -. In some embodiments, L 2 Yes -CR 32 R 33 -. In some embodiments, L 2 It is CH2. In some embodiments, L 2 It is CH(C) 1-4 Alkyl). In some embodiments, L 2 It is CH(CH3). In some embodiments, L 2 It is C(C) 1-4 Alkyl)2. In some embodiments, L 2 It is C(CH3)2. In some embodiments, L 2 Yes -CR 32 R 33 -, where R 32and R 33 Together with the carbon atoms to which they are attached, they form 3- or 4-membered rings (e.g., cyclopropyl).

[0119] In some embodiments, R 1 It is OH. In some embodiments, R 1 It is NH2. In some embodiments, R 1 It is NHCH3. In some embodiments, R 1 It is N(CH3)2. In some embodiments, R 1 It is hydrogen.

[0120] In some embodiments, X is N. In some embodiments, X is CR. 10 In some embodiments, R 10 It is hydrogen (i.e., X is CH). In some embodiments, R 10 It is a halogen (e.g., F), CN, or -OH.

[0121] In some embodiments, J 1 It is N. In some embodiments, J 1 It is CR 30 In some embodiments, R 30 It is hydrogen (i.e., J) 1 It is CH). In some embodiments, R 30 It is a halogen (e.g., F). In some embodiments, R 30 It is C 1-4 Alkyl (e.g., methyl).

[0122] In some embodiments, J 2 It is N. In some embodiments, J 2 It is CR 30 In some embodiments, R 30 It is hydrogen (i.e., J) 2 It is CH). In some embodiments, R 30 It is a halogen (e.g., F). In some embodiments, R 30 It is C 1-4 Alkyl (e.g., methyl).

[0123] In some embodiments, J 1 It is CR 30 And J 2 It is CR 30 In some embodiments, J 1 It is CH and J 2 It is CH. In some embodiments, J 1 and J 2 Not all are N. In some embodiments, J 1 It is N and J 2 It is CR30 In some embodiments, J 1 It is CR 30 And J 2 It is N. In some embodiments, J 1 It is N and J 2 It is N.

[0124] In some embodiments, the compound is a compound having the formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q), (II-R), (II-S), (II-T), (II-U), (II-V), (II-W), (II-X), (II-Y), (II-Z), (II-AA), (II-AB), (II-AC), (II-AD), (II-AE), (II-AF), or (III-A):

[0125] Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts.

[0126] In some embodiments, R 20A It is hydrogen. In some embodiments, R 20A It is a halogen. In some embodiments, R 20A It is F. In some embodiments, R 20A It is Cl. In some embodiments, R 20A It is CN. In some embodiments, R 20A C is C that is arbitrarily replaced by F. 1-4 Alkyl group. In some embodiments, R 20A It is C 1-4 Alkyl group. In some embodiments, R 20A It is methyl. In some embodiments, R 20A C is C that is arbitrarily replaced by F. 1-4 Heteroalkyl. In some embodiments, C 1-4 The heteroalkyl group has one or two heteroatoms that are independently N or O. In some embodiments, R 20A It is an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocycle, or 5-membered heteroaryl). In some embodiments, R 20A It is hydrogen, halogen (e.g., F or Cl), or C.1-4 Alkyl (e.g., methyl or ethyl).

[0127] In some embodiments, R 21A It is hydrogen. In some embodiments, R 21A It is deuterium. In some embodiments, R 21A It is a halogen. In some embodiments, R 21A It is F. In some embodiments, R 21A It is Cl. In some embodiments, R 21A It is CN. In some embodiments, R 21A It is OH. In some embodiments, R 21A C is C that is arbitrarily replaced by F. 1-4 Alkyl group. In some embodiments, R 21A It is C 1-4 Alkyl group. In some embodiments, R 21A It is methyl. In some embodiments, R 21A It is ethyl. In some embodiments, R 21A It is n-propyl. In some embodiments, R 21A It is isopropyl. In some embodiments, R 21A C is C that is arbitrarily replaced by F. 1-4 Heteroalkyl. In some embodiments, C 1-4 The heteroalkyl group has one or two heteroatoms that are independently N or O. In some embodiments, R 21A C is C that is arbitrarily replaced by F. 1-4 Alkyl group. In some embodiments, R 21A It is an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocycle, or 5-membered heteroaryl). In some embodiments, R 21A It is cyclopropyl. In some embodiments, R 21A It is hydrogen, halogen (e.g., F or Cl), or C. 1-4 Alkyl (e.g., methyl or ethyl). In some embodiments, R 21A It is hydrogen, deuterium, or methyl.

[0128] In some embodiments, X 1 It is O. In some embodiments, X 1 It is NR 31 In some embodiments, X 1 It is CR 32 R 33 In some embodiments, X 1 It is C=O.

[0129] In some embodiments, X 2 It is O. In some embodiments, X 2 It is NR31 In some embodiments, X 2 It is CR 32 R 33 In some embodiments, X 2 It is C=O.

[0130] In some embodiments, R 31 It is hydrogen. In some embodiments, R 31 C is optionally replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl group. In some embodiments, R 31 It is methyl. In some embodiments, R 31 It is CF3. In some embodiments, R 31 It is CD3. In some embodiments, R 31 C is arbitrarily replaced 3-6 Carbocyclic groups (e.g., C10) 3-6 Cycloalkyl groups, such as cyclopropyl groups. In some embodiments, R 31 It is an optionally substituted phenyl group. In some embodiments, R 31 It is optionally substituted with a 4- to 6-membered heterocyclic group (e.g., an oxetane). In some embodiments, R 31 It is optionally a substituted 5- or 6-membered heteroaryl group. In some embodiments, R 31 It is SO2(C 1-4 Alkyl). In some embodiments, R 31 It is SO2Me.

[0131] In some embodiments, R 31 Each time it appears, it is independently either hydrogen or C. 1-4 Alkyl group. In some embodiments, R 31 It is either hydrogen or methyl each time it appears. In some embodiments, the nitrogen is not X. 1 or X 2 R 31 It is hydrogen. In some embodiments, nitrogen is represented by an X. 1 or X 2 R 31 It is hydrogen. In some embodiments, nitrogen is represented by an X. 1 or X 2 R 31 It is C 1-3 Alkyl (e.g., methyl).

[0132] In some embodiments, R 31 and adjacent R 32It is linked with one or more spacer atoms to form optionally substituted 3- to 7-membered rings. In this case, ring C becomes a fused bicyclic ring. In some embodiments, the ring is a 4-membered heterocyclic group. In some embodiments, the ring is a 5-membered heterocyclic group. In some embodiments, the ring is a 6-membered heterocyclic group. In some embodiments, ring C is... , , , , , , , , , , ,or Each of these is optionally substituted (e.g., substituted by one or more (e.g., 1, 2, or 3) substituents, each of which is independently oxo, halogenated, OH, NH2, or C optionally substituted by one or more (e.g., 1, 2, or 3) deuterium or F). 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 (heteroalkyl groups).

[0133] In some embodiments, ring C is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or , where # is a bond fused with ring B. In some embodiments, ring C is , , In some embodiments, ring C is In some embodiments, ring C is .

[0134] In some embodiments, rings C and B together, i.e. yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ,in It is M 1 The location, and It is M 2 The position. In some embodiments, ring C-ring B together are... , , In some embodiments, rings C and B together are In some embodiments, rings C and B together are .

[0135] In some embodiments, when a carbon atom of ring C is substituted with a hydroxyl group, the adjacent carbon atom of ring C is substituted with a non-hydrogen R. 32 (For example, C) 1-4 Alkyl groups (such as methyl) and non-hydrogen R 33 (For example, C) 1-4 Alkyl groups, such as methyl, ethyl, or isopropyl, are substituted. In some embodiments, when the ring carbon atom of the ring C is substituted with a hydroxyl group, R... 21A Not hydrogen (e.g., R) 21A It is C 1-4 Alkyl groups, such as methyl, ethyl, or isopropyl.

[0136] In some embodiments, ring D is an optionally substituted 5-membered ring (e.g., a 5-membered heterocyclic group). In some embodiments, ring D is an optionally substituted 6-membered ring (e.g., a 6-membered heterocyclic group).

[0137] In some embodiments, X 3 Yes -O-. In some embodiments, X 3 It is -S(O)-. In some embodiments, X 3It is -S(O)2-. In some embodiments, X 3 It is -S(O)2-NR 31 -. In some embodiments, X 3 Yes -NR 31 -S(O)2-. In some embodiments, X 3 It is -S(O)(NH)-. In some embodiments, X 3 It is -P(O)(R) 34 In some embodiments, X 3 It is -P(O)(R) 34 )-NR 31 - In some embodiments, X 3 Yes -NR 31 -P(O)(R 34 Unless otherwise stated, the X provided in this document is not intended to be used for other purposes. 3 The left side of the group is further away from M. 1 The direction, and the X provided in this article 3 The right side of the group is closer to M. 1 The direction.

[0138] In some embodiments, M 3 It is C. In some embodiments, M 3 It is N.

[0139] In some embodiments, ring E is a optionally substituted phenyl group. In some embodiments, ring E is an optionally substituted 5-membered heteroaryl group (e.g., imidazolyl or pyrazolyl). In some embodiments, ring E is an optionally substituted 6-membered heteroaryl group (e.g., pyridinyl or pyrimidinyl).

[0140] In some embodiments, the compound is a compound having formula (II-A-1), (II-A-2), (II-A-3), (II-A-4), (II-A-5), (II-A-6), (II-A-7), (II-A-8), (II-A-9), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-B-5), (II-B-6), (II-B-7), (II-B-8), (II-B-9), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-C-5), (II-C-6), (II-C-7), (II-C-8), (II-C-9), (II-D-1), (II-D-2), (II-D-3), (II-E-1), (II-F-1), (II-G-1), (II-H-1), (II-I-1), (II-J-1), (II-K-1), (II-L-1), (II-M-1), (II-M-2), (II-M-3), (II-N-1), (II-N-2), (II-N-3), (II-O-1), (II-O-2), (II-O-3), (II-O-4), (II-P-1), (II-P-2), (II-P-3), (II-P-4), (II-Q-1), (II-R-1), (II-R-2), (II-R-3), (II-R-4), (II-R-5), (II-R-6), (II-R-7), (II-R-8), (II-R-9), (II-R-10), (II-S-1), (II-U-1), (II-U-2), (II-U-3), (II-U-4), (II-U-5), (II-U-6), (II-U-7), (II-V-1), (II-V-2), (II-V-3), (II-W-1), (II-W-2), (II-W-3), (II-X-1), (II-X-2), (II-X-3), (II-X-4), (II-Y-1), (II-Y-2), (II-Y-3), (II-Z-1), (II-AA-1), (II-AB-1), (II-AC-1), (II-AD-1), (II-AE-1), or (III-A-1):

[0141] Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts, wherein: X 4 Is -S(O)-, -S(O)2-, -S(O)(NH)-, or -P(O)(R 34 )-.

[0142] In some embodiments, X 4 It is -S(O)-. In some embodiments, X 4 It is -S(O)2-. In some embodiments, X 4 It is -S(O)(NH)-. In some embodiments, X 4 It is -P(O)(R) 34 )-.

[0143] In some embodiments, when the ring carbon atom of ring C is substituted with a hydroxyl group (e.g., formula (II-V-1), (II-V-2), (II-V-3), (II-W-1), (II-W-2), (II-W-3), (II-X-1), (II-X-2), (II-X-3), (II-X-4), (II-Y-1), (II-Y-2), (II-Y-3), (II-Z-1), or (II-AA-1)), the R on the adjacent ring carbon atom of ring C... 32 and R 33 Neither of them are hydrogen (e.g., the R) 32 and R 33 C is independent 1-4 Alkyl groups, such as methyl, ethyl, or isopropyl. In some embodiments, when the ring carbon atom of the ring C is substituted with a hydroxyl group (e.g., formula (II-V-1), (II-V-2), (II-V-3), (II-W-1), (II-W-2), (II-W-3), (II-X-1), (II-X-2), (II-X-3), (II-X-4), (II-Y-1), (II-Y-2), (II-Y-3), (II-Z-1), or (II-AA-1)), R 21A Not hydrogen (e.g., R) 21A It is C 1-4 Alkyl groups, such as methyl, ethyl, or isopropyl.

[0144] In some embodiments, R 32 and R 33Each of these groups, each appearing independently, is (1) hydrogen or deuterium; (2) a halogen (e.g., F or Cl) or a cyano group; (3) OH, NH2, NH(C) 1-4 alkyl) or N(C) 1-4 Alkyl)(C 1-4 (4) C substituted with one or more (e.g., 1, 2 or 3) substituents. 1-4 Alkyl groups, each of which is independently deuterium, F, OH, NH2, NH(C) 1-4 alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), NH(C) 3-6 cycloalkyl), N(C) 1-4 Alkyl)(C 3-6 cycloalkyl), N(C) 3-6 cycloalkyl)(C 3-6 cycloalkyl), or SO2 (C 1-4 (5) C substituted with one or more (e.g., 1, 2 or 3) deuterium or F. 1-4 Alkyl group, or C group optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; (6) optionally substituted C 3-6 Carbocyclic groups (e.g., C10) 3-6 (7) R cycloalkyl, such as cyclopropyl or cyclobutyl), optionally substituted phenyl, optionally substituted 4- to 6-membered heterocyclic or optionally substituted 5- or 6-membered heteroaryl; 32 and R 33 Together with the carbon atoms to which they are attached, they form carbonyl groups (CO); or (8) R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 Carbocyclic groups (e.g., C10) 3-6 Cycloalkyl (such as cyclopropyl or cyclobutyl) or 4- to 6-membered heterocyclic groups, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (e.g., 1, 2, or 3) substituents, each of which is independently oxo, halogenated, OH, NH2, or optionally substituted by one or more (e.g., 1, 2, or 3) deuterium or F groups. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl groups. In some embodiments, two R... 32 It is linked together with one or more spacer atoms to form an optionally substituted 3- to 7-membered ring. In some embodiments, the ring (consisting of two R atoms) 32 (Formed together with spacer atoms) are 4- to 6-membered heterocyclic groups (including those not X) 1 or X 2(nitrogen). In some embodiments, the ring is unsubstituted (not counting the non-X on nitrogen). 1 or X 2 R 31 In some embodiments, the ring is surrounded by one or more (e.g., 1, 2, or 3) deuterium, halogen, CN, OH, or C. 1-3 Alkyl (e.g., methyl) substitution (not counting non-X on nitrogen) 1 or X 2 R 31 ).

[0145] In some embodiments, R 32 Each time it appears, it is independently hydrogen, halogen, OH, or C optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkoxy, and R 33 Each time it appears, it is independently hydrogen, halogen, or optionally C replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl group. In some embodiments, R 32 Each time it appears, it is independently either hydrogen or methyl, and R 33 It is either hydrogen or methyl each time it appears. In some embodiments, R 32 and R 33 Together with the carbon atoms to which they are attached, they form carbonyl (CO) groups. In some embodiments, R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 Carbocyclic groups (e.g., C10) 3-6 Cycloalkyl (e.g., cyclopropyl) or 4- to 6-membered heterocyclic groups (e.g., oxetyl). In some embodiments, R 32 and R 33 Together with the carbon atoms to which they are attached, they form cyclopropyl groups.

[0146] When there is more than one CR 32 R 33 At that time, CR 32 R 33 Each instance of CR is defined independently of the others. In some embodiments, for CR 32 R 33 One example, R 32 Is it hydrogen or C? 1-4 Alkyl (e.g., methyl or ethyl), and R 33 Is it hydrogen or C? 1-4 Alkyl (e.g., methyl or ethyl). In some embodiments, CR 32 R 33One example is CH2. In some embodiments, CR 32 R 33 One example is CH(CH3). In some embodiments, CR 32 R 33 One example is C(CH3)2. In some embodiments, for CR 32 R 33 One example, R 32 and R 33 Together with the carbon atoms attached to them, they form carbonyl (CO) groups. In some embodiments, for CR... 32 R 33 One example, R 32 and R 33 Together with the carbon atoms to which they are attached, they form 3- to 4-membered rings (e.g., cyclopropyl).

[0147] In some embodiments, for those not X 1 or X 2 CR 32 R 33 R 32 and R 33 All are C 1-4 Alkyl, or R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 Carbocyclic or 4- to 6-membered heterocyclic groups. In some embodiments, for those not X 1 or X 2 CR 32 R 33 R 32 and R 33 All are methyl groups. In some embodiments, for those not X 1 or X 2 CR 32 R 33 R 32 and R 33 Together with the carbon atoms to which they are attached, they form cyclopropyl groups.

[0148] In some embodiments, R 34 It is hydrogen. In some embodiments, R 34 C is optionally replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl group. In some embodiments, R 34 It is methyl. In some embodiments, R 34 It is ethyl. In some embodiments, R 34 It is cyclopropyl.

[0149] In some embodiments, R 3It is hydrogen. In some embodiments, R 3 It is a halogen. In some embodiments, R 3 It is F. In some embodiments, R 3 It is Cl. In some embodiments, R 3 It is Br. In some embodiments, R 3 It is CN. In some embodiments, R 3 It is C(O)NR 11 R 12 In some embodiments, R 3 It is C(O)NH2. In some embodiments, R 3 C is optionally replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-6 Alkyl (e.g., C) 1-4 Alkyl group). In some embodiments, R 3 C is arbitrarily replaced 3-8 Carbocyclic group. In some embodiments, R 3 It is a 4- to 10-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, R 3 It is a 5- to 10-membered heteroaryl group having 1 to 4 independently selected cyclic heteroatoms chosen from N, O and S, which are optionally substituted.

[0150] In some embodiments, R 3 It is hydrogen, F, Cl, Br, CN, or C optionally substituted with F. 1-4 alkyl.

[0151] In some embodiments, R 3 C is arbitrarily replaced 1-4 Alkyl group. In some embodiments, R 3 It is optionally selected by one or more, for example, 1 to 3 independently selected from deuterium, F, CN, or OR. C The substituents of C 1-4 Alkyl, wherein R C Each time it appears, it is independently and optionally selected from 1 to 3 independently from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, R 3 It is methyl, CD3, CH2-OMe, CH2-OCD3, ethyl, CHF2, CF2CH3, CH2CH2F, CH2CF2H, or CF3. In some embodiments, R 3 It is CF2CF3.

[0152] In some embodiments, R 3 C is arbitrarily replaced 2-4 alkenyl, for example , ,or In some embodiments, R 3 C is arbitrarily replaced 2-4 alkynyl groups, for example .

[0153] In some embodiments, R 3 Is it OR A In some embodiments, R 3 Is it OR A And R A It is hydrogen, optionally composed of one to three independently selected elements from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0154] In some embodiments, R 3 It is C(O)R B In some embodiments, R 3 It is C(O)R B And R B It is hydrogen, optionally composed of one to three independently selected elements from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0155] In some embodiments, R 3 It is C 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), 4- to 6-membered heterocyclic groups having one or two independently selected cyclic heteroatoms chosen from N, O, and S, such as oxocyclobutyl or tetrahydrofuranyl, or 5- or 6-membered heteroaryl groups having one to four independently selected cyclic heteroatoms chosen from N, O, and S, such as thiazolyl, each optionally having one to three independently selected oxo (if applicable), deuterium, F, CN, G 1 OH, OG 1 NH2, NH(G) 1 ), N(G 1 (G) 1 ), C(O)-NH2, C(O)-NH(G)1 ), and C(O)-N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1 to 3 independently from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0156] In some embodiments, R 3 Selected from: .

[0157] In some embodiments, R 4 It is hydrogen. In some embodiments, R 4 It is deuterium. In some embodiments, R 4 It is a halogen (e.g., F), or optionally substituted C. 1-6 Alkyl, or NR 11 R 12 In some embodiments, R 4 It is NH2.

[0158] In some embodiments, the compounds listed in Table 1, or stereoisomers thereof, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts thereof are provided herein.

[0159] Table 1. List of compounds

[0160] In some embodiments, the compounds listed in Table 1A, or stereoisomers thereof, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts thereof are provided herein.

[0161] Table 1A. List of Compounds

[0162] The compounds in Table 1 or Table 1A may exist in a variety of stereoisomeric forms, such as individual isomers, individual enantiomers and / or diastereomers (if applicable), or mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, when applicable, the compounds shown in Table 1 or Table 1A may have an enantiomer excess (“ee”) of more than about 60%, such as more than about 80%, more than about 90%, more than about 90%, more than about 95%, more than about 98%, more than about 99%, or other enantiomers in undetectable amounts. In some embodiments, when applicable, the compounds shown in Table 1 or Table 1A may also exist as mixtures of stereoisomers (in any ratio), such as racemic mixtures.

[0163] In some embodiments, to the extent applicable, the compound categories provided herein also exclude any single compound specifically known prior to this disclosure. In some embodiments, to the extent applicable, any subclass or species of compound that previously belonged entirely to the compound categories provided herein may also be excluded from such categories of compounds provided herein.

[0164] Given the information provided herein and synthetic knowledge in the art, the compounds described herein can be readily synthesized by those skilled in the art. Exemplary synthesis is also shown in the Examples section.

[0165] As will be apparent to those skilled in the art, conventional protecting groups are necessary to protect certain functional groups from undesirable reactions. Suitable protecting groups for various functional groups, and suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in “Protective Groups in Organic Synthesis”, 4th edition, PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents used in the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other reagents can be prepared by procedures described in the following standard reference texts or by obvious modifications thereof: for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (Wiley, 7th edition); and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any available updated versions up to the date of this application.

[0166] Pharmaceutical Composition This article also provides pharmaceutical compositions comprising one or more of the compounds provided herein.

[0167] Pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients. In some embodiments, a pharmaceutical composition comprises a compound provided herein and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art. Suitable excipients, without limitation, include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavorings, humectants, lubricants, fragrances, preservatives, propellants, anti-sticking agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st edition, AR Gennaro (Lipincott, Baltimore, MD, Williams & Wilkins, 2005; incorporated herein by reference), describes the various excipients used to formulate pharmaceutical compositions and the known techniques for preparing pharmaceutical compositions.

[0168] The pharmaceutical composition may comprise any one or more compounds provided herein. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount (e.g., for treating breast or ovarian cancer) of a compound provided herein. In some embodiments, the pharmaceutical composition may comprise a compound selected from the compounds provided herein that has a CDK4 / cyclin D1 IC50 level designated as “A” or “B” (“A” in Table 2 provided herein in some embodiments).

[0169] The pharmaceutical compositions described herein can be formulated for delivery via any known route of delivery, including but not limited to oral, nasal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration.

[0170] In some embodiments, the pharmaceutical composition is formulated for oral administration. The oral formulation can exist in discrete units, such as capsules, pills, tablets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients used to prepare the oral administration composition are known in the art. Suitable, non-limiting excipients include, for example, agar, alginate, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, and peanut oil. Oil), potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearic fumarate, sucrose, surfactant, talc, astragalus gum, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[0171] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulation may be, for example, an aqueous solution, suspension, or emulsion. Excipients used to prepare the parenteral formulation are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, wheat germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0172] The compounds described herein can be used alone, in combination with each other, or in combination with one or more other therapeutic agents, such as other anticancer therapeutic agents, such as mitosis inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as protein tyrosine kinase and / or serine / threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immunotumor agents, etc. In some embodiments, one or more of the compounds provided herein may be used in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src / Abl, RTK / Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK2, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2, or Hsp90, or immunomodulators, such as PD-1 or PD-L1 antagonists, OX40 agonists, or 4-1BB agonists. In some embodiments, one or more of the compounds provided herein may be used in combination with standard therapeutic agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable alternative anticancer therapies include any of those known in the art, such as those approved by regulatory agencies such as the U.S. Food and Drug Administration for the appropriate cancer. Some examples of suitable alternative anticancer therapies also include those described as suitable for use in combination with CDK inhibitors as described in WO 2019 / 207463, WO 2020 / 224568, etc., the contents of which are incorporated herein by reference in their entirety.

[0173] When used in combination with one or more other therapeutic agents, the compounds or pharmaceutical compositions provided herein may be administered to a subject simultaneously or sequentially with such other therapeutic agents in any order. In some embodiments, a pharmaceutical composition may comprise one or more compounds provided herein and one or more other therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition comprising one or more compounds provided herein may be included in a kit that also comprises a separate pharmaceutical composition comprising one or more other therapeutic agents.

[0174] Pharmaceutical compositions may comprise various amounts of the compounds provided herein, depending on various factors such as the intended use of the compound and its potency and selectivity. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of the compounds provided herein. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of the compounds provided herein and one or more pharmaceutically acceptable excipients. As used herein, a therapeutically effective amount of the compounds provided herein is an amount that is effective in treating the disease or disorder provided herein, such as breast cancer or ovarian cancer, and may depend on the recipient of treatment, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0175] How to use Not limited by any particular theory, the compounds provided herein have a variety of uses. For example, the compounds provided herein can be used as therapeutic active substances for the treatment and / or prevention of CDK4-mediated diseases or disorders. Accordingly, this document also provides methods for using one or more of the compounds provided herein or pharmaceutical compositions provided herein for the treatment or prevention of CDK4-mediated diseases or disorders in subjects in need, such as for the treatment of cancer in subjects in need.

[0176] In some embodiments, this document provides a method for inhibiting abnormal cell growth in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, the abnormal cell growth is CDK4-related cancer.

[0177] In some embodiments, this document provides methods for inhibiting CDK activity in a subject or biological sample. In some embodiments, this document provides methods for inhibiting CDK4 activity in a subject or biological sample, the method comprising contacting the subject or biological sample with an effective amount of a compound or pharmaceutical composition provided herein.

[0178] In some embodiments, this document provides methods for treating or preventing CDK-mediated, particularly CDK4-mediated, diseases or disorders in subjects of need. In some embodiments, the method includes administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, the CDK4-mediated disease or disorder is cancer.

[0179] In some embodiments, this document provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound provided herein or an effective amount of a pharmaceutical composition provided herein.

[0180] In some embodiments, this document provides for the use of the compounds or pharmaceutical compositions provided herein in the manufacture of a medicament for treating cancer. In some embodiments, this document provides for the use of the compounds or pharmaceutical compositions provided herein in the treatment of cancer. In some embodiments, this document provides for the use of the compounds or pharmaceutical compositions provided herein in the treatment of cancer. In some embodiments, this document provides for the use of the compounds or pharmaceutical compositions provided herein in the treatment of cancer in a method of treating cancer, wherein the method includes administering an effective amount of the compounds or pharmaceutical compositions provided herein to a subject in need.

[0181] In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer, thyroid cancer, and combinations thereof. In some embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and / or gastric cancer.

[0182] In some embodiments, the cancer is breast cancer, such as ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer may be endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer may be advanced or metastatic breast cancer.

[0183] In some embodiments, the cancer is ovarian cancer.

[0184] In some embodiments, the compounds provided herein are administered as first-line therapy. In other embodiments, the compounds provided herein are administered as second-line (or later-stage) therapy. In some embodiments, the compounds provided herein are administered as second-line (or later-stage) therapy after treatment with an endocrine therapy agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, the compounds provided herein are administered as second-line (or later-stage) therapy after treatment with an endocrine therapy agent, such as an aromatase inhibitor, SERM, or SERD. In some embodiments, the compounds provided herein are administered as second-line (or later-stage) therapy after treatment with a CDK4 / CDK6 inhibitor. In some embodiments, the compounds provided herein are administered as second-line (or later-stage) therapy after treatment with one or more chemotherapy regimens, including taxanes or platinum agents. In some embodiments, the compounds provided herein are administered as second-line (or later-stage) therapy after treatment with a HER2-targeting agent, such as trastuzumab.

[0185] In some embodiments, this document provides a method for treating or preventing breast cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition provided herein. In some embodiments, the breast cancer is selected from: ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the breast cancer is selected from endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0186] In some embodiments, the compounds provided herein for use in the methods provided herein have CDK4 / cyclin D1 IC4 concentrations of less than 100 nM or less than 10 nM as measured / calculated according to Biological Example 1 herein. 50 In some embodiments, the compounds provided herein for use in the methods provided herein are selected from CDK4 / cyclin D1 ICs having been designated as “A” or “B” in Table 2 herein, and designated as “A” in some embodiments. 50 Horizontal compounds.

[0187] In some embodiments, the compounds provided herein for use in the methods provided herein are selective for CDK4 relative to CDK6. In some embodiments, the compounds provided herein for use in the methods provided herein may also be selective for CDK4 relative to other CDKs. As a non-limiting example, the selectivity ratio may be greater than about 5 times, greater than about 10 times, greater than about 25 times, greater than about 50 times, greater than about 100 times, greater than about 200 times, greater than about 300 times, greater than about 400 times, greater than about 500 times, greater than about 600 times, greater than about 800 times, or greater than about 1000 times, wherein the selectivity can be determined by IC1 50 The selectivity of CDK4 relative to CDK6 (or other CDKs) is measured by means of ratios of values. In some embodiments, the selectivity of CDK4 relative to CDK6 (or other CDKs) is measured by ICs for CDK6 (or other CDKs). 50 Values ​​and ICs for CDK4 50 It is measured by the ratio of values.

[0188] In some embodiments, this document provides a method for inhibiting the proliferation of cancer cells in a subject, the method comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof in an amount that effectively inhibits cell proliferation.

[0189] In some embodiments, this document provides a method for inhibiting cancer cell invasiveness in a subject, the method comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof in an amount that effectively inhibits cell invasiveness.

[0190] In some embodiments, this document provides a method for inducing apoptosis in cancer cells of a subject, the method comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof in an amount that effectively induces apoptosis.

[0191] In some embodiments, this document provides a method for inhibiting cancer cell metastasis in a subject, the method comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof in an amount that effectively inhibits cell metastasis.

[0192] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the administration is oral. In some embodiments, the administration is parenteral injection, such as intravenous injection.

[0193] The compounds provided herein can be used as monotherapy or in combination therapy. In some embodiments of the methods provided herein, one or more of the compounds provided herein may be administered as the sole or only active ingredient. In some embodiments of the methods provided herein, one or more of the compounds provided herein may also be administered co-administered with additional therapeutic agents, simultaneously or sequentially to subjects in need. Additional therapeutic agents can typically be additional anticancer agents, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase and / or serine / threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immunotumor agents, etc. In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, SERD, or SERM. In some embodiments, one or more of the compounds provided herein may be administered in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src / Abl, RTK / Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK2, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2, or Hsp90, or immunomodulators, such as PD-1 or PD-L1 antagonists, OX40 agonists, or 4-1BB agonists. In some embodiments, one or more of the compounds provided herein may be administered in combination with standard therapeutic agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable alternative anticancer therapies include any of those known in the art, such as those approved by regulatory agencies such as the U.S. Food and Drug Administration for the appropriate cancer. Some examples of suitable alternative anticancer therapies also include those described as suitable for use in combination with CDK inhibitors as described in WO 2019 / 207463, WO 2020 / 224568, etc., the contents of which are incorporated herein by reference in their entirety.

[0194] Dosing regimens (including the dosages of the methods provided herein) may vary and be adjusted depending on the recipient of treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0195] Example The various starting materials, intermediates, and compounds described herein can be separated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Characterization of these compounds can be performed using conventional methods, such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. The abbreviations used in the Examples section should be understood to have their common meaning in the art, unless otherwise specifically stated or clearly contrary to the context. The examples are merely illustrative and do not limit the claimed invention in any way.

[0196] Exemplary embodiments of the steps for performing the synthesis of the products provided herein are described in more detail below. Some of the examples discussed herein can be prepared by separation from the corresponding racemic mixtures. As will be understood by those skilled in the art, prior to the chiral separation step, for example by supercritical fluid chromatography (SFC), the compounds described in the Examples section are in the form of racemic and / or stereoisomer mixtures, with relative stereochemistry indicated in bold rather than wedges in the chemical structure diagram. It should be understood that the enantiomer excess (“ee”) and / or diastereomer excess (“de”) reported for these examples represent exemplary procedures provided herein and are not limiting; those skilled in the art will understand that, given the information provided herein, such enantiomers with different ee and / or de, such as higher ee and / or higher de, can be obtained.

[0197] In some illustrative examples, the synthesis of deuterated compounds is shown. It should be understood, within the scope of application, that the corresponding non-deuterated (i.e., naturally abundant) compounds are prepared by the same method, except that they use the corresponding non-deuterated starting materials or intermediates.

[0198] Example 1.(3) S 4 R )-4-((5-chloro-4-(7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydropyrido[4,3- c [[Pyriminin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2] H -pyran-3-ol(1)

[0199] At 0°C, triethylamine (4.81 g, 47.5 mmol, 6.62 mL) and diphenylphosphoazide (17.4 g, 63.4 mmol, 13.7 mL) were added to a solution of 2,2-dimethylpentan-4-ynyl acetic acid (1.1 g, 4.00 g, 31.7 mmol) in toluene (40 mL). The mixture was stirred at 80°C for 2 hours, followed by the addition of benzyl alcohol (13.7 g, 126 mmol, 13.1 mL), and the resulting mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give benzyl (2-methylpentan-4-ynyl-2-yl)carbamate (1.2 g, 5.00 g, 68.2%) as a colorless oil. 1 H NMR (400 MHz, CDCl3-) d ) δ = 7.37 - 7.32 (m, 5H), 5.08 (s, 2H), 4.88(br s, 1H), 2.63 (d, J = 1.5 Hz, 2H), 2.03 (s, 1H), 1.41 (s, 6H).

[0200] To a solution of (2-methylpentan-4-yn-2-yl)carbamate (1.2, 5.00 g, 21.6 mmol) and 4-chloro-2-fluoro-6-iodoaniline (5.10 g, 18.8 mmol) in acetonitrile (24 mL), bis(triphenylphosphine)palladium(II) dichloride (659 mg, 940 μmol), cuprous iodide (322 mg, 1.69 mmol), and triethylamine (19.0 g, 188 mmol, 26.2 mL) were added. The resulting mixture was stirred at 50°C for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain benzyl 5-(2-amino-5-chloro-3-fluorophenyl)-2-methylpent-4-yn-2-yl)carbamate (1.3, 6.10 g, 86.6%) as a yellow solid. 1 H NMR (400 MHz, CDCl3-) d ) δ = 7.38 - 7.31 (m,5H), 7.03 - 6.93 (m, 2H), 5.09 (s, 2H), 4.88 (br s, 1H), 2.94 (s, 2H), 1.45(s, 6H).

[0201] At 0°C, HBr (109 g, 215 mmol, 73 mL, 16 wt.%) and NaNO₂ (1.19 g, 17.3 mmol) were added to a solution of (5-(2-amino-5-chloro-3-fluorophenyl)-2-methylpentan-4-yn-2-yl)carbamate (1.3 g, 5.90 g, 15.7 mmol) in acetone (130 mL). The mixture was stirred at 0°C for 10 min, followed by the addition of NaBr (32.4 g, 314 mmol, 10 mL) in water (50 mL). The resulting mixture was stirred at 45°C for 1 h. The mixture was concentrated under vacuum and extracted with dichloromethane (60 mL × 2). The combined organic layers were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain benzyl (1-(4-bromo-6-chloro-8-fluoropyrin-3-yl)-2-methylpropyl-2-yl)carbamate (1.4, 4.60 g, 62.6%) as a yellow solid. LC-MS (ESI) m / z 466.1 [M+H] + .

[0202] To a solution of (1-(4-bromo-6-chloro-8-fluoropyrin-3-yl)-2-methylpropyl-2-yl)carbamate (1.4, 2.00 g, 4.29 mmol) in THF (20 mL) and H₂O (2 mL), NaHCO₃ (720 mg, 8.57 mmol, 333 μL), 1,1'-bis(di-tert-butylphosphine)ferrocene palladium(II) dichloride (279 mg, 428 μmol), and potassium vinyltrifluoroborate (574 mg, 4.29 mmol) were added. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (100 mL) and then extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain a yellow solid (1.5, 970 mg, 54.7%) of benzyl (1-(6-chloro-8-fluoro-4-vinylcenolin-3-yl)-2-methylpropyl-2-yl)carbamate. LC-MS (ESI) m / z 414.1 [M+H] + .

[0203] At 0°C, NaIO4 (3.36 g, 15.7 mmol) and K2OsO4·2H2O (115 mg, 314 μmol) were added to a solution of (1-(6-chloro-8-fluoro-4-vinylcenolin-3-yl)-2-methylpropyl-2-yl)carbamate (1.5, 1.30 g, 3.14 mmol) in THF (100 mL) and H2O (20 mL). The mixture was stirred at 20°C for 12 hours, followed by the addition of NaIO4 (3.36 g, 15.7 mmol) and K2OsO4·2H2O (57.8 mg, 157 μmol) at 0°C, and the resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was quenched with water (150 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground at 20°C with dichloromethane / ethyl acetate / methyl tert-butyl ether (1 / 1 / 8) for 20 minutes to give a white solid of 9-chloro-7-fluoro-1-hydroxy-3,3-dimethyl-3,4-dihydropyrido[4,3- c ] cinnamon-2(1 H Benzyl formate (1.6, 920 mg, 70.4%). LC-MS (ESI) m / z 416.0 [M+H] + .

[0204] To 9-chloro-7-fluoro-1-hydroxy-3,3-dimethyl-3,4-dihydropyrido[4,3- c ] cinnamon-2(1 H Benzyl formate (1.6, 600 mg, 1.44 mmol) and bis(pinacol)diboron (476 mg, 1.88 mmol) were added to a solution of dioxane (10 mL) with XPhos (137 mg, 288 μmol), Pd2(dba)3 (132 mg, 144 μmol), and KOAc (424 mg, 4.33 mmol). The mixture was stirred at 100°C for 1.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give (2-((benzyloxy)carbonyl)-7-fluoro-1-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydropyridino[4,3- c (1.7, 1.92 g, crude) boronic acid (Crude). LC-MS (ESI) m / z 426.0 [M+H] + .

[0205] To (2-((benzyloxy)carbonyl)-7-fluoro-1-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydropyrido[4,3- c 9-(2,5-dichloropyrimidin-4-yl)boronic acid (1.7, 1.92 g, crude) and 2,4,5-trichloropyrimidine (423 mg, 2.31 mmol) in a solution of dioxane (15 mL) and H2O (3 mL) were mixed with Pd(dppf)Cl2 (105 mg, 144 μmol) and K2CO3 (398 mg, 2.88 mmol). The mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1-hydroxy-3,3-dimethyl-3,4-dihydropyridino[4,3-] as a white solid. c ] cinnamon-2(1 H Benzyl formate (1.8, 460 mg). LC-MS (ESI) m / z 528.2 [M+H] + .

[0206] To 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1-hydroxy-3,3-dimethyl-3,4-dihydropyrido[4,3- c ] cinnamon-2(1 H Benzyl formate (1.8, 100 mg, 189 μmol) was added to a solution of dichloromethane (2 mL) with trifluoroacetic acid (767 mg, 6.73 mmol, 0.5 mL) and Et3SiH (182 mg, 1.57 mmol, 0.25 mL), and the mixture was stirred at 0°C for 15 minutes. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown oily substance, 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-3,4-dihydropyrido[4,3- c ] cinnamon-2(1 H Benzyl formate (1.9, 90.0 mg, crude). LC-MS (ESI) m / z 512.2 [M+H] + .

[0207] At -70°C, 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-3,4-dihydropyrido[4,3-] c ] cinnamon-2(1 H Benzyl formate (1.9, 90.0 mg, crude) was added dropwise to a solution of BBr3 (263 μL, 2 M) in dichloromethane (5 mL), and the mixture was stirred at -70°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with water (5 mL) at -70°C and then extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydropyrido[4,3-]carboxy[ ... c [Criminal] (1.10, 66.0 mg, crude). LC-MS (ESI) m / z 378.1 [M+H] + .

[0208] To 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydropyrido[4,3- c ] cinnarizine (1.10, 66.0 mg, crude) and (3 S 4 R )-4-aminotetrahydro-2 H 3-pyran-3-ol hydrochloride (80.4 mg, 523 μmol) was added to a solution of DMSO (2 mL) with K₂CO₃ (144 mg, 1.05 mmol), KF (60.8 mg, 1.05 mmol), and 18-crown-6 (18.4 mg, 69.8 μmol). The mixture was stirred at 120°C for 45 min. The reaction mixture was cooled to room temperature, and then NaBH₄ (9.94 mg, 262 μmol) was added, followed by stirring at 20°C for 10 min. The resulting mixture was filtered, and the filtrate was subjected to preparative HPLC to obtain a pale yellow solid (3... S 4 R )-4-((5-chloro-4-(7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydropyrido[4,3- c [[Pyriminin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2] H 3-Pyran-3-ol (1, 13.0 mg). LC-MS (ESI) m / z 459.1 [M+H] + . 1 H NMR (400 MHz, CD3CN-) d3) δ = 8.42 (s, 1H), 8.23 ​​(s, 1H),7.88 (br d, J = 10.8 Hz, 1H), 6.06 (br d, J = 7.6 Hz, 1H), 4.44 (s, 2H), 3.94 -3.84 (m, 3H), 3.55 (br d, J = 6.6 Hz, 1H), 3.42 (br d, J = 2.2 Hz, 1H), 3.21 (s,2H), 3.16 - 3.09 (m, 1H), 2.06 - 2.02 (m, 1H), 1.65 - 1.56 (m, 1H), 1.23 (s,6H).

[0209] Example 2.(3) S 4 R )-4-((5-chloro-4-(6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydroimidazo[1,2- a :5,4- c' [Bipyridin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2 H -pyran-3-ol(2)

[0210] A mixture of 5-bromo-3-fluoropyridin-2-amine (2.1, 3.20 g, 16.8 mmol), tert-butyl 2,2-dimethyl-4-oxopiperidin-1-carboxylate (5.70 g, 25.2 mmol), and elemental sulfur (2.70 g, 84.0 mmol) in DMSO (4.20 g) was stirred at 120°C for 16 hours in a sealed tube. The mixture was concentrated under reduced pressure, subjected to silica gel column chromatography, and further purified by preparative TLC (PE:EA = 3:1) to give 8-bromo-6-fluoro-3,3-dimethyl-3,4-dihydroimidazo[1,2-] as a yellow solid. a :5,4- c ']Bipyridine-2(1 H 2-Tetrabutyl formate (2.2, 135 mg, 1.8%). LC-MS (ESI) m / z 398.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.02 (d, J= 9.6 Hz, 1H), 4.72 (s, 2H), 2.95 (s, 2H), 1.55 (s, 6H), 1.49 (s, 9H).

[0211] To 8-bromo-6-fluoro-3,3-dimethyl-3,4-dihydroimidazo[1,2- a :5,4- c ']Bipyridine-2(1 H 2-(tert-butyl formate) (2.2, 135 mg, 0.34 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,4-dioxane (172 mg, 0.68 mmol) and potassium acetate (66.5 mg, 0.68 mmol) in 1,4-dioxane (12 mL) were mixed with Pd2(dba)3 (15.0 mg, 0.034 mmol) and Xphos (32.0 mg, 0.068 mmol). The resulting mixture was stirred at 90°C for 4 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a brown oily substance (2-(tert-butyloxycarbonyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydroimidazo[1,2- a :5,4- c Bipyridin-8-yl)boronic acid (2.3, 360 mg, crude). LC-MS (ESI) m / z 364.1 (M+H) + .

[0212] (2-(tert-butoxycarbonyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydroimidazo[1,2- a :5,4- c A mixture of 8-(2,5-dichloropyrimidin-4-yl)boronic acid (2.3, 360 mg, crude), 2,4,5-trichloropyrimidine (75.0 mg, 0.41 mmol), Pd(dppf)Cl2 (26.0 mg, 0.034 mmol), and Na2CO3 (73.0 mg, 0.68 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3,3-dimethyl-3,4-dihydroimidazo[1,2-] as a yellow solid.a :5,4- c ']Bipyridine-2(1 H tert-butyl formate (2.4, 55.0 mg, two-step 35%). LC-MS (ESI) m / z 466.2 (M+H) + .

[0213] 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3,3-dimethyl-3,4-dihydroimidazo[1,2- a :5,4- c ']Bipyridine-2(1 H )-tert-butyl formate (2.4, 55.0 mg, 0.12 mmol), (3 S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (7, 21.4 mg, 0.14 mmol), 18-crown-6 (6.20 mg, 0.024 mmol), potassium fluoride (21.0 mg, 0.36 mmol), and potassium carbonate (16 mg, 0.12 mmol) in DMSO (2 mL) was stirred at 105°C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (10 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to preparative TLC to give 8-(5-chloro-2-(((3)) as a yellow solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,3-dimethyl-3,4-dihydroimidazo[1,2-] a :5,4- c ']Bipyridine-2(1 H 2,5-Tetrabutyl formate (2.5, 60.0 mg, 93%). LC-MS (ESI) m / z 547.0 (M+H) + .

[0214] To 8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,3-dimethyl-3,4-dihydroimidazo[1,2-] a :5,4- c ']Bipyridine-2(1 Htert-butyl formate (2.5, 60.0 mg, 0.11 mmol) was added to a solution of tert-butyl formate in methanol (3 mL) with hydrochloric acid (3 mL, 4 M in dioxane), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and then concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), followed by the addition of NaBH4 (4 mg, 0.11 mmol). The mixture was stirred at room temperature for 10 minutes and filtered. The filtrate was subjected to preparative HPLC to give a white solid (3... S 4 R )-4-((5-chloro-4-(6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydroimidazo[1,2- a :5,4- c ']bipyridine-8-yl)pyrimidin-2-yl)amino)tetrahydro-2 H 3-Pyran-3-ol (2, 10.9 mg, 22%). LC-MS (ESI) m / z 447.2 (M+H) + . 1 H NMR (400 MHz, CD3OD- d 4) δ8.66 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 7.66 (d, J = 11.6 Hz, 1H), 4.42 (s,2H), 4.08 - 3.84 (m, 3H), 3.65-3.55 (m, 1H), 3.53 - 3.43 (m, 1H), 3.21 (t, J =11.2, 1H), 2.95 (s, 2H), 2.18 - 2.02 (m, 1H), 1.70-1.55 (m, 1H), 1.42 (s, 6H).

[0215] Example 3.9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3,5-trimethyl-1,3,4,5-tetrahydrobenzo[ c [1,6]Naphthyl-6(2 H )-ketone (3)

[0216] To a solution of 4-chloro-2-fluorobenzoic acid (3.1 g, 4.00 g, 22.9 mmol) in DMF (60 mL), (diacetoxyiodo)benzene (8.10 g, 25.2 mmol), I₂ (6.40 g, 25.2 mmol), and Pd(OAc)₂ (0.26 g, 1.14 mmol) were added. The resulting mixture was stirred at 120°C for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL) and washed with saturated aqueous Na₂S₂O₃ (30 mL × 3), 1 N HCl (30 mL × 3), and brine (50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated to give 4-chloro-2-fluoro-6-iodobenzoic acid (3.2 g, 3.80 g, 44%) as a dark brown oil. LC-MS (ESI) m / z 298.7 (MH) + .

[0217] Oxaloyl chloride (3.20 g, 24.9 mmol) and DMF (5 drops) were added to a solution of 4-chloro-2-fluoro-6-iodobenzoic acid (3.2, 2.50 g, 8.30 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (40 mL), followed by the addition of ammonium hydroxide (15 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum and diluted with brine (50 mL). The mixture was then adjusted to pH 3–4 with 1 N HCl aqueous solution and extracted with ethyl acetate (200 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-chloro-2-fluoro-6-iodobenzoamide (3.3, 1.60 g, 64%) as a white solid. LC-MS (ESI) m / z 299.8 (M+H) + .

[0218] A mixture of 4-chloro-2-fluoro-6-iodobenzamide (3.3, 1.20 g, 4.00 mmol), tert-butyl 2,2-dimethyl-4-oxopiperidin-1-carboxylate (1.40 g, 6.00 mmol), CuBr (57.0 mg, 0.40 mmol), and Cs₂CO₃ (2.60 g, 8.00 mmol) in DMSO (25 mL) was stirred at 80°C for 24 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with brine (30 mL × 4). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-chloro-7-fluoro-3,3-dimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[] as a white solid. c [1,6]Naphthyl-2(1 H tert-butyl formate (3.4, 240 mg, 16%). LC-MS (ESI) m / z 381.0 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 11.31 (brs, 1H), 7.36 (s, 1H), 7.11 (d, J = 10.4 Hz, 1H), 4.54 (s, 2H), 2.76 (s, 2H), 1.52 (s, 9H), 1.25 (s, 6H).

[0219] At 0°C, 9-chloro-7-fluoro-3,3-dimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[ c [1,6]Naphthyl-2(1 H Iodimethane (179 mg, 1.26 mmol) was added to a mixture of tert-butyl formate (3.4, 320 mg, 0.84 mmol) and Cs₂CO₃ (547 mg, 1.68 mmol, 2.0 equivalence) in DMF (10 mL), and the resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (10 mL × 4). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-chloro-7-fluoro-3,3,5-trimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[] as a white solid. c [1,6]Naphthyl-2(1 H tert-butyl formate (3.5, 201 mg, 60%). LC-MS (ESI) m / z395.2 (M+H) + . 1 H NMR(400 MHz, CDCl3) δ 7.35(s, 1H), 7.10 (d, J = 11.2 Hz, 1H), 4.54 (s, 2H), 3.58 (s, 3H), 2.82 (s, 2H), 1.51 (s, 9H), 1.49 (s, 6H).

[0220] To 9-chloro-7-fluoro-3,3,5-trimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[ c [1,6]Naphthyl-2(1 H A mixture of tert-butyl formate (3.5 mg, 170 mg, 0.43 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronylcyclopentane (164 mg, 0.64 mmol), and potassium acetate (85.0 mg, 0.86 mmol) in 1,4-dioxane (10 mL) was supplemented with Pd2(dba)3 (40.0 mg, 0.043 mmol) and Xphos (42.0 mg, 0.086 mmol). The resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oily substance, (2-(tert-butoxycarbonyl)-7-fluoro-3,3,5-trimethyl-6-oxo-1,2,3,4,5,6-hexahydrobenzo[]. c [1,6]Naphthid-9-yl)boronic acid (3.6, 220 mg, crude). LC-MS (ESI) m / z 405.0 (M+H) + .

[0221] The crude product (2-(tert-butoxycarbonyl)-7-fluoro-3,3,5-trimethyl-6-oxo-1,2,3,4,5,6-hexahydrobenzo[] cA mixture of [1,6]naphthidin-9-yl)boronic acid (3.6, 220 mg, crude), 2,4,5-trichloropyrimidine (95.0 mg, 0.52 mmol), Pd(dppf)Cl2 (33.0 mg, 0.044 mmol), and Na2CO3 (95.0 mg, 0.88 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3,5-trimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[ c [1,6]Naphthyl-2(1 H tert-butyl formate (3.7, 210 mg). LC-MS (ESI) m / z 507.0 (M+H) + .

[0222] 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3,5-trimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[ c [1,6]Naphthyl-2(1 H )-tert-butyl formate (3.7, 175 mg, 0.34 mmol), (3 S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (48.0 mg, 0.41 mmol), 18-crown-6 (18.0 mg, 0.068 mmol), potassium carbonate (48.0 mg, 0.34 mmol), and potassium fluoride (60.0 mg, 1.02 mmol) in DMSO (4 mL) was stirred at 110°C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with water (10 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to preparative TLC to give 9-(5-chloro-2-(((3)) as a yellow solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3,5-trimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[ c [1,6]Naphthyl-2(1 Htert-butyl formate (3.8, 163 mg, 82%). LC-MS (ESI) m / z 588.0 (M+H) + .

[0223] To 9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3,5-trimethyl-6-oxo-3,4,5,6-tetrahydrobenzo[ c [1,6]Naphthyl-2(1 H 9-(5-chloro-2-(((3.8, 163 mg, 0.28 mmol) tert-butyl formate was dissolved in methanol (5 mL) in hydrochloric acid (5 mL, 4 M in dioxane), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (5 mL), and then adjusted to pH 8 with saturated sodium bicarbonate solution (0.3 mL). The resulting mixture was filtered, and the filtrate was subjected to preparative HPLC to give 9-(5-chloro-2-(((3)) tert-butyl formate as a yellow solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3,5-trimethyl-1,3,4,5-tetrahydrobenzo[ c [1,6]Naphthyl-6(2 H )-keto (3, 37.9 mg, 28%). LC-MS (ESI) m / z 488.0 (M+H) + . 1 H NMR (400 MHz, CD3OD- d 4) δ 8.38 (s, 1H), 7.82 (s, 1H), 7.58 (d, J = 12.4Hz, 1H), 4.02 (s, 2H), 3.99 - 3.87 (m, 3H), 3.61 (dt, J = 9.2, 4.4 Hz, 1H), 3.56 (s, 3H), 3.48 (t, J = 11.6 Hz, 1H), 3.21 (t, J = 11.6 Hz,, 1H), 2.69 (s,2H), 2.15 - 2.07 (m, 1H), 1.70 - 1.54 (m, 1H), 1.27 (s, 6H).

[0224] Example 4.9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[ c [2,6]Naphthyl-4(1 H )-Ketone (4)

[0225] 1-Bromobut-2-yne (455 g, 3.44 mol) was added to a mixture of 4-chloro-2-fluoroaniline (4.1, 500 g, 3.44 mol) and K₂CO₃ (523 g, 3.79 mol) in acetone (5 L), and the resulting mixture was stirred at 70°C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a yellow oil. N -(but-2-yn-1-yl)-4-chloro-2-fluoroaniline (4.2, 550 g, 81%). LC-MS (ESI) m / z 198.2 (M+H) + .

[0226] Towards N Iodine (1417 g, 5.58 mol) was added to a mixture of 6-(but-2-yn-1-yl)-4-chloro-2-fluoroaniline (4.2 g, 550 g, 2.79 mol) and NaHCO3 (469 g, 5.58 mol) in acetone (5 L), and the resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous solution of Na2S2O3 (1 L) and extracted with ethyl acetate (4 L × 3). The organic layer was washed with brine (2 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-chloro-8-fluoro-3-iodo-4-methylquinoline (4.3 g, 130 g, 14%) as a brown solid. LC-MS (ESI) m / z 322.5 (M+H) + .

[0227] Add to a solution of 6-chloro-8-fluoro-3-iodo-4-methylquinoline (4.3, 20.0 g, 62.3 mmol) in CCl4 (250 mL) N1,4-Bromosuccinimide (22.1 g, 124 mmol) and benzoyl peroxide (3.00 g, 12.4 mmol). The resulting mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and then subjected to silica gel column chromatography to give 4-(bromomethyl)-6-chloro-8-fluoro-3-iodoquinoline (4.4 g, 11.5 g, 46%) as a brown solid. LC-MS (ESI) m / z 400.1 (M+H) + .

[0228] To a solution of 4-(bromomethyl)-6-chloro-8-fluoro-3-iodoquinoline (4.4, 11.5 g, 28.7 mmol) and ethyl 2-amino-2-methylpropionate hydrochloride (7.20 g, 43.1 mmol) in acetonitrile (120 mL), K₂CO₃ (9.90 g, 71.9 mmol) and TBAI (1.00 g, 2.87 mmol) were added. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and then subjected to silica gel column chromatography to give ethyl 2-(((6-chloro-8-fluoro-3-iodoquinoline-4-yl)methyl)amino)2-methylpropionate (4.5, 6.20 g, 48%) as a yellow solid. LC-MS (ESI) m / z 451.2 (M+H) + .

[0229] At -70°C, ethyl 2-(((6-chloro-8-fluoro-3-iodoquinoline-4-yl)methyl)amino)-2-methylpropionate (4.5, 6.20 g, 13.8 mmol) was added dropwise to a solution of 2-(((6-chloro-8-fluoro-3-iodoquinoline-4-yl)methyl)amino)-2-methylpropionate in 60 mL of THF. i -PrMgCl·LiCl (21.2 mL, 27.5 mmol, 1.30 N), and the resulting mixture was stirred at -70°C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with ethyl acetate (150 mL × 3). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-chloro-7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[] as a yellow solid. c [2,6]Naphthyl-4(1 H )-Ketone (4.6, 2.20 g, 57%). LC-MS (ESI) m / z 279.3 (M+H) + .

[0230] To 9-chloro-7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[ c [2,6]Naphthyl-4(1 H A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl)-1,4-dioxane (600 mg, 2.37 mmol) and potassium acetate (423 mg, 4.31 mmol) in 1,4-dioxane (10 mL) was supplemented with Pd2(dba)3 (197 mg, 0.21 mmol) and Xphos (205 mg, 0.43 mmol). The resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a brown oily substance (7-fluoro-3,3-dimethyl-4-oxo-3,4-dihydrobenzo[] c [2,6]Naphthid-9-yl)boronic acid (4.7, 800 mg, crude). LC-MS (ESI) m / z 287.3 (M+H) + .

[0231] (7-fluoro-3,3-dimethyl-4-oxo-3,4-dihydrobenzo[ c A mixture of [2,6]naphthid-9-yl)boronic acid (4.7, 800 mg, crude), 2,4,5-trichloropyrimidine (468 mg, 2.58 mmol), Pd(dppf)Cl2 (157 mg, 0.21 mmol), and Na2CO3 (457 mg, 4.31 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethylbenzo[ c [2,6]Naphthyl-4(3 H )-Keto (4.8, 150 mg, two-step 18%). LC-MS (ESI) m / z 389.2 (M+H) + .

[0232] 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethylbenzo[ c [2,6]Naphthyl-4(3 H)-keto (4.8, 150 mg, 0.38 mmol), (3 S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (70.0 mg, 0.46 mmol), 18-crown-6 (20.0 mg, 0.07 mmol), potassium carbonate (48.0 mg, 0.34 mmol), and potassium fluoride (66.0 mg, 1.14 mmol) in DMSO (4 mL) was stirred at 110°C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to preparative TLC (DCM / MeOH = 10 / 1) to give 9-(5-chloro-2-(((3)) as a yellow solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethylbenzo[ c [2,6]Naphthyl-4(3 H )-Keto (4.9, 80.0 mg, 44%). LC-MS (ESI) m / z 470.1 (M+H) + .

[0233] To 9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethylbenzo[ c [2,6]Naphthyl-4(3 H 9-(5-chloro-2-(((3)-one) (4.9, 80.0 mg, 0.17 mmol) was added to a solution of NaBH3CN (11.0 mg, 0.17 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 0.5 h under a nitrogen atmosphere. The reaction mixture was subjected to preparative HPLC to give 9-(5-chloro-2-(((3)-one) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[ c [2,6]Naphthyl-4(1 H )-keto (4, 10.8 mg, 13%). LC-MS (ESI) m / z472.0 (M+H) + . 1 H NMR (400 MHz, methanol-) d 4) δ 9.34 (s,1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.09 (d, J = 11.2 Hz, 1H), 4.66 (s, 2H), 4.06- 3.83 (m, 3H), 3.66 - 3.56 (m, 1H), 3.47 (t, J = 11.2 Hz, 1H), 3.20 (t, J = 10.4Hz, 1H), 2.10 (d, J = 13.2 Hz, 1H), 1.62 (d, J = 11.6 Hz, 1H), 1.38 (s, 6H).

[0234] Example 5.9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthyl-4-ol (5a) and 9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthyl-4-ol (5b)

[0235] To 9-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethyl-2,3-dihydrobenzo[ c [2,6]Naphthyl-4(1 H 9-(5-chloro-2-(((3)-one) (4, 90.0 mg, 0.19 mmol) was dissolved in methanol (4 mL) and NaBH4 (14.4 mg, 0.38 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC to give 9-(5-chloro-2-(((3)-one) as a white solid.S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthyl-4-ol (5, 45.9 mg, 51%) was further separated by chiral SFC to obtain: Isomer 1: (5a, 100% de); retention time: 1.445 min; LC-MS (ESI): m / z 474.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-) d 6) δ 9.01 (s, 1H), 8.47 (s, 1H), 8.26 - 8.11 (m, 1H), 7.97 - 7.79 (m, 1H), 7.67 - 7.44 (m, 1H), 5.66 (d, J = 7.2 Hz, 1H), 4.94 (d, J =5.8 Hz, 1H), 4.38 (d, J = 6.0 Hz, 1H), 4.35 - 4.14 (m, 2H), 3.92 - 3.70 (m,4H), 3.53 - 3.37 (m, 2H), 3.05 (t, J = 10.4 Hz, 1H), 2.07 - 1.83 (m, 1H), 1.58 - 1.40 (m, 1H), 1.11 (s, 3H), 0.98 (s, 3H).

[0236] Isomer 2: (5b, 99% de); retention time: 1.570 min; LC-MS (ESI): m / z 474.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-) d 6) δ 9.01 (s, 1H), 8.47 (s, 1H), 8.26 - 8.10 (m, 1H), 7.93- 7.80 (m, 1H), 7.71 - 7.46 (m, 1H), 5.66 (d, J = 7.0 Hz, 1H), 4.94 (d, J = 5.5Hz, 1H), 4.39 (d,J = 6.6 Hz, 1H), 4.34 - 4.17 (m, 2H), 3.91 - 3.74 (m, 3H), 3.59 - 3.36 (m, 3H), 3.05 (t, J = 10.4 Hz, 1H), 2.07 - 1.84 (m, 1H), 1.60 -1.39 (m, 1H), 1.11 (s, 3H), 0.98 (s, 3H).

[0237] Analytical methods: Column: ChiralPak IG, 250 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: B 40% over 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 40°C.

[0238] Preparative separation method: Instrument: Waters SFC150AP preparative SFC; Column: DAIICEL CHIRALCEL OD (250mm) 30 mm, 10 μm); mobile phase: A, CO2, and B, IPA (0.1% NH4+). 3· H2O); gradient: B% = 50% isocratic elution mode; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 35 degrees Celsius; system back pressure: 120 bar.

[0239] Example 6.(3) S 4 R )-4-((5-chloro-4-(4,4,7-trifluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthil-9-yl)pyrimidin-2-yl)amino)tetrahydro-2 H -pyran-3-ol (13)

[0240] 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,3-dimethylbenzo[ c [2,6]Naphthyl-4(3 HA mixture of 9-(2,5-dichloropyrimidin-4-yl)-4,4,7-trifluoro-3,3-dimethyl-3,4-dihydrobenzo[] ketone (4.8, 30.0 mg, 0.10 mmol) and diethylaminosulfonium trifluoride (1 mL) was stirred at 70°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (20 mL) and extracted with dichloromethane (20 mL × 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to preparative TLC (EtOAc / PE = 1 / 1) to give 9-(2,5-dichloropyrimidin-4-yl)-4,4,7-trifluoro-3,3-dimethyl-3,4-dihydrobenzo[] ketone as a white solid. c [2,6] Naphthylidine (13.1, 15.0 mg, 47%). LC-MS (ESI): m / z 411.3 (M+H) + .

[0241] 9-(2,5-dichloropyrimidin-4-yl)-4,4,7-trifluoro-3,3-dimethyl-3,4-dihydrobenzo[ c [2,6] Naphthyl (13.1, 15.0 mg, 0.04 mmol), (3) S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (14.0 mg, 0.09 mmol), 18-crown-6 (1.00 mg, 0.01 mmol), potassium carbonate (12.6 mg, 0.09 mmol), and potassium fluoride (5.30 mg, 0.09 mmol) in DMSO (3 mL) was stirred at 110°C for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow solid (3... S 4 R )-4-((5-chloro-4-(4,4,7-trifluoro-3,3-dimethyl-3,4-dihydrobenzo[ c [2,6]Naphthil-9-yl)pyrimidin-2-yl)amino)tetrahydro-2 H 3-Pyran-3-ol (13.2, 30.0 mg, crude). LC-MS (ESI): m / z 492.1 (M+H) + .

[0242] To (3) S 4 R )-4-((5-chloro-4-(4,4,7-trifluoro-3,3-dimethyl-3,4-dihydrobenzo[c [2,6]Naphthil-9-yl)pyrimidin-2-yl)amino)tetrahydro-2 H 3-pyran-3-ol (13.2, 30.0 mg, crude) was added to a solution of dichloromethane (3 mL) with NaBH3CN (1.9 mg, 0.03 mmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was subjected to preparative HPLC to give a white solid (3... S 4 R )-4-((5-chloro-4-(4,4,7-trifluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthil-9-yl)pyrimidin-2-yl)amino)tetrahydro-2 H 3-Pyran-3-ol (13, 6.40 mg, two-step 35%). LC-MS (ESI): m / z 494.0 (M+H) + . 1 H NMR (400 MHz, methanol-) d 4) δ 9.13 (s, 1H), 8.37 (d, J = 13.2 Hz, 2H), 8.05 (d, J = 11.2 Hz, 1H), 4.53 (s, 2H), 4.04 - 3.86 (m, 3H), 3.65 - 3.55 (m, 1H), 3.47 (t, J = 11.6 Hz, 1H), 3.19 (t, J = 10.4 Hz, 1H), 2.10 (d, J = 13.2 Hz, 1H), 1.62 (d, J = 10.0 Hz, 1H), 1.31 (s, 6H).

[0243] Example 7.7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (14)

[0244] At 0°C, CH3Li (107 mL, 1.6 mol / L in diethyl ether) was added to a solution of 2-amino-5-bromo-3-fluorobenzoic acid (14.1 g, 10.0 g, 42.7 mmol) in THF (60 mL), and the mixture was stirred at 0°C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, diluted with water (30 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(2-amino-5-bromo-3-fluorophenyl)ethyl-1-one (14.2 g, 8.60 g, 86.7%). LC-MS (ESI): m / z 232.1 [M+H] + .

[0245] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)ethyl-1-one (14.2, 1.00 g, 4.31 mmol) and cyclopentane-1,3-dione (507 mg, 5.17 mmol) in acetic acid (6 mL) was stirred at 110°C for 10 hours. The mixture was concentrated under vacuum to remove acetic acid, redissolved in ethyl acetate (30 mL), and washed with brine (15 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-9-methyl-2,3-dihydro-1-ethylhexane. H -cyclopentadienyl[1,2-] b Quinoline-1-one (14.3, 178 mg, 14%). LC-MS (ESI): m / z 294.1 [M+H] + .

[0246] At 0°C, 7-bromo-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinolin-1-one (14.3, 178 mg, 0.60 mmol) was added to a solution of CH3MgBr (1.21 mL, 1 mol / L in THF) in 5 mL of THF, and the mixture was stirred at 0°C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl, extracted with ethyl acetate (10 mL × 3), and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] bQuinoline-1-ol (14.4, 85.0 mg, 45.3%). LC-MS (ESI): m / z 310.0 [M+H] + .

[0247] To 7-bromo-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (14.4, 85.0 mg, 0.27 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (83.5 mg, 0.33 mmol) in dioxane (5 mL) were mixed with Pd(dppf)Cl2 (20.3 mg, 0.03 mmol) and KOAc (80.6 mg, 0.82 mmol), and the resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-fluoro-1,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (14.5, 120 mg, crude). LC-MS (ESI): m / z 358.2 [M+H] + .

[0248] To 2,4,5-trichloropyrimidine (0.031 mL, 0.27 mmol) and 5-fluoro-1,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydro-1 H 1,2-Cyclopentadieno[1,2-b]quinoline-1-ol (14.5, 97.9 mg, crude) was added to a mixture of dioxane (6 mL) and H₂O (1 mL) with Pd(PPh₃)₄ (31.6 mg, 0.027 mmol) and K₂CO₃ (75.7 mg, 0.55 mmol), and the resulting mixture was stirred at 100°C for 3 hours under nitrogen atmosphere. The reaction mixture was diluted with brine (10 mL), extracted with ethyl acetate (10 mL × 3), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (14.6, 69.0 mg). LC-MS (ESI): m / z 378.1 [M+H] + .

[0249] To 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (14.6, 69.0 mg, 0.18 mmol) and (3) S 4 R 7-(5-aminotetrahydropyran-3-ol hydrochloride) (42.0 mg, 0.24 mmol) was mixed with KF (21.1 mg, 0.36 mmol) and K₂CO₃ (50.4 mg, 0.36 mmol) in DMSO (3 mL). The resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 7-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (14, 22.0 mg, 26.3%). LC-MS (ESI): m / z 459.2 [M+H] + . 1 H NMR (500 MHz, DMSO-) d 6) δ 8.47 (s, 1H), 8.41 - 8.29 (m, 1H), 7.90 - 7.79 (m, 1H), 7.63 - 7.48 (m, 1H), 5.56 (s, 1H), 4.94 (d, J =5.4 Hz, 1H), 3.87 - 3.80 (m, 3H), 3.53 - 3.46 (m, 1H), 3.37 - 3.30 (m, 1H), 3.08 - 3.01 (m, 3H), 2.83 (s, 3H), 2.27 - 2.17 (m, 2H), 2.05 - 1.90 (m, 1H), 1.56 - 1.44 (m, 4H).

[0250] Example 8.7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H-pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (15)

[0251] Cyclohexane-1,3-dione (579 mg, 5.17 mmol) was added to a solution of 1-(2-amino-5-bromo-3-fluorophenyl)ethyl-1-one (14.2 g, 1.00 g, 4.31 mmol) in acetic acid (6 mL), and the mixture was stirred at 110°C for 10 hours. The mixture was concentrated under vacuum to remove acetic acid, redissolved in ethyl acetate (30 mL), and washed with brine (15 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-9-methyl-1,2,3,4-tetrahydroacridin-1-one (15.1 g, 352 mg, 26.5%). LC-MS (ESI): m / z 308.0 [M+H] + .

[0252] At 0°C, CH3MgBr (2.28 mL, 1 mol / L in THF) was added to a solution of 7-bromo-5-fluoro-9-methyl-1,2,3,4-tetrahydroacridin-1-one (15.1, 352 mg, 1.14 mmol) in THF (5 mL), and the mixture was stirred at 0°C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, extracted with ethyl acetate (10 mL × 3), and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (15.2, 189 mg, 51%). LC-MS (ESI): m / z 324.1 [M+H] + .

[0253] Pd(dppf)Cl2 (43.2 mg, 0.058 mmol) and KOAc (171 mg, 1.75 mmol) were added to a mixture of 7-bromo-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (15.2, 189 mg, 0.583 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyl-2-yl)-1,3,2-dioxoborhecyl-2-yl) in dioxane (10 mL). The resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-fluoro-1,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxabortiacyclopentan-2-yl)-1,2,3,4-tetrahydroacridin-1-ol (15.3 mg, 250 mg, crude). LC-MS (ESI): m / z 372.2 [M+H] + .

[0254] Pd(PPh3)4 (33.5 mg, 0.03 mmol) and K2CO3 (80.1 mg, 0.58 mmol) were added to a mixture of 2,4,5-trichloropyrimidine (0.033 mL, 0.29 mmol) and 5-fluoro-1,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2,3,4-tetrahydroacridin-1-ol (15.3, 107 mg, crude) in dioxane (6 mL) and H2O (1 mL), and the resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with brine (10 mL), extracted with ethyl acetate (10 mL × 3), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (15.4, 70.0 mg). LC-MS (ESI): m / z 392.1 [M+H] + .

[0255] To 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (15.4, 70.0 mg, 0.18 mmol) and (3 S 4 R7-(5-aminotetrahydropyran-3-ol hydrochloride) (42.0 mg, 0.24 mmol) was mixed with KF (20.7 mg, 0.36 mmol) and K₂CO₃ (49.3 mg, 0.36 mmol) in DMSO (3 mL). The resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 7-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (15, 26.0 mg, 30.8%). LC-MS (ESI): m / z 473.2 [M+H] + . 1 H NMR (500 MHz, DMSO-) d 6) δ 8.46 (s, 1H), 8.43 - 8.32 (m, 1H), 7.88 - 7.76 (m, 1H), 7.62 - 7.49 (m, 1H), 5.28 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 3.92 - 3.77 (m,3H), 3.56 - 3.47 (m, 1H), 3.33 - 3.29 (m, 1H), 3.10 - 3.01 (m, 3H), 3.03 (s,3H), 2.05 - 1.84 (m, 5H), 1.57 (s, 3H), 1.55 - 1.45 (m, 1H).

[0256] Example 9.5-Fluoro-7-(5-Fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (16)

[0257] Pd(PPh3)4 (27.9 mg, 0.024 mmol) and K2CO3 (66.9 mg, 0.48 mmol) were added to a mixture of 2,4-dichloro-5-fluoropyrimidine (40.4 mg, 0.24 mmol) and 5-fluoro-1,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2,3,4-tetrahydroacridin-1-ol (15.3 mg, 90.0 mg, crude) in dioxane (6 mL) and H2O (1 mL), and the resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with brine (10 mL), extracted with ethyl acetate (10 mL × 3), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (16.1, 65.0 mg). LC-MS (ESI): m / z 392.1 [M+H] + .

[0258] To 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1,9-dimethyl-1,2,3,4-tetrahydroacridin-1-ol (16.1, 70.0 mg, 0.178 mmol) and (3 S 4 R 5-F-7-(5-fluoro-2-(((3-)-)-aminotetrahydropyran-3-ol hydrochloride (42 mg, 0.24 mmol) was added to a mixture of DMSO (3 mL) with KF (23.1 mg, 0.40 mmol) and K2CO3 (55.1 mg, 0.40 mmol), and the resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 5-fluoro-7-(5-fluoro-2-(((3-)-)-)-)-aminotetrahydropyran-3-ol hydrochloride (42 mg, 0.24 mmol) in DMSO (3 mL), and the resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 5-fluoro-7-(5-fluoro-2- S 4 R )-3-hydroxytetrahydro-2 H 1,9-Dimethyl-1,2,3,4-Tetrahydroacryl-1-ol (16, 20.0 mg, 22%). LC-MS (ESI): m / z 457.1 [M+H] + . 1 H NMR (500 MHz, DMSO-) d 6) δ 8.62 (s, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.02 (d, J = 11.6Hz, 1H), 7.29 (d,J = 7.8 Hz, 1H), 5.30 (s, 1H), 4.94 (d, J = 5.3 Hz, 1H), 3.85 -3.82 (m, 3H), 3.55 - 3.48 (m, 1H), 3.42 - 3.28 (m, 2H), 3.11 - 3.07 (m, 2H),3.06 (s, 3H), 2.05 - 1.92 (m, 4H), 1.91 - 1.81 (m, 1H), 1.57 (s, 3H), 1.55 -1.50 (m, 1H).

[0259] Example 10. R )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3-methyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol and ( S )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3-methyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol

[0260] 1-Bromobut-2-yne (455 g, 3.44 mol) was added to a mixture of 4-chloro-2-fluoroaniline (17.1 g, 500 g, 3.44 mol) and K₂CO₃ (523 g, 3.79 mol) in acetone (5 L), and the resulting mixture was stirred at 70°C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a yellow oil. N -(but-2-yn-1-yl)-4-chloro-2-fluoroaniline (17.2, 550 g, 81%). LC-MS (ESI) m / z 198.2 [M+H] + .

[0261] Towards NIodine (1417 g, 5.58 mol) was added to a mixture of 17.2 g (550 g, 2.79 mol) and NaHCO3 (469 g, 5.58 mol) in acetone (5 L), and the resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with a saturated aqueous solution of Na2S2O3 (1 L) and extracted with ethyl acetate (4 L × 3). The organic layer was washed with brine (2 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-chloro-8-fluoro-3-iodo-4-methylquinoline (17.3 g, 130 g, 14%) as a brown solid. LC-MS (ESI) m / z 322.5 [M+H] + .

[0262] Add to a solution of 6-chloro-8-fluoro-3-iodo-4-methylquinoline (17.3, 20.0 g, 62.3 mmol) in CCl4 (250 mL) N 1,4-Chlorosuccinimide (16.6 g, 124 mmol) and benzoyl peroxide (3.01 g, 12.4 mmol). The resulting mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography to give 6-chloro-4-(chloromethyl)-8-fluoro-3-iodoquinoline (17.4 g, 11.5 g, 46%) as a brown solid. LC-MS (ESI) m / z 355.9 [M+H] + .

[0263] At 0°C, sodium hydride (640 mg, 16.0 mmol, 60% wt in mineral oil) was slowly added to a solution of ethyl 3-ethoxy-3-oxopropionate (3.50 mL, 23.0 mmol) in anhydrous DMF (40.0 mL). The mixture was stirred at 0°C for 10 minutes, followed by the addition of 6-chloro-4-(chloromethyl)-8-fluoro-3-iodoquinoline (17.4 g, 3.56 g, 10.0 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum to give a residue, which was subjected to silica gel column chromatography to give diethyl 2-((6-chloro-8-fluoro-3-iodoquinoline-4-yl)methyl)malonate (17.5 g, 4.10 g, 85%) as a yellow oil. LCMS (ESI): m / z 480.0 [M+H] + .

[0264] Under a nitrogen atmosphere at -78°C, n-butyllithium (10.0 mL, 22.0 mmol, 2.2 mol / L in n-hexane) was added dropwise to a solution of diethyl 2-((6-chloro-8-fluoro-3-iodoquinoline-4-yl)methyl)malonate (17.5 g, 4.79 g, 10.0 mmol) in anhydrous THF (600 mL), and the mixture was stirred at -78°C for 10 min. The reaction mixture was quenched with saturated NH4Cl (50.0 mL) and then concentrated under vacuum to remove most of the tetrahydrofuran. The resulting mixture was filtered, and the filter cake was washed with water and dried under vacuum to give 8-chloro-6-fluoro-3-oxo-2,3-dihydro-1-butyl ether as a yellow solid. H -cyclopentadiene[ c Ethyl quinoline-2-carboxylate (17.6, 2.38 g, 77%). LCMS (ESI): m / z 308.0 [M+H] + .

[0265] 8-chloro-6-fluoro-3-oxo-2,3-dihydro-1 H -cyclopentadiene[ c Ethyl quinoline-2-carboxylate (17.6 g, 1.33 g, 4.32 mmol) was added to a suspension in DMSO / H2O (15 mL / 2 mL). p -TsOH (294 mg, 2.16 mmol) was added, and the mixture was stirred at 120°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and then extracted with ethyl acetate (60 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-1,2-dihydro-3-O-dichlorosilane as a gray solid. H -cyclopentadiene[ c Quinoline-3-one (17.7, 449 mg, 44%). LCMS (ESI): m / z 236.0 [M+H] + .

[0266] In a nitrogen atmosphere at -78°C, 8-chloro-6-fluoro-1,2-dihydro-3- H -cyclopentadiene[ cQuinolin-3-one (17.7, 600 mg, 2.54 mmol) was rapidly added to a solution of methyl magnesium bromide (8.40 mL, 3 M in diethyl ether) in anhydrous DCM (12 mL), and the mixture was stirred at -78°C for 10 min. The reaction mixture was quenched with saturated NH4Cl (5 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-3-methyl-2,3-dihydro-1-methyl as a yellow solid. H -cyclopentadiene[ c Quinoline-3-ol (17.8, 456 mg, 71%). LCMS (ESI): m / z 252.0 [M+H] + .

[0267] 8-chloro-6-fluoro-3-methyl-2,3-dihydro-1 H -cyclopentadiene[ c Xphos (105 mg, 0.22 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), and KOAc (325 mg, 3.30 mmol) were added to a mixture of quinoline-3-ol (17.8, 278 mg, 1.10 mmol) and bis(pinacol)diboron (420 mg, 1.65 mmol) in dioxane (20 mL). The resulting mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give a brown oily substance, 6-fluoro-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (17.9, 350 mg, 73%). LCMS (ESI): m / z 344.2 [M+H] + .

[0268] 6-Fluoro-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ cA mixture of quinoline-3-ol (17.9 mg, 350 mg, 1.02 mmol) and 2,4,5-trichloropyrimidine (280 mg, 1.53 mmol) in dioxane (6 mL) / water (0.6 mL) was supplemented with Pd(PPh3)4 (118 mg, 0.102 mmol) and K2CO3 (423 mg, 3.06 mmol). The resulting mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3-methyl-2,3-dihydro-1-yl fluoropyrimidine as a yellow solid. H -cyclopentadiene[ c Quinoline-3-ol (17.10, 141 mg, 38%). LCMS (ESI): m / z 364.0 [M+H] + .

[0269] To 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3-methyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (17.10, 140 mg, 0.384 mmol) and (3 S 4 R )-4-aminotetrahydro-2 H 3-pyran-3-ol hydrochloride (118 mg, 0.769 mmol) was added to a mixture in anhydrous DMSO (4 mL). N,N -Diisopropylethylamine (1.54 mmol, 0.25 mL) was used, and the resulting mixture was stirred at 90°C for 1.5 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 8-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3-methyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (17, 62.0 mg, 38%) was further separated by chiral SFC to obtain: Isomer 1: (17a, 100% de); retention time: 1.035 min; LCMS (ESI): m / z 445.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d6) δ 8.98 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.89(d, J = 11.6 Hz, 1H), 7.61 (s, 1H), 5.48 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 3.88- 3.75 (m, 4H), 3.55 - 3.44 (m, 1H), 3.40 - 3.36 (m, 1H), 3.23 - 3.12 (m,1H), 3.05 (t, J = 10.4 Hz, 1H), 2.32 - 2.23 (m, 2H), 2.00 - 1.91 (m, 1H), 1.58 (s, 3H), 1.56 - 1.44 (m, 1H).

[0270] Isomer 2: (17b, 100% de); retention time: 1.768 min; LCMS (ESI): m / z 445.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 8.98 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.89(d, J = 11.7 Hz, 1H), 7.60 (s, 1H), 5.48 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 3.91- 3.77 (m, 4H), 3.53 - 3.46 (m, 1H), 3.40 - 3.35 (m, 1H), 3.24 - 3.12 (m,1H), 3.10 - 3.00 (m, 1H), 2.34 - 2.20 (m, 2H), 2.01 - 1.88 (m, 1H), 1.58 (s, 3H), 1.55 - 1.45 (m, 1H).

[0271] Analytical methods: Instrument: SHIMADZU-20AD-XR; Column: Cellulose SZ, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, EtOH; Gradient: B 50%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-LC06; Column: Cellulose SZ, 30 250 mm, 5 μm; Mobile phase: A, Hex (10 mM NH3), and B, EtOH; Gradient: B 50%; Flow rate: 40 mL / min; High pressure: 70 bar; Column temperature: 25°C; Wavelength: 253 nm / 230 nm; Cycle time: approximately 13 min.

[0272] Example 11.(3) S 4 R )-4-((5-chloro-4-(( S )-5-fluoro-9-methyl-1-(methylamino)-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-7-yl)pyrimidin-2-yl)amino)tetrahydro-2 H -pyran-3-ol and (3 S 4 R )-4-((5-chloro-4-(( R )-5-fluoro-9-methyl-1-(methylamino)-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-7-yl)pyrimidin-2-yl)amino)tetrahydro-2 H -pyran-3-ol

[0273] Under a nitrogen atmosphere at -20°C, methyllithium (53.4 mL, 85.5 mmol, 1.6 M in diethyl ether) was added dropwise to a solution of 2-amino-5-bromo-3-fluorobenzoic acid (18.1 g, 5.00 g, 21.3 mmol) in tetrahydrofuran (50 mL), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(2-amino-5-bromo-3-fluorophenyl)ethyl-1-one (18.2 g, 6.70 g, 89%) as a yellow solid. LC-MS (ESI): m / z 232.0 [M+H] + .

[0274] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)ethyl-1-one (18.2 g, 2.40 g, 10.3 mmol), cyclopentane-1,3-dione (2.03 g, 20.7 mmol), and p-toluenesulfonic acid (0.79 g, 4.13 mmol) in toluene (20 mL) was stirred at 130°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-9-methyl-2,3-dihydro-1-ethyl-1-one as a gray solid. H -cyclopentadiene[ b Quinoline-1-one (18.3, 1.10 g, 36%). LC-MS (ESI): m / z 294.0 [M+H] + .

[0275] 7-bromo-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-one (18.3, 320 mg, 1.09 mmol), methylamine hydrochloride (735 mg, 10.9 mmol), and sodium cyanoborohydride (205 mg, 3.26 mmol) in methanol (10.0 mL) was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro- N 9-Dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-amine (18.4, 280 mg, 83%). LC-MS (ESI): m / z 309.0 [M+H] + .

[0276] At 25°C, 7-bromo-5-fluoro- N 9-Dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-amine (18.4, 260 mg, 0.84 mmol) and triethylamine (0.35 mL, 2.52 mmol) in dichloromethane (3.0 mL) was reacted with di-tert-butyl dicarbonate (459 mg, 2.10 mmol) for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a yellow oil (7-bromo-5-fluoro-9-methyl-2,3-dihydro-1-ethylhexyl) H -cyclopentadiene[ bQuinoline-1-yl)(methyl)carbamate tert-butyl ester (18.5, 100 mg, 29%). LC-MS (ESI): m / z 409.1 [M+H] + .

[0277] (7-bromo-5-fluoro-9-methyl-2,3-dihydro-1) H -cyclopentadiene[ b A mixture of quinoline-1-yl)(methyl)carbamate tert-butyl ester (18.5 mg, 90.0 mg, 0.220 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl pentane (72.6 mg, 0.286 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (18.0 mg, 0.022 mmol), and potassium acetate (43.2 mg, 0.44 mmol) in dioxane (1.0 mL) was stirred at 90°C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. At room temperature, water (0.2 mL), tetrakis(triphenylphosphine)palladium (25.3 mg, 0.022 mmol), potassium carbonate (60.6 mg, 0.44 mmol), and 2,4,5-trichloropyrimidine (44.2 mg, 0.241 mmol) were added to the mixture, and the resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a yellow oil (7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-yl)(methyl)carbamate tert-butyl ester (18.6, 110 mg, crude). LC-MS (ESI): m / z 477.1 [M+H] + .

[0278] (7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-yl)(methyl)carbamate tert-butyl ester (18.6, 110 mg, crude), (3 S 4 RA mixture of 4-aminotetrahydropyran-3-ol hydrochloride (48.2 mg, 0.31 mmol), potassium fluoride (48.7 mg, 0.84 mmol), and potassium carbonate (57.9 mg, 0.42 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 120°C for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (7-(5-chloro-2-(((3))) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-yl)(methyl)carbamate tert-butyl ester (18.7, 100 mg, crude). LC-MS (ESI): m / z 558.2 [M+H) + .

[0279] (7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-yl)(methyl)carbamate tert-butyl ester (18.7, 100 mg, crude) and hydrochloric acid (1.0 mL, 4 mol / L in dioxane) in ethyl acetate (1 mL) was stirred at 25°C for 4 hours. The mixture was concentrated under reduced pressure and neutralized to pH 7 with saturated NaHCO3 solution. The resulting mixture was subjected to preparative HPLC to give a white solid (3... S 4 R )-4-((5-chloro-4-(5-fluoro-9-methyl-1-(methylamino)-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-7-yl)pyrimidin-2-yl)amino)tetrahydro-2 H -pyran-3-ol (18, 43.6 mg), which was further separated by chiral SFC to obtain: Isomer 1: (18a, 99.7% de); retention time: 3.105 min. LC-MS (ESI): m / z 458.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-)d 6) δ 8.46 (s, 1H), 8.45 - 8.2 (m, 1H), 7.97 - 7.76 (m, 1H), 7.68 - 7.45 (m, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.37 - 4.3 (m, 1H), 3.92 - 3.76 (m, 3H), 3.55 - 3.44 (m, 1H), 3.40 - 3.20 (m, 2H), 3.09 - 3.01(m, 1H), 3.0 - 2.90 (m, 1H), 2.72 (s, 3H), 2.34 (s, 3H), 2.20 - 2.10 (m, 2H), 2.05 - 1.85 (m, 1H), 1.59 - 1.42 (m, 1H).

[0280] Isomer 2: (18b, 100% de); retention time: 5.633 min; LC-MS (ESI): m / z 458.2 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.46 (s, 1H), 8.45 - 8.2 (m, 1H), 7.97 - 7.76 (m, 1H), 7.68 - 7.45 (m, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.42 - 4.3 (m, 1H), 3.92 - 3.76 (m, 3H), 3.55 - 3.44 (m, 1H), 3.40 - 3.20 (m, 2H), 3.09 - 3.01(m, 1H), 3.0 - 2.90 (m, 1H), 2.73 (s, 3H), 2.35 (s, 3H), 2.20 - 2.10 (m, 2H), 2.05 - 1.88 (m, 1H), 1.59 - 1.42 (m, 1H).

[0281] Analytical methods: Instrument: SHIMADZU-20AD-XR; Column: CHIRALPAK IK-3, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, EtOH; Gradient: B 50%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-03; Column: CHIRALPAK IH-3, 20 250 mm, 5 μm; Mobile phase: A, Hex (0.1% NH3), and B, EtOH; Gradient: B 50%; Flow rate: 40 mL / min; High pressure: 135 bar; Column temperature: 25°C; Wavelength: 257 nm / 232 nm.

[0282] Example 12. R )-7-(5-chloro-2-(((3) R 4 R )-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-7-(5-chloro-2-(((3) R 4 R )-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0283] At 25°C, a solution of 2-amino-3-fluorobenzyl-1-carboxynitrile (19.1 g, 15.0 g, 110 mmol) in dichloromethane (150 mL) was added. N 2-Bromosuccinimide (21.6 g, 121 mmol) was mixed and stirred at 25°C for 12 hours. The reaction mixture was quenched with saturated sodium sulfite (200 mL) and extracted with dichloromethane (150 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-amino-5-bromo-3-fluorobenzyl-1-carboxynitrile (19.2, 23.0 g, 97%) as a purple solid. LC-MS (ESI): m / z 215.0 [M+H] + .

[0284] Under a nitrogen atmosphere at 0°C, isopropyl magnesium bromide (41.5 mL, 116 mmol) was added dropwise to a solution of 2-amino-5-bromo-3-fluorobenzyl-1-carboxynitrile (19.2 g, 5.00 g, 23.3 mmol) in tetrahydrofuran (50.0 mL), and the mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(2-amino-5-bromo-3-fluorophenyl)-2-methylpropane-1-one (19.3 g, 4.10 g, 68%) as a yellow solid. LC-MS (ESI): m / z 260.0 [M+H] + .

[0285] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)-2-methylpropane-1-one (19.3, 4.10 g, 15.8 mmol) and cyclopentane-1,3-dione (1.86 g, 18.9 mmol) in hydrochloric acid solution (40 mL, 2 mol / L in ethanol) was stirred at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (100 mL). The resulting mixture was adjusted to pH 8 with saturated sodium carbonate solution and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was ground with petroleum ether:ethyl acetate = 5:1 (20 mL) to give 7-bromo-5-fluoro-9-isopropyl-2,3-dihydro-1-one as a gray solid. H -cyclopentadiene[ b Quinoline-1-one (19.4 g, 2.30 g, 45%). LC-MS (ESI): m / z 322.0 [M+H] + .

[0286] Under a nitrogen atmosphere, at -78°C, 7-bromo-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[ bQuinolin-1-one (19.4 g, 1.30 g, 4.04 mmol) was added to a solution of methyl magnesium bromide (13.5 mL, 40.4 mmol) in dichloromethane (13 mL), and the mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (10 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1-methyl as a yellow solid. H -cyclopentadiene[ b Quinoline-1-ol (19.5, 10 g, 73%). LC-MS (ESI): m / z 338.1 [M+H] + .

[0287] To 7-bromo-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-ol (19.5, 100 mg, 0.30 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronylpentane (97.6 mg, 0.38 mmol) in dioxane (2 mL) was supplemented with 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (24.2 mg, 0.030 mmol) and potassium acetate (58.0 mg, 0.59 mmol). The resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. Water (0.4 mL), potassium carbonate (71.7 mg, 0.52 mmol), tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol), and 2,4,5-trichloropyrimidine (61.9 mg, 0.34 mmol) were added to the mixture, and the mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1-yl) as a yellow oil. H -cyclopentadiene[ b Quinoline-1-ol (19.6, 150 mg, crude). LC-MS (ESI): m / z 406.1 [M+H] + .

[0288] 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (19.6, 100 mg, crude), (3) R 4 R )-4-amino-1-(methanesulfonyl)piperidine-3-ol (72 mg, 0.37 mmol) and N,N A mixture of diisopropylethylamine (95.4 mg, 0.74 mmol) in anhydrous dimethyl sulfoxide (1 mL) was stirred at 90°C for 5 hours. The reaction mixture was filtered and subjected to preparative HPLC to give 7-(5-chloro-2-(((3)) as a white solid. R 4 R )-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (19, 62.3 mg) was further separated by chiral SFC to obtain: Isomer 1: (19a, 100% de); retention time: 1.371 min. LC-MS (ESI): m / z 564.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 8.70 - 8.50 (m, 1H), 8.48 (s, 1H), 7.95 - 7.75(m, 1H), 7.65 - 7.50 (m, 1H), 5.63 (s, 1H), 5.24 (d, J = 4.4 Hz, 1H), 4.56 -4.45 (m, 1H), 3.90 - 3.75 (m, 1H), 3.69 - 3.56 (m, 2H), 3.54 - 3.45 (m, 1H), 3.10 - 2.95 (m, 2H), 2.90 (s, 3H), 2.88 - 2.75 (m, 1H), 2.70 - 2.60 (m, 1H), 2.3 - 2.17 (m, 2H), 2.15 - 1.97 (m, 1H), 1.61 - 1.46 (m, 10H).

[0289] Isomer 2: (19b, 99.9% de); retention time: 1.870 min; LC-MS (ESI): m / z 564.2 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.70 - 8.50 (m, 1H), 8.48 (s, 1H), 7.95 - 7.75(m, 1H), 7.65 - 7.50 (m, 1H), 5.63 (s, 1H), 5.33 - 5.13 (m, 1H), 4.56 - 4.45(m, 1H), 3.90 - 3.75 (m, 1H), 3.67 - 3.56 (m, 2H), 3.54 - 3.45 (m, 1H), 3.1 -2.95 (m, 2H), 2.90 (s, 3H), 2.88 - 2.75 (m, 1H), 2.70 - 2.57 (m, 1H), 2.3 -2.17 (m, 2H), 2.15 - 1.97 (m, 1H), 1.61 - 1.46 (m, 10H).

[0290] Analytical methods: Instrument: SHIMADZU-20AD-XR; Column: Cellulose SZ, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, EtOH; Gradient: B 50%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-LC06; Column: Cellulose SZ, 30 250 mm, 5 μm; Mobile phase: A, Hex (10 mM NH3), and B, EtOH; Gradient: B 50%; Flow rate: 40 mL / min; High pressure: 66 bar; Column temperature: 25°C; Wavelength: 257 nm / 234 nm.

[0291] Example 13. R )-5-fluoro-7-(5-fluoro-2-(((3) R 4 R )-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-5-fluoro-7-(5-fluoro-2-(((3)R 4 R )-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0292] To 7-bromo-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-ol (19.5 mg, 100 mg, 0.30 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl) (97.6 mg, 0.38 mmol) in dioxane (2 mL) was supplemented with 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (24.2 mg, 0.030 mmol) and potassium acetate (58.0 mg, 0.59 mmol). The resulting mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere and then cooled to room temperature. Water (0.4 mL), potassium carbonate (71.7 mg, 0.52 mmol), tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol), and 2,4-dichloro-5-fluoropyrimidine (63.60 mg, 0.38 mmol) were added to the mixture, and the resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1-yl) as a yellow oil. H -cyclopentadiene[ b Quinoline-1-ol (20.1, 120 mg, crude). LC-MS (ESI): m / z 390.1 [M+H] + .

[0293] 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (20.1, 120 mg, crude), (3) R 4 R )-4-amino-1-(methanesulfonyl)piperidine-3-ol (89.7 mg, 0.46 mmol) and N,NA mixture of diisopropylethylamine (0.149 mL, 0.923 mmol) and dimethyl sulfoxide (1 mL) was stirred at 90°C for 5 hours. The reaction mixture was filtered and subjected to preparative HPLC to give a yellow solid of 5-fluoro-7-(5-fluoro-2-(((3) R 4 R )-3-hydroxy-1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (20, 56.4 mg) was further separated by chiral SFC to obtain: Isomer 1: (20a, 100% de); retention time: 1.285 min. LC-MS (ESI): m / z 548.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 8.91 (s, 1H), 8.52 (d, J = 3.9 Hz, 1H), 8.04 (d, J =11.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 5.65 (s, 1H), 5.25 (d, J = 4.5 Hz, 1H),4.61 - 4.40 (m, 1H), 3.95 - 3.75 (m, 1H), 3.70 - 3.59 (m, 2H), 3.56 - 3.47(m, 1H), 3.10 - 2.96 (m, 2H), 2.95 - 2.82 (m, 4H), 2.71 - 2.62 (m, 1H), 2.30 - 2.17 (m, 2H), 2.16 - 2.05 (m, 1H), 1.62 - 1.50 (m, 10H).

[0294] Isomer 2: (20b, 100% de); retention time: 1.798 min; LC-MS (ESI): m / z 548.2 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.90 (s, 1H), 8.52 (d, J = 3.9 Hz, 1H), 8.04 (d, J=11.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 5.64 (s, 1H), 5.24 (d, J = 4.5 Hz, 1H),4.61 - 4.40 (m, 1H), 3.95 - 3.75 (m, 1H), 3.70 - 3.58 (m, 2H), 3.56 - 3.47(m, 1H), 3.10 - 2.96 (m, 2H), 2.95 - 2.82 (m, 4H), 2.71 - 2.62 (m, 1H), 2.30 - 2.17 (m, 2H), 2.16 - 2.05 (m, 1H), 1.62 - 1.50 (m, 10H).

[0295] Analytical methods: Instrument: SHIMADZU-20AD-XR; Column: Cellulose SZ, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, EtOH; Gradient: B 50%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-LC06; Column: Cellulose SZ, 30 250 mm, 5 μm; Mobile phase: A, Hex (10 mM NH3), and B, EtOH; Gradient: B 50%; Flow rate: 40 mL / min; High pressure: 112 bar; Column temperature: 25°C; Wavelength: 254 nm / 227 nm.

[0296] Example 14. R )-6-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-3-methyl-2,3-dihydrofurano[2,3-] b Quinoline-3-ol and ( S )-6-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-3-methyl-2,3-dihydrofurano[2,3-] b Quinoline-3-ol

[0297] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)-2-methylprop-1-one (19.3, 32.0 g, crude), ethyl 3-ethoxy-3-oxopropionate (56.0 mL, 369 mmol), and DBU (18.4 mL, 123 mmol) was stirred at 150°C for 3 hours. The reaction mixture was cooled to room temperature and then ground with a mixture of 2 N HCl aqueous solution (50 mL), water (100 mL), and petroleum ether (50 mL). The resulting mixture was filtered, and the filter cake was washed with PE / EA (3 / 1, 50 mL). The solid was collected and dried under vacuum to give 6-bromo-8-fluoro-2-oxo-4-(propyl-2-yl)-1-methylpropionate as a yellow solid. H ethyl quinoline-3-carboxylate (21.1, 30.0 g). LC-MS (ESI): m / z 356.3 [M+H] + .

[0298] To 6-bromo-8-fluoro-2-oxo-4-(propyl-2-yl)-1 H A mixture of ethyl quinoline-3-carboxylate (21.1 g, 25.0 g, 70.2 mmol) and ethyl hydroxyacetate (8.77 g, 84.2 mmol) in toluene (250 mL) was added (tributyl- λ 5-Fluoride acetonitrile (23.7 g, 98.2 mmol) was added, and the mixture was stirred at 100°C for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl 6-bromo-2-[(2-ethoxy-2-oxoethyl)oxy]-8-fluoro-4-(prop-2-yl)quinoline-3-carboxylate (21.2, 28.0 g, 90%) as a yellow oil. LC-MS (ESI): m / z 442.1 [M+H] + .

[0299] At room temperature, ethyl 6-bromo-2-[(2-ethoxy-2-oxoethyl)oxy]-8-fluoro-4-(prop-2-yl)quinoline-3-carboxylate (21.2 g, 1.00 g, 2.26 mmol) was added dropwise to a solution of 6-bromo-2-[(2-ethoxy-2-oxoethyl)oxy]-8-fluoro-4-(prop-2-yl)quinoline-3-carboxylate (21.2 g, 1.00 g, 2.26 mmol) in THF (10 mL). t -BuOK (4.52 mL, 4.52 mmol, 1 mol / L in THF) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 2 N HCl (3 mL), diluted with water (30 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 6-bromo-8-fluoro-3-oxo-4-(propyl-2-yl)-2,3-dihydrofurano[2,3-b Ethyl quinoline-2-carboxylate (21.3, 400 mg, crude). LC-MS (ESI): m / z 396.1 [M+H] + .

[0300] At 0°C, 6-bromo-8-fluoro-3-oxo-4-(propyl-2-yl)-2,3-dihydrofurano[2,3-] b Ethyl quinoline-2-carboxylate (21.3, 400 mg, crude) was slowly added to a solution of ethanol (3 mL) with 6 N H2SO4 (1 mL), and the mixture was stirred at 100°C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated NaHCO3 solution (15 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-bromo-8-fluoro-4-(propyl-2-yl)-2,3-dihydrofurano[2,3-] as a colorless oil. b Quinoline-3-one (21.4, 320 mg, two-step yield 44%). LC-MS (ESI): m / z 324.1 [M+H] + .

[0301] At -60°C, 6-bromo-8-fluoro-4-(propyl-2-yl)-2,3-dihydrofurano[2,3-] b Quinolin-3-one (21.4, 360 mg, 1.14 mmol) was added to a solution of CH3MgBr (4.93 mL, 3 mol / L in THF) in DCM (6 mL), and the mixture was stirred at -60°C for 30 min. The reaction mixture was quenched with 2 N HCl (3 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-bromo-8-fluoro-3-methyl-4-(propyl-2-yl)-2,3-dihydrofurano[2,3-] as a colorless oil. b Quinoline-3-ol (21.5, 140 mg, 41.7%). LC-MS (ESI): m / z 340.0 [M+H] + .

[0302] To 6-bromo-8-fluoro-3-methyl-4-(propyl-2-yl)-2,3-dihydrofurano[2,3- bA mixture of quinoline-3-ol (21.5 mg, 140 mg, 0.41 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (156 mg, 0.62 mmol) in dioxane (3 mL) was supplemented with Pd(dppf)Cl2 (30.5 mg, 0.041 mmol) and KOAc (121 mg, 1.23 mmol). The resulting mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere and then cooled to room temperature. Under a nitrogen atmosphere, water (1 mL), 2,4,5-trichloropyrimidine (94 μL, 0.82 mmol), K₂CO₃ (171 mg, 1.24 mmol), Pd(PPh₃)₄ (47.7 mg, 0.041 mmol), and PPh₃ (43.35 mg, 0.165 mmol) were added to the mixture, and the resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a brown oily substance, 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropyl-3-methyl-2,3-dihydrofurano[2,3- b Quinoline-3-ol (21.7, 130 mg, two-step yield 77.1%). LC-MS (ESI): m / z 408.1 [M+H] + .

[0303] 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-3-methyl-4-(propyl-2-yl)-2,3-dihydrofurano[2,3- b Quinoline-3-ol (21.7, 130 mg, 0.32 mmol), (3 S 4 R )-4-aminotetrahydropyran-3-ol hydrochloride (146 mg, 0.95 mmol) and N,N A mixture of diisopropylethylamine (166 μL, 0.95 mmol) in DMSO (2 mL) was stirred at 110°C for 2 hours. The reaction mixture was filtered and subjected to preparative HPLC to give 6-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-3-methyl-2,3-dihydrofurano[2,3-] bQuinoline-3-ol (21, 78.3 mg, 50%) was further separated by chiral SFC to obtain: Isomer 1: (21a, 100% de); retention time: 0.920 min; LC-MS (ESI): m / z 489.1 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.58 (s, 1H), 8.45 (s, 1H), 8.02 - 7.72 (m, 1H), 7.54 (d, J = 7.0 Hz, 1H), 6.13 (s, 1H), 4.96 (s, 1H), 4.48 (d, J = 9.2 Hz, 1H), 4.39 (d, J = 9.6 Hz, 1H), 4.23 - 4.14 (m, 1H), 3.92 - 3.76 (m, 3H), 3.55 - 3.46(m, 1H), 3.29 - 3.25 (m, 1H), 3.02 (t, J = 10.4 Hz, 1H), 2.03 - 1.88 (m, 1H), 1.63 (s, 3H), 1.60 - 1.44 (m, 7H).

[0304] Isomer 2: (21b, 100% de); retention time: 1.359 min; LC-MS (ESI): m / z 489.1 [M+H]+. 1 H NMR (400 MHz, DMSO-) d 6) δ 8.57 (s, 1H), 8.45 (s, 1H), 7.99 - 7.72 (m, 1H), 7.53 (d, J = 7.2 Hz, 1H), 6.12 (s, 1H), 4.95 (d, J = 5.3 Hz, 1H), 4.48 (d, J = 9.3Hz, 1H), 4.40 (d, J = 9.3 Hz, 1H), 4.24 - 4.13 (m, 1H), 3.91 - 3.77 (m, 3H), 3.54 - 3.47 (m, 1H), 3.31 - 3.22 (m, 1H), 3.02 (t, J= 10.8 Hz, 1H), 2.06 -1.89 (m, 1H), 1.64 (s, 3H), 1.59 - 1.45 (m, 7H).

[0305] Analytical methods: Instrument: SHIMADZU-20AD-XR; Column: CHIRALPAK IK-3, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, IPA; Gradient: B 50%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-LC07; Column: CHIRALPAK IK, 30 250 mm, 5 μm; Mobile phase: A, Hex (10 mM NH3), and B, IPA; Gradient: B 50%; Flow rate: 40 mL / min; High pressure: 121 bar; Column temperature: 25°C; Wavelength: 202 nm / 260 nm; Cycle time: approximately 15 min.

[0306] Example 15. R )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0307] A mixture of 2-amino-5-bromo-3-fluorobenzoic acid (18.1 g, 10.0 g, 42.7 mmol) and cyclopentane-1,3-dione (5.03 g, 51.3 mmol) in Eaton reagent (50 mL) was stirred at 135°C for 1.5 hours. The mixture was cooled to room temperature and diluted with water (100 mL). The pH of the resulting mixture was slowly adjusted to 7 with solid NaOH at 0°C, and then filtered. The filter cake was collected and subjected to silica gel column chromatography to give 7-bromo-5-fluoro-9-hydroxy-2,3-dihydro-1,3-dione as a brown solid. H -cyclopentadienyl[1,2-] b Quinoline-1-one (22.1 g, 1.50 g, 11.8%). LC-MS (ESI): m / z 296.0 [M+H] + .

[0308] 7-bromo-5-fluoro-9-hydroxy-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b A mixture of quinoline-1-one (22.1 g, 1.50 g, 5.06 mmol) and POCl3 (7 mL) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature and slowly quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-9-chloro-5-fluoro-2,3-dihydro-1-oxoquinoline-1-one as a yellow solid. H -cyclopentadienyl[1,2-] b Quinoline-1-one (22.2, 540 mg, 33.9%). LC-MS (ESI): m / z 314.0 [M+H] + .

[0309] To 7-bromo-9-chloro-5-fluoro-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-one (22.2 g, 1.00 g, 3.18 mmol) was added to a solution of acetonitrile (10 mL) with dimethylamine (7.9 mL, 15.9 mmol, 2 mol / L in THF), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-9-(dimethylamino)-5-fluoro-2,3-dihydro-1- H -cyclopentadienyl[1,2-] bQuinoline-1-one (22.3, 710 mg, 69.1%). LC-MS (ESI): m / z 323.2 [M+H] + .

[0310] At 0°C, 7-bromo-9-(dimethylamino)-5-fluoro-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinolin-1-one (22.3, 710 mg, 2.19 mmol) was rapidly added to a solution of magnesium methyl bromide (3.66 mL, 10.9 mmol, 3 mol / L) in DCM (7 mL), and the mixture was stirred at 0°C for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-bromo-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1-yl. H -cyclopentadienyl[1,2-] b Quinoline-1-ol (22.4, 700 mg, 93.9%). LC-MS (ESI): m / z 339.1 [M+H] + .

[0311] 7-bromo-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-ol (22.4 g, 700 mg, 2.06 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl (1.05 g, 4.13 mmol), potassium acetate (405 mg, 4.13 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloromethane complex (153 mg, 0.206 mmol) in dioxane (10 mL) was stirred at 90°C for 4 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature. Under a nitrogen atmosphere, water (4 mL), 2,4,5-trichloropyrimidine (0.46 mL, 4.00 mmol), Pd(PPh3)4 (231 mg, 0.20 mmol), and K2CO3 (552 mg, 4.00 mmol) were added to the mixture, and the resulting mixture was stirred at 90°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-(2,5-dichloropyrimidin-4-yl)-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1-yl) as a yellow solid. H -cyclopentadienyl[1,2-] bQuinoline-1-ol (22.6, 170 mg, two-step yield 20.8%). LC-MS (ESI): m / z 407.3 [M+H] + .

[0312] 7-(2,5-dichloropyrimidin-4-yl)-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (22.6, 170 mg, 0.417 mmol), (3) S 4 R 4-Aminotetrahydropyran-3-ol hydrochloride (96.2 mg, 0.63 mmol) and N,N A mixture of diisopropylethylamine (162 mg, 1.25 mmol) in DMSO (2 mL) was stirred at 120°C for 2 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 7-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-(dimethylamino)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (22, 72.0 mg, 35.4%) was further separated by chiral SFC to obtain: Isomer 1: (22a, 100% de); retention time: 2.18 min, LC-MS (ESI): m / z 488.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 8.58 - 8.30 (m, 2H), 7.84 (s, 1H), 7.57 (s, 1H), 5.41 (s, 1H), 4.97 (d, J = 5.5 Hz, 1H), 3.95 - 3.71 (m, 3H), 3.58 - 3.49 (m,1H), 3.42 - 3.35 (m, 1H), 3.25 - 2.92 (m, 10H), 2.20 (t, J = 7.3 Hz, 2H), 1.98(s, 1H), 1.65 (d, J = 1.7 Hz, 3H).

[0313] Isomer 2: (22b, 100% de); retention time: 3.88 min, LC-MS (ESI): m / z 488.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 8.55 - 8.35 (m, 2H), 7.84 (s, 1H), 7.58 (s, 1H), 5.42 (s, 1H), 4.97 (d, J = 5.3 Hz, 1H), 3.95 - 3.72 (m, 3H), 3.56 - 3.47 (m,1H), 3.42 - 3.35 (m, 1H), 3.21 - 2.94 (m, 10H), 2.23 - 2.15 (m, 2H), 1.97 (s,1H), 1.65 (s,3H).

[0314] Analytical separation method: Instrument: SHIMADZU-20AD-XR; Column: CHIRALPAK IK-3, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, IPA; Gradient: B 50%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-LC07; Column: CHIRALPAK IK, 30 250 mm, 5 μm; Mobile phase: A, Hex (10 mM NH3), and B, IPA; Gradient: B 50%; Flow rate: 40 mL / min; High pressure: 128 bar; Column temperature: 25°C; Wavelength: 250 nm / 202 nm; Cycle time: approximately 48 min; Sample preparation: Dissolve the compound in approximately 3 mL of EtOH / DCM; Injection: 2 mL / injection.

[0315] Example 16. R )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol and ( S )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H-pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol

[0316] Under a nitrogen atmosphere, lithium diisopropylamino (29.5 mL, 59.0 mmol, 2 mol / L in THF) was added dropwise to a solution of methyl isobutyrate (6.28 mL, 54.8 mmol) in THF (120 mL) at -78°C. The mixture was stirred at -78°C for 30 min, followed by the dropwise addition of a solution of 6-chloro-4-(chloromethyl)-8-fluoro-3-iodoquinoline (17.4 g, 15.0 g, 42.14 mmol) in THF (80 mL) at the same temperature. The resulting mixture was heated to room temperature and stirred under a nitrogen atmosphere for 3 h. The reaction mixture was quenched with saturated NH4Cl solution (30 mL), diluted with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain methyl 3-(6-chloro-8-fluoro-3-iodoquinoline-4-yl)-2,2-dimethylpropionate (23.1 g, 12.0 g, 67.5%) as a yellow solid. LC-MS (ESI) m / z 422.0 [M+H] + .

[0317] Under a nitrogen atmosphere at -78°C, methyl 3-(6-chloro-8-fluoro-3-iodoquinoline-4-yl)-2,2-dimethylpropionate (23.1 g, 33.0 g, 78.3 mmol) in THF (200 mL) was added dropwise with n-butyllithium (37.6 mL, 93.9 mmol, 2.5 mol / L in THF), and the mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (20 mL), diluted with water (200 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-2,2-dimethyl-1,2-dihydro-3-dimethylpropionate as a pale yellow solid. H -cyclopentadiene[ c Quinoline-3-one (23.2, 10.3 g, 49.9%). LC-MS (ESI) m / z 264.1 [M+H] + .

[0318] Under a nitrogen atmosphere, at -78°C, 8-chloro-6-fluoro-2,2-dimethyl-1,2-dihydro-3- H -cyclopentadiene[ c Quinolin-3-one (23.2 g, 2.50 g, 9.48 mmol) was added dropwise to a solution of dichloromethane (20 mL) with magnesium methyl bromide (15.8 mL, 47.4 mmol, 3 mol / L in THF), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated NH4Cl solution (8 mL), diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1-methyl ether as a white solid. H -cyclopentadiene[ c Quinoline-3-ol (23.3 g, 2.10 g, 79.2%). LC-MS (ESI) m / z 280.1 [M+H] + .

[0319] 8-chloro-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1 H -cyclopentadiene[ c A mixture of quinoline-3-ol (23.3 g, 2.10 g, 7.51 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxoboronylcyclopentane) (2.86 g, 11.3 mmol), tris(dibenzylacetone)dipalladium (1.37 g, 1.50 mmol), potassium acetate (2.21 g, 22.5 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (716 mg, 1.50 mmol) in dioxane (15 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a brown solid, 6-fluoro-2,2,3-trimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (23.4 g, 2.54 g, 91.1%). LC-MS (ESI): m / z 372.2 [M+H] + .

[0320] 6-fluoro-2,2,3-trimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ c A mixture of quinoline-3-ol (23.4 g, 2.00 g, 5.38 mmol), 2,4,5-trichloropyrimidine (1.58 g, 8.62 mmol), tetrakis(triphenylphosphine)palladium (934 mg, 0.81 mmol), and potassium carbonate (1.49 g, 10.8 mmol) in dioxane / water (10 mL / 2.5 mL) was stirred at 90°C for 1.5 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1-yl fluoropyrimidine as a yellow solid. H -cyclopentadiene[ c Quinoline-3-ol (23.5 g, 1.70 g, 80.4%). LC-MS (ESI): m / z 392.1 [M+H] + .

[0321] 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (23.5 g, 1.70 g, 4.33 mmol), (3 S 4 R )-4-aminotetrahydropyran-3-ol hydrochloride (812 mg, 6.93 mmol) and N,N A mixture of diisopropylethylamine (2.86 mL, 17.3 mmol) in dimethyl sulfoxide (8 mL) was stirred at 110°C for 2.5 hours. The reaction mixture was filtered, and the filtrate was subjected to silica gel column chromatography to give 8-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2,3-trimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (23, 1.40 g, 68.3%) was further separated by chiral SFC to obtain: Isomer 1: (23a, 100% de); retention time: 1.387 min. LCMS (ESI): m / z 473.4 [M+H] + . 1HNMR (400 MHz, DMSO- d 6) δ 8.96 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 7.89 (d, J =11.2 Hz, 1H), 7.58 (s, 1H), 5.18 (s, 1H), 4.93 (d, J = 5.4 Hz, 1H), 3.86 - 3.75(m, 3H), 3.58 - 3.42 (m, 1H), 3.36 - 3.33 (m, 1H), 3.19 - 2.96 (m, 3H), 1.97- 1.91 (m, 1H), 1.55 - 1.45 (m, 1H), 1.43 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H).

[0322] Isomer 2: (23b, 100% de); retention time: 3.841 min. LCMS (ESI): m / z 473.4 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.96 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 7.88 (d, J =11.9 Hz, 1H), 7.58 (s, 1H), 5.18 (s, 1H), 4.93 (d, J = 5.4 Hz, 1H), 3.86 - 3.75(m, 3H), 3.59 - 3.39 (m, 1H), 3.36 - 3.33 (m, 1H), 3.19 - 2.96 (m, 3H), 1.97- 1.91 (m, 1H), 1.59 - 1.47 (m, 1H), 1.43 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H).

[0323] Analytical methods: Column: ChiralPak IH, 100 × 4.6 mm ID, 5 µm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 40% over 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 40°C. SFC separation method: SHIMADZU PREP SOLUTION SFC; ChiralPak IH, 150 × 20 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH + 0.1% NH4OH; Gradient: B 40%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 15 min.

[0324] Example 17.(3) S 4 R )-4-((5-chloro-4-(3,3-diethyl-7-fluoro-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthil-9-yl)pyrimidin-2-yl)amino)tetrahydro-2 H -pyran-3-ol

[0325] A mixture of 6-chloro-4-(chloromethyl)-8-fluoro-3-iodoquinoline (17.4, 18.0 g, 50.5 mmol), methyl 2-amino-2-ethylbutyrate (1.35 g, 9.27 mmol), K₂CO₃ (27.9 g, 202 mmol), and KI (0.84 g, 5.05 mmol) in MeCN (200 mL) was stirred at 80°C for 16 hours. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with DCM (100 mL × 2). The combined organic layers were washed with water (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was milled with PE / EtOAc (approximately 5 / 1, 50 mL) and filtered. The filtrate was concentrated under vacuum to give methyl 2-(((6-chloro-8-fluoro-3-iodoquinolin-4-yl)methyl)amino)-2-ethylbutyrate (24.1 g, 16.0 g, 68.1%) as a yellow solid. LC-MS (ESI): m / z 465.0 [M+H] + .

[0326] At -78°C, a solution of methyl 2-(((6-chloro-8-fluoro-3-iodoquinoline-4-yl)methyl)amino)-2-ethylbutyrate (24.1 g, 15.0 g, 32.2 mmol) in THF (100 mL) was added dropwise to a solution of isopropyl magnesium chloride-lithium chloride complex (74.5 mL, 96.8 mmol) in THF (200 mL), and the mixture was stirred at -78°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with 2 N HCl (40 mL), neutralized with NaHCO3 (20 mL), and extracted with ethyl acetate (250 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, followed by grinding with PE / EtOAc (5 / 1) to obtain 9-chloro-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyrido[4,3-] as a white solid. c Quinoline-4-one (24.2, 5.00 g, 50.5%). LC-MS (ESI): m / z 307.1 [M+H] + .

[0327] At 0°C, 9-chloro-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyrido[4,3- c Quinoline-4-one (24.2 g, 1.50 g, 4.89 mmol) was added to a solution of MeOH (20 mL) with NaBH4 (0.18 g, 4.89 mmol), and the mixture was stirred at 0°C for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 9-chloro-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydrobenzo[] as a yellow solid. c [2,6]Naphthyl-4-ol (24.3, 500 mg, 33.1%). LC-MS (ESI): m / z 309.1 [M+H] + 。

[0328] At 0°C, 9-chloro-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyrido[4,3- cTFA (793 μL, 10.3 mmol) was added to a mixture of quinoline-4-ol (24.3, 400 mg, 1.29 mmol) and Et3SiH (827 μL, 5.18 mmol), and the mixture was stirred at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (3 mL), and extracted with petroleum ether (5 mL × 3). The aqueous phase was adjusted to pH 8 with saturated NaHCO3 solution and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-chloro-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyrido[4,3- c Quinoline (24.4, 370 mg, 97.3%). LC-MS (ESI): m / z 293.1 [M+H] + .

[0329] To 9-chloro-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyrido[4,3- c A mixture of quinoline (24.4 mg, 185 mg, 0.63 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentanane (240 mg, 0.95 mmol) in dioxane (5 mL) was supplemented with Pd2(dba)3 (28.9 mg, 0.032 mmol), Xphos (30.1 mg, 0.063 mmol), and KOAc (186 mg, 1.90 mmol). The resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. Water (0.6 mL), 2,4,5-trichloropyrimidine (215 μL, 1.87 mmol), K₂CO₃ (259 mg, 1.87 mmol), and Pd(PPh₃)₄ (72.2 mg, 0.062 mmol) were added to the mixture, and the resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9-(2,5-dichloropyrimidine-4-yl)-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyrido[4,3- c Quinoline (24.6, 250 mg, crude). LC-MS (ESI): m / z 405.1 [M+H] + .

[0330] 9-(2,5-dichloropyrimidin-4-yl)-3,3-diethyl-7-fluoro-1,2,3,4-tetrahydropyridine[4,3- c ]Quinoline (24.6, 250 mg, crude product), (3 S 4 R A mixture of 4-aminotetrahydropyran-3-ol hydrochloride (189 mg, 1.23 mmol) and DIEA (305 μL, 1.85 mmol) in DMSO (1.5 mL) was stirred at 100°C for 1 hour. The reaction mixture was filtered and subjected to preparative HPLC to give a white solid (3-aminotetrahydropyran-3-ol hydrochloride). S 4 R )-4-((5-chloro-4-(3,3-diethyl-7-fluoro-1,2,3,4-tetrahydrobenzo[ c [2,6]Naphthil-9-yl)pyrimidin-2-yl)amino)tetrahydro-2 H 3-Pyran-3-ol (24, 64.0 mg, 21% yield in three steps). LC-MS (ESI) m / z 486.2 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.74 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 11.4 Hz, 1H), 7.68 - 7.44 (m, 1H), 5.05 -4.85 (m, 1H), 4.28 (s, 2H), 3.91 - 3.75 (m, 3H), 3.34 - 3.29 (m, 2H), 3.08 -3.01 (m, 1H), 2.76 (s, 2H), 2.07 - 1.87 (m, 1H), 1.56 - 1.29 (m, 5H), 0.86(t, J = 7.4 Hz, 6H).

[0331] Example 18. R )-6-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3- b Quinoline-3-ol and ( S )-6-(5-chloro-2-(((3) S 4 R)-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3- b Quinoline-3-ol

[0332] Ethyl magnesium bromide (232 mL, 232 mmol, 1 mol / L) was added to a solution of 2-amino-5-bromo-3-fluorobenzyl-1-carboxynitrile (19.2, 10.0 g, 46.5 mmol) in tetrahydrofuran (50 mL) at -10°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), diluted with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(2-amino-5-bromo-3-fluorophenyl)prop-1-one (25.1, 11.0 g, 96%) as a yellow solid. LC-MS (ESI): m / z 246.0 [M+H] + .

[0333] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)prop-1-one (25.1 g, 9.70 g, 39.4 mmol), ethyl 3-ethoxy-3-oxopropionate (30 mL, 197 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (6.00 g, 39.4 mmol) was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl 6-bromo-4-ethyl-8-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylate (25.2 g, 6.30 g, 47%) as a yellow solid. LC-MS (ESI): m / z 342.0 [M+H] + .

[0334] A mixture of ethyl 6-bromo-4-ethyl-8-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylate (25.2 g, 3.00 g, 8.77 mmol), ethyl 2-hydroxyacetate (1.19 g, 11.4 mmol), and 2-(tributyl-15-phosphonyl)acetonitrile (3.17 g, 13.2 mmol) in toluene (30 mL) was stirred at 100°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl 6-bromo-2-(2-ethoxy-2-oxoethoxy)-4-ethyl-8-fluoroquinoline-3-carboxylate (25.3 g, 2.70 g, 72%) as a yellow oil. LC-MS (ESI): m / z 428.0 [M+H] + .

[0335] At 0°C, potassium tert-butoxide (7.9 mL, 7.9 mmol) was added to a solution of ethyl 6-bromo-2-(2-ethoxy-2-oxoethoxy)-4-ethyl-8-fluoroquinoline-3-carboxylate (25.3 g, 2.6 g, 6.07 mmol) in tetrahydrofuran (260 mL), and the mixture was stirred at 0°C for 30 min. The reaction mixture was quenched at 0°C with aqueous hydrochloric acid (3.1 mL, 6.2 mmol, 2 mol / L). The mixture was diluted with water (400 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-bromo-4-ethyl-8-fluoro-3-hydroxyfuran[2,3-] as a yellow solid. b Ethyl quinoline-2-carboxylate (25.4 g, 2.60 g, crude product). LC-MS (ESI): m / z 382.0 [M+H] + .

[0336] 6-Bromo-4-ethyl-8-fluoro-3-hydroxyfurano[2,3- b A mixture of ethyl quinoline-2-carboxylate (25.4 g, 2.60 g, crude) and sulfuric acid (7.8 mL, 46.8 mmol) in ethanol (20 mL, 342 mmol) was stirred at 100°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-bromo-4-ethyl-8-fluorofurano[2,3-] as a yellow solid. b Quinoline-3(2) H )-ketone( 25.5, 900 mg). LC-MS(ESI): m / z 310.0 [M+H] + .

[0337] At -78°C, 6-bromo-4-ethyl-8-fluorofurano[2,3- b Quinoline-3(2) H 6-Bromo-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3-]one (25.5, 800 mg, 2.58 mmol) was added to a solution of dichloromethane (8 mL) with magnesium methyl bromide (8.6 mL, 25.8 mmol), and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-bromo-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3-]one as a yellow solid. b Quinoline-3-ol (25.6, 620 mg, 74%). LC-MS (ESI): m / z 326.0 [M+H] + .

[0338] 6-Bromo-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3- b A mixture of quinoline-3-ol (25.6 mg, 300 mg, 0.92 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (467 mg, 1.84 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (75.3 mg, 0.092 mmol), and potassium acetate (181 mg, 1.84 mmol) in dioxane (3 mL) was stirred at 90°C for 3 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature. Under a nitrogen atmosphere, water (0.6 mL), potassium carbonate (254 mg, 1.84 mmol), 2,4,5-trichloropyrimidine (506 mg, 2.76 mmol), and tetrakis(triphenylphosphine)palladium(0) (106 mg, 0.092 mmol) were added to the mixture, and the mixture was stirred at 100°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 6-(2,5-dichloropyrimidin-4-yl)-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3-] as a yellow oil. bQuinoline-3-ol (25.7, 350 mg, two-step yield 97%). LC-MS (ESI): m / z 394.0 [M+H) + .

[0339] 6-(2,5-dichloropyrimidin-4-yl)-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3- b Quinoline-3-ol (25.7, 430 mg, 1.09 mmol), (3 S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (419 mg, 2.73 mmol), potassium fluoride (253 mg, 4.36 mmol), and potassium carbonate (452 ​​mg, 3.27 mmol) in dimethyl sulfoxide (4 mL) was stirred at 120°C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-(5-chloro-2-(((3)) as a yellow solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-4-ethyl-8-fluoro-3-methyl-2,3-dihydrofurano[2,3- b Quinoline-3-ol (25, 303 mg, 58%) was further separated by chiral SFC to obtain: Isomer 1: (25a, 99.98% de); retention time: 0.577 min. LC-MS (ESI): m / z 475.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-) d 6) δ 8.45 (s, 1H), 8.41 - 8.2 (m, 1H), 8.01 - 7.72(m, 1H), 7.66 - 7.46 (m, 1H), 6.05 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.52 -4.38 (m, 2 H), 3.92 - 3.74 (m, 3H), 3.58 - 3.43 (m, 1H), 3.33 - 3.16 (m, 3 H), 3.10 - 2.97 (m, 1H), 2.06 - 1.85 (m, 1H), 1.68 (s, 3H), 1.57 - 1.46 (m, 1H),1.35 (t, J = 7.5 Hz, 3H).

[0340] Isomer 2: (25b, 99.88% de); retention time: 0.867 min; LC-MS (ESI): m / z 475.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.45 (s, 1H), 8.41 - 8.2 (m, 1H), 8.01 - 7.72(m, 1H), 7.66 - 7.46 (m, 1H), 6.05 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.52 -4.38 (m, 2 H), 3.92 - 3.74 (m, 3H), 3.58 - 3.43 (m, 1H), 3.33 - 3.16 (m, 3H), 3.10 - 2.97 (m, 1H), 2.06 - 1.85 (m, 1H), 1.68 (s, 3H), 1.57 - 1.46 (m,1H), 1.35 (t, J = 7.5 Hz, 3H).

[0341] Analytical methods: Instrument: Agilent 1260; Column: CHIRALPAK IG-3, 4.6 50 mm, 3.0 μm; Mobile phase: A, Hex (0.1% DEA), and B, EtOH; Gradient: B 30%; Flow rate: 1.67 mL / min; High pressure: 110 bar; Column temperature: 25°C; Wavelength: 254 nm. SFC method: Instrument: GILSON-LC03; Column: CHIRALPAK IG, 30 250 mm, 5 μm; Mobile phase: A, MtBE (10 mMNH3), and B, MeOH; Gradient: B 30%; Flow rate: 40 mL / min; High pressure: 112 bar; Column temperature: 25°C; Wavelength: 259 nm / 206 nm.

[0342] Example 19. R )-9-chloro-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-9-chloro-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0343] At -60°C, 7-bromo-9-chloro-5-fluoro-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinolin-1-one (22.2, 180 mg, 0.57 mmol) was added to a solution of dichloromethane (5 mL) with CH3MgBr (0.95 mL, 3 mol / L in THF), and the mixture was stirred at -60°C for 30 min. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-bromo-9-chloro-5-fluoro-1-methyl-2,3-dihydro-1-methyl as a yellow solid. H -cyclopentadienyl[1,2-] b Quinoline-1-ol (26.1, 130 mg, 68.7%). LC-MS (ESI): m / z 330.0 [M+H] + .

[0344] 7-bromo-9-chloro-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] bA mixture of quinoline-1-ol (26.1 mg, 370 mg, 1.12 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl (426 mg, 1.68 mmol), Pd(dppf)Cl2 (83.0 mg, 0.11 mmol), and KOAc (329 mg, 3.36 mmol) in dioxane (7 mL) was stirred at 100°C for 1 hour under a nitrogen atmosphere. Then, under a nitrogen atmosphere, water (2 mL), 2,4,5-trichloropyrimidine (256 μL, 2.23 mmol), K₂CO₃ (463 mg, 3.35 mmol), Pd(PPh₃)₄ (129 mg, 0.11 mmol), and PPh₃ (117 mg, 0.45 mmol) were added to the mixture, and the resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a brown oily substance, 9-chloro-7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1-yl ... H -cyclopentadienyl[1,2-] b Quinoline-1-ol (26.3, 600 mg, crude). LC-MS (ESI): m / z 398.0 [M+H] + .

[0345] 9-chloro-7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (26.3, 550 mg, crude), (3) S 4 R A mixture of 4-aminotetrahydropyran-3-ol hydrochloride (423 mg, 2.76 mmol) and DIEA (698 μL, 4.14 mmol) in MeCN (7 mL) was stirred at 110°C for 2 hours. The reaction mixture was filtered and subjected to preparative HPLC to give 9-chloro-7-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ bQuinoline-1-ol (26,293 mg) was separated by chiral SFC to obtain: Isomer 1: (26a, 100% de); retention time: 1.641 min. LCMS (ESI): m / z 479.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.48 (s, 2H), 8.01 (d, J = 10.4 Hz, 1H), 7.61 (s, 1H), 5.65 (s, 1H), 4.95 (d, J = 5.3 Hz, 1H), 3.86 - 3.77 (m, 3H), 3.55 - 3.49 (m,1H), 3.31 - 3.28 (m, 1H), 3.22 - 2.99 (m, 3H), 2.34 - 2.19 (m, 2H), 1.99 -1.85 (m, 1H), 1.63 (s, 3H), 1.56 - 1.45 (m, 1H).

[0346] Isomer 2: (26b, 100% de); retention time: 2.653 min. LCMS (ESI): m / z 479.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.48 (s, 2H), 8.01 (d, J = 9.7 Hz, 1H), 7.62 (s, 1H), 5.65 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 3.90 - 3.76 (m, 3H), 3.54 - 3.48 (m,1H), 3.31 - 3.27 (m, 1H), 3.23 - 3.00 (m, 3H), 2.34 - 2.18 (m, 2H), 1.99 -1.84 (m, 1H), 1.63 (s, 3H), 1.57 - 1.43 (m, 1H).

[0347] Analytical methods: Column: ChiralPak AS, 100 × 4.6 mm ID, 3 µm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 30% over 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 40°C. SFC separation method: Waters Thar 80 preparative SFC; Column: ChiralPak AS, 250 × 30 mm ID, 5 µm; Mobile phase: A, CO2, and B, MEOH (0.1% 2 mol / L NH3 in MeOH); Gradient: B 50%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 10 min.

[0348] Example 20. R )-5-fluoro-7-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-1,9-dimethyl-2,3-dihydro-1H-cyclopentadienyl[ b Quinoline-1-ol and ( S )-5-fluoro-7-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0349] Under a nitrogen atmosphere, at -78°C, 7-bromo-5-fluoro-9-methyl-2,3-dihydro-1 H -cyclopentadiene[ b A solution of quinolin-1-one (18.3 g, 1.50 g, 5.10 mmol) in tetrahydrofuran (15 mL) was mixed with methyl magnesium bromide (17.0 mL, 51.0 mmol), and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-5-fluoro-1,9-dimethyl-2,3-dihydro-1-methyl bromo-1-one as a yellow solid. H -cyclopentadiene[ bQuinoline-1-ol (27.1 g, 1.40 g, 89%). LC-MS (ESI): m / z 310.0 [M+H] + .

[0350] 7-bromo-5-fluoro-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b A mixture of quinoline-1-ol (27.1 mg, 700 mg, 2.25 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronyl-2-yl (802 mg, 3.16 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (185 mg, 0.226 mmol), and potassium acetate (443 mg, 4.51 mmol) in dioxane (7 mL) was stirred at 90°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water (1.5 mL), potassium carbonate (623 mg, 4.51 mmol), tetrakis(triphenylphosphine)palladium(O) (261 mg, 0.226 mmol), and 2,4-dichloro-5-fluoropyrimidine (753 mg, 4.51 mmol) were added to the mixture, and the resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1-yl) as a yellow solid. H -cyclopentadiene[ b Quinoline-1-ol (27.2, 640 mg, two-step yield 78%). LC-MS (ESI): m / z 348.1 [M+H] + .

[0351] 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (27.2, 640 mg, 1.77 mmol), (3) S 4 R )-4-aminotetrahydro-2 HA mixture of pyran-3-ol hydrochloride (679 mg, 4.42 mmol), potassium fluoride (411 mg, 7.08 mmol), and potassium carbonate (733 mg, 5.31 mmol) in dimethyl sulfoxide (6 mL) was stirred at 120°C for 4 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a yellow solid of 5-fluoro-7-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-1,9-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (27,473 mg, 61%) was further separated by chiral SFC to obtain: Isomer 1: (27a, 100% de); retention time: 1,300 min. LCMS (ESI): m / z 443.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.59 (s, 1H), 8.49 (d, J = 3.8 Hz, 1H), 8.04 (d, J = 11.9Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 5.58 (s, 1H), 4.95 (d, J = 5.3 Hz, 1H), 3.87 -3.79 (m, 3H), 3.59 - 3.48 (m, 1H), 3.39 - 3.34 (m, 1H), 3.09 - 3.00 (m, 3H), 2.85 (s, 3H), 2.28 - 2.16 (m, 2H), 2.06 - 1.98 (m, 1H), 1.57 - 1.46 (m, 4H).

[0352] Isomer 2: (27b, 100% de); retention time: 2.225 min. LCMS (ESI): m / z 443.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6) δ 8.59 (s, 1H), 8.49 (d, J = 3.8 Hz, 1H), 8.05 (d, J = 12.1Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 5.58 (s, 1H), 4.95 (d, J = 5.4 Hz, 1H), 3.88 -3.79 (m, 3H), 3.58 - 3.47 (m, 1H), 3.39 - 3.34 (m, 1H), 3.09 - 3.00 (m, 3H), 2.85 (s, 3H), 2.28 - 2.15 (m, 2H), 2.06 - 1.98 (m, 1H), 1.56 - 1.45 (m, 4H).

[0353] Analytical methods: Column: ChiralPak IH, 100 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 30% over 8 min; Flow rate: 2.5 mL / min; Back pressure: 100 bar; Column temperature: 40°C. SFC separation method: Waters Thar 80 preparative SFC; ChiralPak IH, 150 × 20 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 7 mol / L NH3 in MeOH); Gradient: B 30%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 8 min.

[0354] Example 21. R )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol and ( S )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ cQuinoline-3-ol

[0355] At -78°C, add to a solution of 2-acetylcyclopentan-1-one (28.1 g, 5.00 g, 39.6 mmol) in dichloromethane (100 mL). N,N -Diisopropylethylamine (13.8 mL, 79.3 mmol) and trifluoromethanesulfonic anhydride (7.3 mL, 43.6 mmol) were added, and the mixture was stirred at -78°C for 30 minutes. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-acetylcyclopent-1-en-1-yltrifluoromethanesulfonate (28.2 g, 9.10 g, 89% yield) as a yellow oil. LC-MS (ESI): m / z 259.1 [M+H] + .

[0356] Tetra(triphenylphosphine)palladium (4.07 g, 3.52 mmol) and potassium carbonate (14.6 g, 105.6 mmol) were added to a mixture of 2-acetylcyclopent-1-en-1-yl trifluoromethanesulfonate (28.2, 9.10 g, 35.2 mmol) and 4-chloro-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (9.56 g, 35.2 mmol) in 1,4-dioxane (100 mL) and water (10 mL), and the mixture was stirred at 100°C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 8-chloro-6-fluoro-4-methyl-2,3-dihydro-1-ethylhexane as a yellow solid. H -cyclopentadiene[ c Quinoline (28.3 g, 5.42 g, 66% yield). LC-MS (ESI): m / z 236.1 [M+H] + .

[0357] To 8-chloro-6-fluoro-4-methyl-2,3-dihydro-1 H -cyclopentadiene[ cA mixture of quinoline (28.3 g, 5.42 g, 23.0 mmol), 2-peroxide-2-methylpropane (27.6 mL, 138 mmol, 5 mol / L), and sodium bicarbonate (3.86 g, 46.0 mmol) in dichloromethane (100 mL) was supplemented with tetrakis(caprolactam)dirhodium(II) (440 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 48 hours, followed by the addition of 2-peroxide-2-methylpropane (27.6 mL, 138 mmol, 5 mol / L), sodium bicarbonate (3.86 g, 46.0 mmol), and tetrakis(caprolactam)dirhodium(II) (250 mg, 0.38 mmol). The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 8-chloro-6-fluoro-4-methyl-1,2-dihydro-3-ethyl as a yellow solid. H -cyclopentadiene[ c Quinoline-3-one (28.4, 2.58 g, 45%). LC-MS (ESI): m / z 250.1 [M+H] + .

[0358] Under a nitrogen atmosphere at -78°C, 8-chloro-6-fluoro-4-methyl-1,2-dihydro-3- H -cyclopentadiene[ c Quinolin-3-one (28.4 g, 0.96 g, 3.85 mmol) was rapidly added to a solution of dichloromethane (50 mL) with magnesium methyl bromide (6.4 mL, 19.2 mmol, 3 mol / L), and the mixture was heated to room temperature and stirred for 1 hour. The mixture was poured into a saturated aqueous solution of ammonium chloride (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-3,4-dimethyl-2,3-dihydro-1-ethylhexylene as a yellow solid. H -cyclopentadiene[ c Quinoline-3-ol (28.5 g, 0.96 g, 94% yield). LC-MS (ESI): m / z 266.1 [M+H] + .

[0359] To 8-chloro-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ cA mixture of quinoline-3-ol (28.5 g, 1.43 g, 5.38 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (2.05 g, 8.07 mmol) and potassium acetate (1.58 g, 16.15 mmol) in 1,4-dioxane (35 mL) was supplemented with 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl (515 mg, 1.08 mmol) and tris(dibenzylacetone)dipalladium (494 mg, 0.54 mmol). The reaction mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. Under a nitrogen atmosphere, 2,4,5-trichloropyrimidine (2.63 g, 16.14 mmol), water (3.5 mL), tetrakis(triphenylphosphine)palladium (624 mg, 0.54 mmol), and potassium carbonate (1.49 g, 10.8 mmol) were added to the mixture, and the resulting mixture was stirred at 90°C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1-ethylhexyl chloride as a yellow solid. H -cyclopentadiene[ c Quinoline-3-ol (28.7 g, 1.44 g, two-step yield 71%). LC-MS (ESI): m / z 378.1 [M+H] + .

[0360] 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (28.7 g, 1.44 g, 3.81 mmol), potassium carbonate (1.05 g, 7.62 mmol), potassium fluoride (664 mg, 11.43 mmol) and (3 S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (877 mg, 5.71 mmol) in dimethyl sulfoxide (15 mL) was stirred at 90°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(5-chloro-2-(((3)) as a yellow solid.S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (28, 1.02 g, 58% yield) was further separated by chiral SFC to obtain: Isomer 1: (28a, 100% de); retention time: 2.960 min. LCMS (ESI): m / z 459.1 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.46 (s, 1H), 8.13 (s, 1H), 7.83 (d, J = 11.4 Hz, 1H),7.56 (s, 1H), 5.47 (s, 1H), 4.93 (d, J = 5.4 Hz, 1H), 3.89 - 3.76 (m, 3H), 3.54- 3.45 (m, 1H), 3.36 - 3.32 (m, 1H), 3.27 - 3.25 (m, 1H), 3.09 - 3.03 (m, 2H), 2.81 (s, 3H), 2.37 - 2.21 (m, 2H), 1.94 (s, 1H), 1.55 - 1.45 (m, 4H).

[0361] Isomer 2: (28b, 99.24% de); retention time: 4.170 min. LCMS (ESI): m / z 459.1 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.46 (s, 1H), 8.13 (s, 1H), 7.83 (d, J = 10.8 Hz,1H), 7.56 (s, 1H), 5.47 (s, 1H), 4.92 (d, J= 5.4 Hz, 1H), 3.90 - 3.76 (m, 3H), 3.55 - 3.45 (m, 1H), 3.36 - 3.32 (m, 1H), 3.31 - 3.25 (m, 1H), 3.09 - 3.02(m, 2H), 2.81 (s, 3H), 2.38 - 2.19 (m, 2H), 1.98 - 1.92 (m, 1H), 1.56 - 1.44 (m, 4H).

[0362] Analytical methods: Column: ChiralPak AD, 100 × 4.6 mm ID, 3 µm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 50% over 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 40°C. SFC separation method: Waters Thar 80 preparative SFC; ChiralPak AD, 250 × 30 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 7 mol / L NH3 in MeOH); Gradient: B 50%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 20 min.

[0363] Example 22. R )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol and ( S )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol

[0364] To 8-chloro-6-fluoro-2,2-dimethyl-1,2-dihydro-3 H -cyclopentadiene[ cQuinolin-3-one (23.2, 660 mg, 2.50 mmol) was slowly added to a solution of MeOH (3 mL) and THF (3 mL) with NaBH4 (189 mg, 5.00 mmol), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-2,2-dimethyl-2,3-dihydro-1-ethylhexylene as a white solid. H -cyclopentadiene[ c Quinoline-3-ol (29.1, 634 mg, 95.3%). LC-MS (ESI): m / z 266.1 [M+H] + .

[0365] 8-chloro-6-fluoro-2,2-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c A mixture of quinoline-3-ol (29.1 g, 2.00 g, 7.53 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (2.87 g, 11.3 mmol), tris(dibenzylacetone)dipalladium (1.38 g, 1.51 mmol), potassium acetate (2.22 g, 22.6 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (718 mg, 1.51 mmol) in dioxane (15 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a brown solid, 6-fluoro-2,2-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (29.2, 2.31 g, 85.9%). LC-MS (ESI): m / z 358.2 [M+H] + .

[0366] 6-fluoro-2,2-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ cA mixture of quinoline-3-ol (29.2 g, 2.31 g, 6.46 mmol), 2,4,5-trichloropyrimidine (1.90 g, 10.4 mmol), tetrakis(triphenylphosphine)palladium (1.12 g, 0.97 mmol), and potassium carbonate (1.79 g, 13.0 mmol) in dioxane / water (12 mL / 3 mL) was stirred at 90°C for 1.5 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-1-yl fluoropyrimidine as a yellow solid. H -cyclopentadiene[ c Quinoline-3-ol (29.3 g, 1.82 g, 74.4%). LC-MS (ESI): m / z 378.1 [M+H] + .

[0367] 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (29.3 g, 1.82 g, 4.81 mmol), (3 S 4 R )-4-aminotetrahydropyran-3-ol hydrochloride (1.33 g, 8.66 mmol) and N,N A mixture of diisopropylethylamine (3.18 mL, 19.2 mmol) in dimethyl sulfoxide (12 mL) was stirred at 110°C for 2.5 hours. The reaction mixture was filtered, and the filtrate was subjected to silica gel column chromatography to give 8-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (29, 1.46 g, 66.1%) was further separated by chiral SFC to obtain: Isomer 1: (29a, 100% de); retention time: 1.531 min. LCMS (ESI): m / z 459.4 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.89 (d,J =11.6 Hz, 1H), 7.59 (s, 1H), 5.61 (d, J = 6.4 Hz, 1H), 4.93 (d, J = 5.4 Hz, 1H), 4.87 (d, J = 6.3 Hz, 1H), 3.85 - 3.77 (m, 3H), 3.55 - 3.48 (m, 1H), 3.38 - 3.31(m, 1H), 3.18 - 2.93 (m, 3H), 2.01 - 1.95 (m, 1H), 1.57 - 1.43 (m, 1H), 1.21 (s, 3H), 1.01 (s, 3H).

[0368] Isomer 2: (29b, 100% de); retention time: 3.436 min. LCMS (ESI): m / z 459.4 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.89 (d, J =11.8 Hz, 1H), 7.59 (s, 1H), 5.61 (d, J = 6.3 Hz, 1H), 4.93 (d, J = 5.2 Hz, 1H), 4.87 (d, J = 6.1 Hz, 1H), 3.85 - 3.76 (m, 3H), 3.51 - 3.33 (m, 2H), 3.18 - 2.95(m, 3H), 2.01 - 1.95 (m, 1H), 1.57 - 1.43 (m, J = 9.2 Hz, 1H), 1.21 (s, 3H), 1.01 (s, 3H).

[0369] Analytical methods: Column: ChiralPak IH, 100 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 40% over 8 min; Flow rate: 2 mL / min; Column temperature: 40°C. SFC separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak IH, 250 × 20 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 7 mol / L NH3 in MeOH); Gradient: B 50%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 7 min.

[0370] Example 23. R )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2-] c Quinoline-3-ol and ( S )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2-] c Quinoline-3-ol

[0371] Add 3-acetyldihydrofuran-2 (3... H )-ketone (17.6 g, 137 mmol), and the mixture was stirred at 120°C for 24 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid ( Z )-3-(1-((4-chloro-2-fluorophenyl)imino)ethyl)dihydrofuran-2(3 H )-Ketone (30.2, 17.6 g, crude product). LC-MS (ESI): m / z 256.2 [M+H] + .

[0372] Add phosphorus oxychloride (70 mL) and ( Z )-3-(1-((4-chloro-2-fluorophenyl)imino)ethyl)dihydrofuran-2(3H A mixture of 4,6-dichloro-3-(2-chloroethyl)-8-fluoro-2-methylquinoline (30.2, 17.6 g, crude) was stirred at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The resulting mixture was adjusted to pH 7 with saturated sodium carbonate solution and then extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4,6-dichloro-3-(2-chloroethyl)-8-fluoro-2-methylquinoline (30.3, 10.8 g) as a yellow solid. LC-MS (ESI): m / z 292.0 [M+H] + .

[0373] A mixture of acetic acid (60 mL) and 4,6-dichloro-3-(2-chloroethyl)-8-fluoro-2-methylquinoline (30.3 g, 7.2 g, 24.6 mmol) was stirred at 120°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The resulting mixture was adjusted to pH 7 with saturated sodium carbonate solution and then extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-4-methyl-2,3-dihydrofurano[3,2-] as a yellow solid. c Quinoline (30.4 g, 2.42 g, 41% yield). LC-MS (ESI): m / z 238.1 [M+H] + .

[0374] To 8-chloro-6-fluoro-4-methyl-2,3-dihydrofurano[3,2- cQuinoline (30.4 g, 2.42 g, 10.2 mmol), 2-peroxide-2-methylpropane (12 mL, 60.0 mmol, 5 mol / L), and sodium bicarbonate (1.71 g, 20.4 mmol) were added to a mixture of dichloromethane (40 mL) and tert-butanol (10 mL) with tetrakis(caprolactam)-rhodium(II) (336 mg, 0.51 mmol). The mixture was stirred at room temperature for 24 hours, followed by the addition of 2-peroxide-2-methylpropane (12 mL, 60.0 mmol, 5 mol / L), sodium bicarbonate (1.71 g, 20.4 mmol), and tetrakis(caprolactam)-rhodium(II) (336 mg, 0.51 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 8-chloro-6-fluoro-4-methylfurano[3,2-] as a yellow solid. c Quinoline-3(2) H )-Keto (30.5, 240 mg, 9%). LC-MS (ESI): m / z 252.1 [M+H] + .

[0375] At room temperature, to 8-chloro-6-fluoro-4-methylfurano[3,2- c Quinoline-3(2) H )-ketone (30.5, 170 mg, 3.85 mmol) was added to a solution of dichloromethane (10 mL) with magnesium methyl bromide (1.10 mL, 3.30 mmol, 3 mol / L), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (10 mL) and extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2-] as a yellow solid. c Quinoline-3-ol (30.6, 170 mg, 93% yield). LC-MS (ESI): m / z 268.2 [M+H] + .

[0376] To 8-chloro-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2- cQuinoline-3-ol (30.6, 210 mg, 0.78 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (297 mg, 1.17 mmol) and potassium acetate (230 mg, 2.34 mmol) were added to a mixture of 1,4-dioxane (7 mL) with 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl (76.0 mg, 0.16 mmol) and tris(dibenzylacetone)dipalladium (73.0 mg, 0.08 mmol). The mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. To the mixture, 2,4,5-trichloropyrimidine (428 mg, 2.34 mmol), water (1 mL), tetrakis(triphenylphosphine)palladium (92.0 mg, 0.08 mmol), and potassium carbonate (216 mg, 1.56 mmol) were added, and the resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2-] as a yellow solid. c Quinoline-3-ol (30.8, 150 mg, two-step yield 51%). LC-MS (ESI): m / z 380.0 [M+H] + .

[0377] 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2- c Quinoline-3-ol (30.8 mg, 150 mg, 0.39 mmol), potassium carbonate (108 mg, 0.78 mmol), potassium fluoride (69.0 mg, 1.18 mmol) and (3 S 4 R )-4-aminotetrahydro-2 H A mixture of pyran-3-ol hydrochloride (91.0 mg, 0.59 mmol) in dimethyl sulfoxide (3 mL) was stirred at 90°C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (5 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(5-chloro-2-(((3)) as a white solid. S 4 R)-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydrofurano[3,2-] c Quinoline-3-ol (30, 21.8 mg, 12% yield) was further separated by chiral SFC to obtain: Isomer 1: (30a, 100% de); retention time: 3.433 min. LCMS (ESI): m / z 461.3 [M+H] + . 1 HNMR(400 MHz, CDCl3) δ 8.29 (s, 1H), 8.04 (s, 1H), 7.76 (dd, J = 11.8, 1.7 Hz, 1H), 5.38 (d, J = 6.4 Hz, 1H), 4.82 (d, J = 10.4 Hz, 1H), 4.61 (d, J = 10.3 Hz, 1H), 4.09 (dd, J = 11.3, 4.8 Hz, 1H), 3.99 (dd, J = 11.5, 3.9 Hz, 1H), 3.92 -3.83 (m, 1H), 3.66 (d, J = 4.7 Hz, 1H), 3.52 - 3.42 (m, 1H), 3.31 (s, 1H), 3.26- 3.17 (m, 1H), 2.84 (s, 3H), 2.07 - 2.02 (m, 1H), 1.85 (s, 3H), 1.77 - 1.66(m, 1H).

[0378] Isomer 2: (30b, 100% de); retention time: 4.732 min. LCMS (ESI): m / z 461.4 [M+H] + . 1 HNMR(400 MHz, CDCl3) δ 8.25 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 11.1 Hz, 1H), 5.50 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 10.3 Hz, 1H), 4.59 (d,J = 10.3 Hz, 1H), 4.09 (dd, J = 11.2, 4.9 Hz, 1H), 4.01 (dd, J = 11.6, 3.6 Hz, 1H), 3.95 - 3.87 (m,1H), 3.70 - 3.62 (m, 1H), 3.54 - 3.46 (m, 1H), 3.32 - 3.10 (m, 1H), 2.83 (s,3H), 2.15 - 2.06 (m, 1H), 1.83 (s, 3H), 1.76 - 1.66 (m, 1H).

[0379] Analytical methods: Column: ChiralPak C-IC, 100 × 4.6 mm ID, 3 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 40% over 8 min; Flow rate: 2.0 mL / min; Column temperature: 40°C. SFC separation method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak C-IC, 250 × 30 mm ID, 5 µm; Mobile phase: A, CO2, and B, IPA (0.1% 7 mol / L NH3 in MeOH); Gradient: B 45%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 16 min.

[0380] Example 24. R )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol and ( S )-8-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol

[0381] Under a nitrogen atmosphere, lithium diisopropylamino (100 mL, 200 mmol, 2 mol / L in THF) was added dropwise to a solution of 3,3-dimethylcyclopentan-1-one (31.1 g, 18.7 g, 166 mmol) in THF (200 mL) at -78°C, and the mixture was stirred at -78°C for 30 min, followed by the dropwise addition of acetyl chloride (14.2 mL, 200 mmol). The resulting mixture was stirred at -78°C for 2.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL) and diluted with saturated aqueous NaCl solution (300 mL). The aqueous layer was extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was subjected to silica gel column chromatography to give 2-acetyl-4,4-dimethylcyclopentan-1-one (31.2 g, 9.10 g, crude product) as a yellow oil. LC-MS (ESI): m / z 155.1 [M+H] + .

[0382] At -78°C, 2-acetyl-4,4-dimethylcyclopentan-1-one (31.2 g, 9.10 g, crude product) and N,N - Diisopropylethylamine (20.5 mL, 118.0 mmol) was added dropwise to a mixture in DCM (60 mL) with trifluoromethanesulfonic anhydride (11.9 mL, 70.8 mmol), and the mixture was stirred at -78°C for 30 min. The reaction mixture was concentrated under vacuum, and the residue was subjected to silica gel column chromatography to give 2-acetyl-4,4-dimethylcyclopent-1-en-1-yltrifluoromethanesulfonate (31.3 g, 5.20 g) as a yellow oil. LC-MS (ESI): m / z 287.1 [M+H] + .

[0383] A mixture of 2-acetyl-4,4-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (31.3 g, 5.20 g, 18.1 mmol), 4-chloro-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (5.92 g, 21.8 mmol), tetra(triphenylphosphine)palladium(O) (3.15 g, 2.72 mmol), and K₂CO₃ (7.53 g, 54.5 mmol) in dioxane (30 mL) and water (6 mL) was stirred at 100°C for 6 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under vacuum and subjected to silica gel column chromatography to give 8-chloro-6-fluoro-2,2,4-trimethyl-2,3-dihydro-1-yl trifluoromethanesulfonate as a white solid. H -cyclopentadiene[c Quinoline (31.4 g, 2.75 g, 57.4%). LC-MS (ESI): m / z 264.1 [M+H] + .

[0384] To 8-chloro-6-fluoro-2,2,4-trimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline (31.4 g, 2.75 g, 10.4 mmol), tetra(caprolactam) dirhodium (343 mg, 0.52 mmol), and NaHCO3 (1.75 g, 20.8 mmol) were slowly added to a mixture in DCM (15 mL) with 2-peroxide-2-methylpropane (20.8 mL, 104.2 mmol, 5 mol / L). The reaction mixture was stirred at room temperature for 3 days, with 2-peroxide-2-methylpropane (41.7 mL, 208.5 mmol, 5 mol / L) added in portions during the reaction. The reaction mixture was slowly added to a saturated aqueous solution of sodium thiosulfate (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was subjected to silica gel chromatography to give 8-chloro-6-fluoro-2,2,4-trimethyl-1,2-dihydro-3-trimethylolpropane as a white solid. H -cyclopentadiene[ c Quinoline-3-one (31.5, 380 mg, 13%). LC-MS (ESI): m / z 278.1 [M+H] + .

[0385] Under a nitrogen atmosphere, at -78°C, 8-chloro-6-fluoro-2,2,4-trimethyl-1,2-dihydro-3- H -cyclopentadiene[ c Quinolin-3-one (31.5, 380 mg, 1.37 mmol) was added dropwise to a solution of dichloromethane (6 mL) with magnesium methyl bromide (2.28 mL, 6.84 mmol, 3 mol / L in THF), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (5 mL), diluted with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1-ethylhexyl chloride as a white solid. H -cyclopentadiene[ cQuinoline-3-ol (31.6, 360 mg, 89.5%). LC-MS (ESI): m / z 294.1 [M+H] + .

[0386] 8-Chloro-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1 H -cyclopentadiene[ c A mixture of quinoline-3-ol (31.6, 360 mg, 1.22 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (467 mg, 1.84 mmol), tris(dibenzylacetone)dipalladium (225 mg, 0.25 mmol), potassium acetate (361 mg, 3.67 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (117 mg, 0.25 mmol) in dioxane (6 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a brown solid, 6-fluoro-2,2,3,4-tetramethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (31.7, 424 mg, 89.8%). LC-MS (ESI): m / z 386.2 [M+H] + .

[0387] 6-Fluoro-2,2,3,4-Tetramethyl-8-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadiene[ c A mixture of quinoline-3-ol (31.7 mg, 424 mg, 1.10 mmol), 2,4,5-trichloropyrimidine (323 mg, 1.76 mmol), tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol), and potassium carbonate (304 mg, 2.20 mmol) in dioxane / water (6 mL / 2 mL) was stirred at 90°C for 1.5 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1-yl) as a yellow solid. H -cyclopentadiene[ cQuinoline-3-ol (31.8, 320 mg, 71.6%). LC-MS (ESI): m / z 406.1 [M+H] + .

[0388] 8-(2,5-dichloropyrimidin-4-yl)-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (31.8, 320 mg, 0.79 mmol), (3 S 4 R 4-Aminotetrahydropyran-3-ol hydrochloride (242 mg, 1.57 mmol) and N,N A mixture of diisopropylethylamine (521 µL, 3.15 mmol) and dimethyl sulfoxide (2 mL) was stirred at 110°C for 2 hours. The reaction mixture was filtered, and the filtrate was subjected to preparative HPLC to give 8-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-6-fluoro-2,2,3,4-tetramethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (31,247 mg, 64.4%) was further separated by chiral SFC to obtain: Isomer 1: (31a, 100% de); retention time: 1.028 min. LCMS (ESI): m / z 487.4 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.46 (s, 1H), 8.10 (s, 1H), 7.83 (d, J = 11.7 Hz, 1H),7.56 (s, 1H), 5.11 (s, 1H), 4.90 (s, 1H), 3.85 - 3.77 (m, 3H), 3.51 - 3.47(m, 1H), 3.34 - 3.31 (m, 1H), 3.16 - 2.97 (m, 2H), 2.94 - 2.86 (m, 1H), 2.82(s, 3H), 1.98 - 1.94 (m, 1H), 1.54 - 1.42 (m, 1H), 1.37 (s, 3H), 1.16 (s,3H), 0.95 (s, 3H).

[0389] Isomer 2: (31b, 100% de); retention time: 2.189 min. LCMS (ESI): m / z 487.4 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.46 (s, 1H), 8.10 (s, 1H), 7.83 (d, J = 11.7 Hz, 1H),7.56 (s, 1H), 5.12 (s, 1H), 4.93 (s, 1H), 3.85 - 3.77 (m, 3H), 3.51 - 3.47(m, 1H), 3.34 - 3.31 (m, 1H), 3.12 - 3.03 (m, 2H), 2.94 - 2.86 (m, 1H), 2.82(s, 3H), 1.97 - 1.91 (m, 1H), 1.55 - 1.42 (m, 1H), 1.37 (s, 3H), 1.16 (s,3H), 0.95 (s, 3H).

[0390] Analytical methods: Column: ChiralPak AS, 100 × 4.6 mm ID, 3 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 40% over 8 min; Flow rate: 2.0 mL / min; Column temperature: 40°C. SFC separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak AS, 250 × 30 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 2 mol / L NH3 in MeOH); Gradient: B 50%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 10 min.

[0391] Example 25. R )-9-cyclopropyl-5-fluoro-7-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-9-cyclopropyl-5-fluoro-7-(5-fluoro-2-(((3) S 4R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0392] To 2-amino-5-bromo-3-fluorobenzoic acid (18.1, 8.50 g, 36.3 mmol) and N,O HATU (16.6 g, 43.6 mmol) and DIEA (28.2 g, 218 mmol) were added to a solution of 2-amino-5-bromo-3-fluoro-dimethylhydroxylamine hydrochloride (10.6 g, 109 mmol) in DMF (100 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-amino-5-bromo-3-fluoro-dimethylhydroxylamine hydrochloride as a white solid. N -Methoxy- N -Methylbenzamide (32.1 g, 9.00 g, 89.4%). LCMS (ESI): m / z 277.1 & 279.1 [M+H] + .

[0393] Under a nitrogen atmosphere, at -40°C, 2-amino-5-bromo-3-fluoro- N -Methoxy- N 1-Methylbenzamide (32.1 g, 3.00 g, 10.8 mmol) was added dropwise to a solution of 10 mL of anhydrous THF with magnesium bromide (10.9 mL, 10.8 mmol, 1 mol / L in THF), and the mixture was stirred at -40°C for 5 hours. The reaction mixture was quenched with 20 mL of saturated aqueous NH4Cl solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (2-amino-5-bromo-3-fluorophenyl)(cyclopropyl) methyl ketone (32.2 g, 78.7%) as a yellow solid. LCMS (ESI): m / z 257.9 & 259.9 [M+H] + .

[0394] A mixture of (2-amino-5-bromo-3-fluorophenyl)(cyclopropyl) methyl ketone (32.2 g, 1.50 g, 5.81 mmol) and cyclopentane-1,3-dione (0.68 g, 6.97 mmol) in TFA (15 mL) was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (20 mL). The resulting mixture was adjusted to pH 8 with a saturated aqueous solution of NaHCO3 and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-9-cyclopropyl-5-fluoro-2,3-dihydro-1,3-dione as a brown solid. H -cyclopentadienyl[1,2-] b Quinoline-1-one (32.3, 850 mg, 45.7%). LCMS (ESI): m / z 319.9 & 321.9 [M+H] + .

[0395] Under a nitrogen atmosphere, at 0°C, 7-bromo-9-cyclopropyl-5-fluoro-2,3-dihydro-1-methyl methyl ester was added dropwise to a solution of methyl magnesium bromide (3.20 mL, 9.37 mmol, 3 mol / L in Et₂O) in THF (5 mL). H -cyclopentadienyl[1,2-] b Quinolin-1-one (32.3, 500 mg, 1.56 mmol) was dissolved in THF (2 mL), and the mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-9-cyclopropyl-5-fluoro-1-methyl-2,3-dihydro-1-ylene as a brown solid. H -cyclopentadienyl[1,2-] b Quinoline-1-ol (32.4, 280 mg, 53.3%). LCMS (ESI): m / z 336.1 & 338.1 [M+H] + .

[0396] 7-bromo-5-fluoro-3-methyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] bA mixture of quinoline-3-ol (32.4 mg, 250 mg, 0.84 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (284 mg, 1.11 mmol), Pd(dppf)Cl2.CH2Cl2 (61.0 mg, 0.074 mmol), and potassium acetate (219 mg, 2.23 mmol) in dioxane (12 mL) was stirred at 100°C for 2 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 5-fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl)-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (32.5, 242 mg, 84.9%). LCMS (ESI): m / z 384.2 [M+H] + .

[0397] 5-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b A mixture of quinoline-1-ol (32.5 mg, 250 mg, 0.73 mmol), 2,4,5-trichloropyrimidine (268 mg, 1.46 mmol), Pd(dppf)Cl2.CH2Cl2 (59.8 mg, 0.073 mmol), and K2CO3 (303 mg, 2.19 mmol) in dioxane (3 mL) and water (0.5 mL) was stirred at 90°C for 2 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give a yellow solid of 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1-yl H -cyclopentadienyl[1,2-] b Quinoline-1-ol (32.6, 250 mg, 94.2%). LCMS (ESI): m / z 404.2 [M+H] + .

[0398] To 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadienyl[1,2-] b Quinoline-1-ol (32.6, 200 mg, 0.495 mmol) and (3 S 4 R)-4-aminotetrahydro-2 H 7-(5-chloro-2-(((3-)pyran-3-ol hydrochloride) (92.0 mg, 0.594 mmol) was dissolved in DMSO (3 mL) with potassium fluoride (87.0 mg, 1.485 mmol), 18-crown-6 (27 mg, 0.10 mmol), and K2CO3 (69.0 mg, 0.495 mmol) and the mixture was stirred at 110°C for 2 hours. The reaction mixture was filtered and then subjected to preparative HPLC to give 7-(5-chloro-2-(((3-)pyran-3-ol hydrochloride) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-cyclopropyl-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (32,200 mg, 65.5%) was further separated by chiral SFC to obtain: Isomer 1: (32a, 100% de); retention time: 3.225 min. LCMS (ESI): m / z 485.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.81 (s, 1H), 8.47 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 5.34 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 3.98 - 3.73 (m, 3H), 3.61 - 3.42(m, 1H), 3.38 - 3.32 (m, 1H), 3.28 - 3.15 (m, 1H), 3.10 - 3.00 (m, 1H), 3.02- 2.87 (m, 1H), 2.42 - 2.27 (m, 1H), 2.23 - 2.06 (m, 2H), 2.04 - 1.90 (m,1H), 1.81 (s, 3H), 1.70 - 1.59 (m, 1H), 1.55 - 1.44 (m, 1H), 1.38 - 1.26 (m,1H), 1.20 - 1.09 (m, 1H), 0.71 - 0.57 (m, 1H).

[0399] Isomer 2: (32b, 98.8% de); retention time: 4.208 min. LCMS (ESI): m / z 485.3 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.79 (s, 1H), 8.47 (s, 1H), 7.85 (s, 1H), 7.55 (s, 1H), 5.34 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 3.96 - 3.71 (m, 3H), 3.59 - 3.42(m, 1H), 3.40 - 3.33 (m, 1H), 3.29 - 3.17 (m, 1H), 3.09 - 3.00 (m, 1H), 3.00- 2.88 (m, 1H), 2.43 - 2.28 (m, 1H), 2.24 - 2.06 (m, 2H), 2.05 - 1.89 (m,1H), 1.86 - 1.76 (m, 3H), 1.68 - 1.59 (m, 1H), 1.56 - 1.45 (m, 1H), 1.35 -1.25 (m, 1H), 1.20 - 1.09 (m, 1H), 0.74 - 0.54 (m, 1H).

[0400] Analytical methods: Column: ChiralCel OX, 100 × 4.6 mm ID, 5 µm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 50% over 8 min; Flow rate: 1.8 mL / min; Back pressure: 100 bar; Column temperature: 40°C. SFC separation method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralCel OX, 250 × 20 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 2 mol / L NH3 in MeOH); Gradient: B 50%; Flow rate: 35 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 11 min.

[0401] Example 26. R )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[b Quinoline-1-ol and ( S )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0402] To 7-bromo-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinolin-1-one (19.4, 300 mg, 0.93 mmol) was added to a solution of NaBH4 (70.0 mg, 1.86 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow solid of 7-bromo-5-fluoro-9-isopropyl-2,3-dihydro-1-oxoquinoline. H -cyclopentadiene[ b Quinoline-1-ol (33.1 mg, 300 mg, crude). LCMS (ESI): m / z 324.0 & 326.0 [M+H] + .

[0403] To 7-bromo-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[ bA mixture of quinoline-1-ol (33.1 mg, 300 mg, crude), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentane) (282 mg, 1.11 mmol), and potassium acetate (272 mg, 2.78 mmol) in dioxane (10 mL) was supplemented with Pd(dppf)Cl2 (68.0 mg, 0.093 mmol). The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. Under a nitrogen atmosphere, 2,4,5-trichloropyrimidine (198 mg, 1.08 mmol), water (1.5 mL), Pd(PPh3)4 (63.0 mg, 0.054 mmol), and K2CO3 (223 mg, 1.62 mmol) were added to the mixture, and the resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-isopropyl-2,3-dihydro-1-ethylhexyl chloride as a yellow solid. H -cyclopentadiene[ b Quinoline-1-ol (33.3, 258 mg). LCMS (ESI): m / z 392.0 [M+H] + .

[0404] 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (33.3, 208 mg, 0.53 mmol) was added to a solution of DMSO (2 mL) (3 S 4 R )-4-aminotetrahydro-2 H 7-(5-chloro-2-(((3-)) hydrochloride (162 mg, 1.06 mmol), K₂CO₃ (220 mg, 1.59 mmol), and KF (92.0 mg, 1.59 mmol) were added and the mixture was stirred at 110°C for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give 7-(5-chloro-2-(((3-)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H-pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (33, 98.0 mg, 39%) was further separated by chiral SFC to obtain: Isomer 1: (33a, 99% de); retention time: 1.529 min. LCMS (ESI): m / z 473.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.60 (s, 1H), 8.46 (s, 1H), 7.89 (s, 1H), 7.61 - 7.43 (m, 1H), 5.48 - 5.37 (m, 2H), 4.94 (d, J = 5.4 Hz, 1H), 4.01 - 3.77 (m, 4H), 3.58 - 3.46 (m, 1H), 3.40 - 3.35 (m, 1H), 3.29 - 3.24 (m, 1H), 3.09 - 2.89(m, 2H), 2.44 - 2.30 (m, 1H), 2.09 - 1.89 (m, 2H), 1.61 - 1.47 (m, 7H).

[0405] Isomer 2: (33b, 99% de); retention time: 1.987 min. LCMS (ESI): m / z 473.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.60 (s, 1H), 8.46 (s, 1H), 7.91 (s, 1H), 7.62 - 7.46 (m, 1H), 5.47 - 5.39 (m, 2H), 4.94 (d, J = 5.4 Hz, 1H), 3.99 - 3.77 (m, 4H), 3.56 - 3.45 (m, 1H), 3.39 - 3.36 (m, 1H), 3.28 - 3.23 (m, 1H), 3.09 - 2.91(m, 2H), 2.44 - 2.30 (m, 1H), 2.10 - 1.90 (m, 2H), 1.60 - 1.47 (m, 7H).

[0406] Analytical methods: Column: ChiralPak IH, 100 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 30% over 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C.

[0407] SFC separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak IH, 250 × 20 mm I.D., 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 2 mol / L NH3 in MeOH); Gradient: B 25%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 10 min.

[0408] Example 27. R )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0409] To 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (19.6, 370 mg, 0.91 mmol) was added to a solution of DMSO (6 mL) with (3... S 4 R )-4-aminotetrahydro-2 H3-pyran-3-ol hydrochloride (128 mg, 1.09 mmol), K₂CO₃ (126 mg, 0.91 mmol), KF (159 mg, 2.73 mmol), and 18-crown-6 (48.0 mg, 0.18 mmol) were mixed and stirred at 110°C for 1 hour. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give 7-(5-chloro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (34, 180 mg, 41%) was further separated by chiral SFC to obtain: Isomer 1: (34a, 100% de); retention time: 2.895 min. LCMS (ESI): m / z 487.3 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.72 - 8.51 (m, 1H), 8.47 (s, 1H), 7.98 - 7.74 (m,1H), 7.54 (d, J = 7.6 Hz, 1H), 5.62 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.59 -4.42 (m, 1H), 3.91 - 3.80 (m, 3H), 3.57 - 3.46 (m, 1H), 3.31 - 3.25 (m, 1H), 3.11 - 2.96 (m, 3H), 2.26 - 2.20 (m, 2H), 2.04 - 1.90 (m, 1H), 1.63 - 1.44 (m, 10H).

[0410] Isomer 2: (34b, 100% de); retention time: 3.825 min. LCMS (ESI): m / z 487.3 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6) δ 8.72 - 8.50 (m, 1H), 8.47 (s, 1H), 7.99 - 7.74 (m,1H), 7.54 (d, J = 7.1 Hz, 1H), 5.62 (s, 1H), 4.94 (d, J = 5.4 Hz, 1H), 4.55 -4.46 (m, 1H), 3.93 - 3.75 (m, 3H), 3.56 - 3.44 (m, 1H), 3.30 - 3.26 (m, 1H), 3.09 - 2.93 (m, 3H), 2.27 - 2.15 (m, 2H), 2.03 - 1.87 (m, 1H), 1.59 - 1.45 (m, 10H).

[0411] Analytical methods: Column: ChiralCel OX, 100 × 4.6 mm ID, 5 µm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 40% over 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35°C. SFC separation method: SHIMADZU PREP SOLUTION SFC; Column: ChiralCel OX, 250 × 20 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 2 mol / L NH3 in MeOH); Gradient: B 40%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 10 min.

[0412] Example 28. R )-5-fluoro-7-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-5-fluoro-7-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0413] Under a nitrogen atmosphere, 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (20.1, 190 mg, 0.487 mmol) was added to a solution of DMSO (6 mL) with (3... S 4 R )-4-aminotetrahydro-2 H 3-pyran-3-ol hydrochloride (90.0 mg, 0.585 mmol), potassium carbonate (67.4 mg, 0.487 mmol), 18-crown-6 (25.8 mg, 0.097 mmol), and potassium fluoride (85.0 mg, 1.46 mmol) were mixed and stirred at 110°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give 5-fluoro-7-(5-fluoro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-isopropyl-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol (35, 90.0 mg, 39%) was further separated by chiral SFC to obtain: Isomer 1: (35a, 100% de); retention time: 1.991 min. LC-MS (ESI): m / z 471.3 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.93 (s, 1H), 8.51 (d, J = 4.1 Hz, 1H), 8.04 (d, J =11.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 5.64 (s, 1H), 4.96 (d, J= 5.1 Hz, 1H),4.63 - 4.41 (m, 1H), 4.00 - 3.76 (m, 3H), 3.59 - 3.50 (m, 1H), 3.43 - 3.39(m, 1H), 3.12 - 2.96 (m, 3H), 2.29 - 2.18 (m, 2H), 2.08 - 1.99 (m, 1H), 1.65 - 1.45 (m, 10H).

[0414] Isomer 2: (35b, 98.5% de); retention time: 2.435 min. LC-MS (ESI): m / z 471.3 [M+H] + . 1 H NMR (400 MHz, DMSO-) d 6) δ 8.93 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.04 (d, J = 11.7 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 5.64 (s, 1H), 4.96 (d, J = 5.2 Hz, 1H),4.63 - 4.37 (m, 1H), 3.99 - 3.79 (m, 3H), 3.59 - 3.50 (m, 1H), 3.44 - 3.39(m, 1H), 3.10 - 2.97 (m, 3H), 2.28 - 2.17 (m, 2H), 2.07 - 1.98 (m, 1H), 1.63 - 1.45 (m, 10H).

[0415] Analytical methods: Column: ChiralPak IB 100 × 4.6 mm ID, 3 µm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 30% over 8 min; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 40°C. SFC separation method: Instrument: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak IB, 250 × 30 mm ID, 5 µm; Mobile phase: A, CO2, and B, MeOH (0.1% 2 mol / L NH3 in MeOH); Gradient: B 30%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 9 min.

[0416] Example 29. R )-6-fluoro-8-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol and ( S )-6-fluoro-8-(5-fluoro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol

[0417] To 8-chloro-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (28.5 g, 2.10 g, 7.9 mmol) was added to a solution of dioxane (60 mL) along with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentane) (2.61 g, 10.3 mmol), Xphos (0.75 g, 1.58 mmol), Pd2(dba)3 (1.45 g, 1.58 mmol), and potassium acetate (2.33 g, 23.7 mmol). The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. Under a nitrogen atmosphere, 2,4-dichloro-5-fluoropyrimidine (2.36 g, 14.1 mmol), Pd(PPh3)4 (1.36 g, 1.18 mmol), potassium carbonate (2.17 g, 15.7 mmol), and water (12 mL) were added to the mixture, and the resulting mixture was stirred at 90°C for 12 hours. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (90 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1-yl) as a yellow oil. H -cyclopentadiene[ cQuinoline-3-ol (36.1 g, 2.42 g, two-step yield 84.6%). LC-MS (ESI): m / z 362.1 [M+H] + .

[0418] To 8-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluoro-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (36.1 g, 2.40 g, 6.63 mmol) was added to a solution of 18-crown-6 (0.35 g, 1.33 mmol) in dimethyl sulfoxide (20 mL). S 4 R )-4-aminotetrahydro-2 H 3-pyran-3-ol hydrochloride (1.22 g, 7.96 mmol), potassium carbonate (0.92 g, 6.63 mmol), and potassium fluoride (1.16 g, 19.9 mmol) were mixed and stirred at 110°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (60 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-fluoro-8-(5-fluoro-2-(((3)) as a white solid. S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-3,4-dimethyl-2,3-dihydro-1 H -cyclopentadiene[ c Quinoline-3-ol (36, 1.30 g, crude) was further separated by chiral SFC to obtain: Isomer 1: (36a, 100% de); retention time: 1.405 min. LCMS (ESI): m / z 443.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.50 (d, J = 3.7 Hz, 1H), 8.34 (s, 1H), 8.06 (d, J = 12.4Hz, 1H), 7.30 (d, J= 7.8 Hz, 1H), 5.48 (s, 1H), 4.94 (s, 1H), 3.90 - 3.77 (m,3H), 3.54 - 3.48 (m, 1H), 3.40 - 3.32 (m, 2H), 3.14 - 3.05 (m, 2H), 2.82 (s,3H), 2.39 - 2.20 (m, 2H), 2.04 - 1.99 (m, 1H), 1.58 - 1.43 (m, 4H).

[0419] Isomer 2: (36b, 100% de); retention time: 3.793 min. LCMS (ESI): m / z 443.2 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6) δ 8.50 (d, J = 3.8 Hz, 1H), 8.34 (s, 1H), 8.06 (d, J = 12.0Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 5.49 (s, 1H), 4.93 (d, J = 4.7 Hz, 1H), 3.90 -3.78 (m, 3H), 3.54 - 3.48 (m, 1H), 3.44 - 3.33 (m, 2H), 3.16 - 3.03 (m, 2H), 2.82 (s, 3H), 2.38 - 2.21 (m, 2H), 2.04 - 1.98 (m, 1H), 1.57 - 1.43 (m, 4H).

[0420] Analytical methods: Column: ChiralPak IH, 100 × 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: B 30% over 8 min; Flow rate: 2.5 mL / min; Column temperature: 40°C. SFC separation method: SHIMADZU PREP SOLUTION SFC; Column: ChiralPak IH, 250 × 20 mm ID, 5 µm; Mobile phase: A, CO2, and B, MEOH (0.1% 7 mol / L NH3 in MeOH); Gradient: B 40%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle time: 8 min.

[0421] Example 30. R )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-ethyl-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol and ( S )-7-(5-chloro-2-(((3) S 4 R )-3-hydroxytetrahydro-2 H -pyran-4-yl)amino)pyrimidin-4-yl)-9-ethyl-5-fluoro-1-methyl-2,3-dihydro-1 H -cyclopentadiene[ b Quinoline-1-ol

[0422] Under a nitrogen atmosphere at -40°C, 2-amino-5-bromo-3-fluoro- N -Methoxy- N 1-Methylbenzamide (32.1 g, 2.00 g, 7.20 mmol) was added to a solution of ethyl magnesium bromide (3.6 mL, 7.20 mmol, 2 mol / L in THF) in 30 mL of THF, and the mixture was stirred at -40°C for 5 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(2-amino-5-bromo-3-fluorophenyl)prop-1-one (37.1 g, 1.60 g, 90%) as a yellow solid. LCMS (ESI): m / z 246.0 & 248.0 [M+H] + .

[0423] Concentrated HCl (5 mL) was added to a mixture of 1-(2-amino-5-bromo-3-fluorophenyl)prop-1-one (37.1 g, 1.60 g, 6.50 mmol) and cyclopentane-1,3-dione (770 mg, 7.80 mmol) in ethanol (25 mL), and the resulting mixture was stirred at 100°C for 15 hours. The reaction mixture was adjusted to pH 8 at room temperature with saturated aqueous NaHCO3 solution and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-9-ethyl-5-fluoro-2,3-dihydro-1-propane as a brown solid. H -cyclopentadiene[ b Quinoline-1-one (37.2, 1.50 g, 75%). LCMS (ESI): m / z 308.0 & 310.0 [M+H] + .

[0424] Under a nitrogen atmosphere, at 0°C, 7-bromo-9-ethyl-5-fluoro-2,3-dihydro-1-methyl methyl bromide (7.80 mL, 23.4 mmol) was added to a solution of methyl magnesium bromide (7.80 mL, 23.4 mmol) in THF (30 mL). H -cyclopentadienyl[1,2-] b A solution of quinolin-1-one (37.2 g, 1.20 g, 3.90 mmol) in THF (8 mL) and DCM (8 mL) was prepared, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (30 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7-bromo-9-ethyl-5-fluoro-2,3-dihydro-1-oxoquinoline as a yellow solid. H -cyclopentadiene[ b Quinoline-1-one (37.3g, 1.20g, 66%). LCMS (ESI): m / z 324.0 & 326.0 [M+H] + .

[0425] To 7-bromo-9-ethyl-5-fluoro-2,3-dihydro-1 H -cyclopentadiene[ bA mixture of quinoline-1-one (37.3, 350 mg, 1.08 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentane) (548 mg, 2.16 mmol), and potassium acetate (317 mg, 3.24 mmol) in dioxane (10 mL) was supplemented with Pd(dppf)Cl2 (79 mg, 0.108 mmol). The resulting mixture was stirred at 100°C for 5 hours under a nitrogen atmosphere and then cooled to room temperature. Under a nitrogen atmosphere, 2,4,5-trichloropyrimidine (369 mg, 2.16 mmol), Pd(PPh3)4 (124 mg, 0.108 mmol), water (2.5 mL), and K2CO3 (450 mg, 3.24 mmol) were added to the mixture, and the resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was di...

Claims

1. A compound having formula (I): (I)， Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts, wherein: L 1 is optionally substituted phenylene, optionally substituted 5- or 6-membered heteroarylene, optionally substituted 4- to 8-membered heterocyclylene, or optionally substituted C 3-8 carbocyclylene; R 1 is hydrogen, OH, NH2, NHCH3, or N(CH3)2; X is N or CR 10 ; R 3 It is hydrogen, deuterium, halogen, CN, OR 11 NR 12 R 13 C(O)NR 12 R 13 COOR A COR B C, which is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl group, optionally substituted C 1-4 Heteroalkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted 4- to 10-membered heterocyclic group, or optionally substituted 5- to 10-membered heteroaryl group; R 4 It is hydrogen, deuterium, halogen, or optionally substituted C. 1-6 Alkyl, or NR 12 R 13 ; R 10 It is hydrogen, halogen, CN, -OH, or optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl groups, optionally substituted C 3-8 Carbocyclic group, or optionally substituted 4- to 10-membered heterocyclic group; R 11 It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted 4- to 10-membered heterocyclic group; R 12 and R 13 Each of them, each time it appears, is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted 4- to 10-membered heterocyclic group; or R 12 and R 13 Together with the nitrogen to which they are attached, they form optionally substituted 4- to 10-membered heterocyclic groups or optionally substituted 5- or 6-membered heteroaryl groups; R A It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 5- or 6-membered heteroaryl group, optionally substituted 4- to 10-membered heterocyclic group; R B It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 4- to 10-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl group; J 1 and J 2 Independently N or CR 30 , where R 30 Each time it appears, it is independently hydrogen, halogen, or C optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; R 20A It is a carbon that is hydrogen, deuterium, halogen, CN, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, C substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl, or optionally substituted 3 to 6-membered ring structures; M 1 It is C or N; M 2 It is C or N; Ring B is in M 1 and M 2 The formed bonds are fused to the optionally substituted 5- to 7-membered rings of ring A; Ring C is a 5- to 7-membered ring fused to ring B, which is optionally substituted; and The prerequisite is that the compound is not a compound listed in Table X, or a stereoisomer, mixture of stereoisomers, isotope, or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein... yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ,in It is M 1 The location, and It is M 2 Location; R 21A It is a carbon that is hydrogen, deuterium, halogen, CN, OH, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, C substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl, or optionally substituted 3 to 6-membered ring structures; X 1 It is O, NR 31 , or CR 32 R 33 ; X 2 It is O, NR 31 , or CR 32 R 33 ; Ring D is a 5- to 7-membered ring that is optionally substituted, except for X. 3 All the ring atoms except X are carbon atoms, and X 3 is -O-, -S(O)-, -S(O)2-, -S(O)2-NR 31 -、-NR 31 -S(O)2-, -S(O)(NH)-, -P(O)(R 34 )-、-P(O)(R 34 )-NR 31 - or -NR 31 -P(O)(R 34 )-; M 3 It is C or N; The ring E is a phenyl group that is optionally substituted, or a 5- or 6-membered heteroaryl group that is optionally substituted. R 31 Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, O(C) 1-4 Alkyl), C(O)H, C(O)(C 1-4 Alkyl), C(O)O(C 1-4 Alkyl), C(O)NH2, C(O)NH(C 1-4 Alkyl), C(O)N(C 1-4 Alkyl)2、C(O)(C 3-6 C(O) (phenyl), C(O) (4- to 6-membered heterocyclic group), C(O) (5- or 6-membered heteroaryl group), SO2 (C 1-4 Alkyl), SO2NH2, SO2NH(C 1-4 Alkyl), SO2N(C) 1-4 Alkyl)2, SO2(C 3-6 (Carbocyclic group), SO2 (phenyl), SO2 (4- to 6-membered heterocyclic group), SO2 (5- or 6-membered heteroaryl group), C 3-6 Carbocyclic, phenyl, 4- to 6-membered heterocyclic, or 5- or 6-membered heteroaryl; wherein R 31 The alkyl moiety is optionally and independently substituted with one or more (e.g., 1, 2, or 3) substituents each time it appears, each of which is independently deuterium, halogenated, OH, O(C) 1-4 Alkyl), SO2 (C) 1-4 Alkyl), NH2, NH(C) 1-4 alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), NH(C) 3-6 cycloalkyl), N(C) 1-4 Alkyl)(C 3-6 cycloalkyl), or N(C) 3-6 cycloalkyl)(C 3-6 cycloalkyl); and wherein the R 31 The carbocyclic, phenyl, heterocyclic, and heteroaryl moieties in the C group are each optionally and independently substituted with one or more (e.g., 1, 2, or 3) substituents, each of which is independently oxo, halogenated, OH, NH2, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F groups. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; R 32 and R 33 Each of the elements is independent each time it appears: (1) Hydrogen or deuterium; (2) Halogen or cyano; (3) OH, NH2, NH(C) 1-4 Alkyl), or N(C) 1-4 Alkyl)(C 1-4 alkyl); (4) C that is optionally substituted by one or more (e.g., 1, 2 or 3) substituents 1-4 Alkyl groups, each of which is independently deuterium, F, OH, NH2, NH(C) 1-4 alkyl), N(C) 1-4 Alkyl)(C 1-4 Alkyl), NH(C) 3-6 cycloalkyl), N(C) 1-4 Alkyl)(C 3-6 cycloalkyl), N(C) 3-6 cycloalkyl)(C 3-6 cycloalkyl), or SO2 (C 1-4 alkyl); (5) C that is optionally replaced by one or more (e.g., 1, 2 or 3) deuterium or F 1-4 alkoxy group, or C group optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; (6) C that can be arbitrarily replaced 3-6 Carbocyclic group, optionally substituted phenyl group, optionally substituted 4- to 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl group; (7)R 32 and R 33 Together with the carbon atoms to which they are attached, they form carbonyl groups (CO); (8)R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 A carbocyclic or 4- to 6-membered heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (e.g., 1, 2, or 3) substituents, each of which is independently oxo, halogenated, OH, NH2, or optionally substituted by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl; or (9) Two Rs 32 Linked together with one or more spacer atoms to form optionally substituted 3- to 7-membered rings; or R 31 and adjacent R 32 It is linked together with one or more spacer atoms to form optionally substituted 3- to 7-membered rings; R 34 Each time it appears, it is independently hydrogen, optionally replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, optionally substituted C 3-6 A carbocyclic group, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl group; or R 34 and R 32 It is linked with one or more spacer atoms to form optionally substituted 3- to 7-membered rings; and L 2 C is arbitrarily replaced 1-3 Alkylene.

3. The compound of claim 2, wherein the compound is a compound having the formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (I-AA), (I-AB), (I-AC), (I-AD), (I-AE), or (I-AF): Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts.

4. The compound according to any one of claims 1 to 3, wherein -L 1 -R 1 It has the structure of formula (A): Equation (A), in: Q is (1)O； (2)NR 14 , where R 14 It is hydrogen, G A SO2G A SO2NG B G C S(O)(NH)G A COG A COOG A 、or C(O)NG B G C ; (3) CR 15 R 16 , where R 15 and R 16 They are linked together with the carbon atoms to form optionally substituted 4- to 6-membered heterocycles, which have one or two independent cyclic heteroatoms selected from O and N; or (4) Does not exist; r1 is 1, 2, or 3; and r2 is 0, 1, or 2; When valence is allowed, n is 0, 1, 2, 3, or 4; and (i)R 100 Each time it appears, it is independently selected from halogens (e.g., F or Cl), CN, OH, COOH, G. A OG A NG B G C NG B G C SO2G A NG B G C SO2NG B G C NG B G C S(O)(NH)G A NG B G C COG A NG B G C COOG A NG B G C C(O)NG B G C SO2G A SO2NG B G C S(O)(NH)G A COG A COOG A 、or C(O)NG B G C ; or (ii)R 100 Two instances of R are linked together with one or more spacer atoms to form optionally substituted rings, such as optionally substituted 3- to 6-membered rings, and any remaining R 100 As defined in (i) each time it occurs; in: G A C is independently and arbitrarily replaced each time it appears. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), or optionally substituted 4- to 10-membered heterocyclic group; and G B and G C Each of them, each time it appears, is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or G B and G C They can be linked to form optionally substituted 4- to 10-membered heterocyclic groups or 5- or 6-membered heteroaryl groups.

5. The compound of claim 4, wherein Q is O.

6. The compound of claim 4, wherein Q is NR. 14 .

7. The compound of claim 4, wherein Q is absent.

8. The compound according to any one of claims 4 to 7, wherein n is 0.

9. The compound of claim 8, wherein -L 1 -R 1 yes or .

10. The compound of claim 8, wherein -L 1 -R 1 yes or .

11. The compound of claim 8, wherein -L 1 -R 1 yes , ,or And R 17 C is arbitrarily replaced 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 8-membered heterocycles, or optionally substituted 5- or 6-membered heteroaryl.

12. The compound of claim 8, wherein -L 1 -R 1 yes .

13. The compound according to any one of claims 4 to 7, wherein n is 1 or 2, and R 100 Each time it appears, it is independently selected from F, Cl, CN, OH, and optionally substituted by one or more (e.g., 1, 2, or 3) deuterium, F, or OH. 1-4 Alkyl group, optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F, C 1-4 Alkyl groups, and C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Heteroalkyl groups.

14. The compound of claim 11, wherein n is 1, and R 100 It is F, Cl, CN, OH, methyl, -CH2OH, fluorine-substituted methyl such as CF3, methoxy, or fluorine-substituted methoxy.

15. The compound of claim 14, wherein -L 1 -R 1 yes or .

16. The compound of claim 14, wherein -L 1 -R 1 yes or .

17. The compound according to any one of claims 4 to 7, wherein n is 2, and the two geminal Rs are... 100 They connect together with the carbon atoms to which they are attached to form optional 3 to 6-membered rings.

18. The compound of claim 17, wherein -L 1 -R 1 yes or .

19. The compound of claim 17, wherein -L 1 -R 1 yes or .

20. The compound according to any one of claims 4 to 7, wherein n is 2, and the two non-genomic R... 100 It is linked with one or more spacer atoms to form optionally substituted 4- to 6-membered rings.

21. The compound according to any one of claims 4 to 7, wherein -L 1 -R 1 Having a structure of formula (A-1) or (A-2): Equation (A-1), or Equation (A-2), Where Z is C 1-3 Alkylene, wherein the non-terminal CH2 is optionally replaced by O or NH, and wherein Z is optionally replaced by one or more (e.g., 1 or 2) substituents, each of which is independently a halogen, OH, or C optionally replaced by one or more (e.g., 1, 2 or 3) deuterium or F. 1-4 alkyl.

22. The compound of claim 21, wherein Q is O, NH, or NHR. 17 ,NHC(O)R 17 or NHS(O)2R 17 .

23. The compound of claim 21 or 22, wherein Z is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, or -CH2NHCH2-.

24. The compound according to any one of claims 21 to 23, wherein Z is unsubstituted.

25. The compound of claim 21, wherein -L 1 -R 1 yes , , , , , ,or .

26. The compound of claim 21, wherein -L 1 -R 1 yes , , , , , ,or .

27. The compound according to any one of claims 1 to 26, wherein X is N.

28. The compound according to any one of claims 1 to 27, wherein J 1 It is CR 30 And J 2 It is CR 30 .

29. The compound of claim 28, wherein J 1 It is CH and J 2 It is CH.

30. The compound according to any one of claims 1 to 3, wherein the compound is a compound having the formula (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q), (II-R), (II-S), (II-T), (II-U), (II-V), (II-W), (II-X), (II-Y), (II-Z), (II-AA), (II-AB), (II-AC), (II-AD), (II-AE), (II-AF), or (III-A): Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts.

31. The compound according to any one of claims 1 to 30, wherein R 20A Is it hydrogen, halogen, or C? 1-4 alkyl.

32. The compound of claim 31, wherein R 20A It is F.

33. The compound according to any one of claims 2 to 32, wherein R 21A It is hydrogen, deuterium, halogen, C 1-4 Alkyl groups, or C groups having one or two heteroatoms that are independently oxygen or nitrogen. 1-4 Heteroalkyl groups.

34. The compound of claim 33, wherein R 21A It is hydrogen, deuterium, F, or methyl.

35. The compound according to any one of claims 2 to 34, wherein X 1 It is O.

36. The compound according to any one of claims 2 to 34, wherein X 1 It is NR 31 .

37. The compound according to any one of claims 2 to 34, wherein X 1 It is CR 32 R 33 .

38. The compound of claim 37, wherein X 1 It is C=O.

39. The compound according to any one of claims 2 to 37, wherein X 2 It is O.

40. The compound according to any one of claims 2 to 37, wherein X 2 It is NR 31 .

41. The compound according to any one of claims 2 to 37, wherein X 2 It is CR 32 R 33 .

42. The compound of claim 41, wherein X 2 It is C=O.

43. The compound according to any one of claims 2 to 42, wherein R 31 Each time it appears, it is independently either hydrogen or C. 1-4 alkyl.

44. The compound of claim 43, wherein R 31 Each time it appears, it is independently either hydrogen or methyl.

45. The compound of claim 44, wherein the nitrogen atom is not X. 1 or X 2 R 31 It is hydrogen.

46. ​​The compound according to any one of claims 1 to 45, wherein the ring C is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or , where # is a bond fused with ring B.

47. The compound according to any one of claims 1 to 46, wherein yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ,in It is M 1 The location, and It is M 2 The location.

48. The compound of claim 30, wherein the compound has the formula (II-A-1), (II-A-2), (II-A-3), (II-A-4), (II-A-5), (II-A-6), (II-A-7), (II-A-8), (II-A-9), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-B-5), (II-B-6), (II-B-7), (II-B-8), (II-B-9), (II-C-1), (II-C-2), (II-C-3). (II-C-4), (II-C-5), (II-C-6), (II-C-7), (II-C-8), (II-C-9), (II-D-1), (II-D-2), (II-D-3), (II-E-1), (II-F-1), (II-G-1) , (II-H-1), (II-I-1), (II-J-1), (II-K-1), (II-L-1), (II-M-1), (II-M-2), (II-M-3), (II-N-1), (II-N-2), (II-N-3), (II-O-1 ), (II-O-2), (II-O-3), (II-O-4), (II-P-1), (II-P-2), (II-P-3), (II-P-4), (II-Q-1), (II-R-1), (II-R-2), (II-R-3), (II-R- 4), (II-R-5), (II-R-6), (II-R-7), (II-R-8), (II-R-9), (II-R-10), (II-S-1), (II-U-1), (II-U-2), (II-U-3), (II-U-4), (II- U-5), (II-U-6), (II-U-7), (II-V-1), (II-V-2), (II-V-3), (II-W-1), (II-W-2), (II-W-3), (II-X-1), (II-X-2), (II-X-3), (II -X-4), (II-Y-1), (II-Y-2), (II-Y-3), (II-Z-1), (II-AA-1), (II-AB-1), (II-AC-1), (II-AD-1), (II-AE-1), or (III-A-1): Or its stereoisomers, mixtures of stereoisomers, isotopes, or pharmaceutically acceptable salts, wherein: X 4 These are -S(O)-, -S(O)2-, -S(O)(NH)-, or -P(O)(R 34 )-.

49. The compound of claim 48, wherein X 4 It is -S(O)2-.

50. The compound according to any one of claims 2 to 49, wherein R 32 Each time it appears, it is independently hydrogen, halogen, OH, or C optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl groups, or C groups optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 alkoxy, and R 33 Each time it appears, it is independently hydrogen, halogen, or optionally C replaced by one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 Alkyl; or R 32 and R 33 Together with the carbon atoms to which they are attached, they form carbonyl groups (CO); or R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 Carbon cyclic group or 4 to 6-membered heterocyclic group.

51. The compound of claim 50, wherein R 32 Each time it appears, it is independently either hydrogen or methyl, and R 33 Each time it appears, it is independently either hydrogen or methyl; or R 32 and R 33 Together with the carbon atoms to which they are attached, they form cyclopropyl groups.

52. The compound of claim 50, wherein for those not X 1 or X 2 CR 32 R 33 R 32 and R 33 All are C 1-4 Alkyl, or R 32 and R 33 Together with the carbon atoms to which they are attached, they form C 3-6 Carbon cyclic group or 4 to 6-membered heterocyclic group.

53. The compound of claim 52, wherein for those not X 1 or X 2 CR 32 R 33 R 32 and R 33 All are methyl groups.

54. The compound of claim 52, wherein for those not X 1 or X 2 CR 32 R 33 R 32 and R 33 Together with the carbon atoms to which they are attached, they form cyclopropyl groups.

55. The compound according to any one of claims 1 to 54, wherein R 3 It is a carbon that is hydrogen, F, Cl, Br, CN, or optionally substituted with one or more (e.g., 1, 2, or 3) deuterium or F. 1-4 alkyl.

56. The compound of claim 55, wherein R 3 It is Cl.

57. The compound according to any one of claims 1 to 56, wherein R 4 It is either hydrogen or deuterium.

58. A compound listed in Table 1 or Table 1A, or a pharmaceutically acceptable salt thereof.

59. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 58 and one or more pharmaceutically acceptable excipients.

60. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 58, or the pharmaceutical composition of claim 59.

61. Use of the compound of any one of claims 1 to 58 or the pharmaceutical composition of claim 59 in the manufacture of a medicament for treating cancer.

62. Use of the compound of any one of claims 1 to 58 or the pharmaceutical composition of claim 59 for the treatment of cancer.

63. The compound of any one of claims 1 to 58 or the pharmaceutical composition of claim 59, for use in the treatment of cancer.

64. The compound of any one of claims 1 to 58 or the pharmaceutical composition of claim 59, for use in a method of treating cancer, wherein the method comprises administering an effective amount of the compound provided herein to a subject in need.

65. The method of claim 60, the use of claim 61 or 62, or the compound or composition for use of claim 63 or 64, wherein the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, or thyroid cancer.

66. The method of claim 60, the use of claim 61 or 62, or the compound or composition for use of claim 63 or 64, wherein the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer.

67. The method of claim 60, the use of claim 61 or 62, or the compound or composition for use of claim 63 or 64, wherein the cancer is breast cancer.

68. The method, use, or compound or composition of claim 67, wherein the breast cancer is ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); or inflammatory breast cancer.

69. The method, use, or compound or composition of claim 67, wherein the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition.

70. The method, use, or compound or composition used in claim 67, wherein the breast cancer is advanced or metastatic breast cancer.

71. The method of claim 60, the use of claim 61 or 62, or the compound or composition for use of claim 63 or 64, wherein the cancer is ovarian cancer.

Images