Aminoheteroaryl kinase inhibitors

Abstract

Provided herein are novel compounds (e.g., Formula I), pharmaceutical compositions, and methods of use related to cyclin-dependent kinase (CDK) 4 inhibitors. The compounds herein are generally CDK4 inhibitors that can be used to treat a variety of diseases or disorders, such as cancer. [Formula 1] TIFF2025527170000215.tif23170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Patent Application Nos. PCT / CN2022 / 109075, filed July 29, 2022, PCT / CN2022 / 128578, filed October 31, 2022, and PCT / CN2023 / 078781, filed February 28, 2023, each of which is incorporated herein by reference in its entirety.

[0002] In various embodiments, the present disclosure generally relates to novel heteroaryl compounds, compositions comprising same, methods of preparing same, and methods of using same, for example, inhibiting cyclin-dependent kinases and / or treating or preventing various diseases or disorders described herein. [Background technology]

[0003] Uncontrolled cell proliferation 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, 2014;14:10). In addition to regulating cell cycle progression, these CDKs and cyclins also play important roles in regulating transcription, DNA repair, differentiation, and apoptosis (Palmer and Kaldis, Semin Cell Dev Biol, 2020;107:54-62).

[0004] CDK4 and CDK6 are key regulators of the G1-S transition. D-type cyclins form complexes with CDK4 / 6 and phosphorylate the retinoblastoma (Rb) protein. This relieves Rb-mediated inhibition of the transcription factor E2F, leading 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 cyclins, mutations, gene deletion, or transcriptional silencing of the endogenous CDK4 / 6 inhibitor p16 (CDKN2A) have all been reported as mechanisms leading to pathway activation (Dickson, Mol Cancer Res. 2014;20:3379-3383). In breast cancer, dysregulation of the CDK4 / 6 pathway is associated with resistance to endocrine therapy (Ding et al., Int J Mol Sci. 2020;21:1960).

[0005] In recent years, targeted inhibition of CDKs has demonstrated considerable therapeutic potential in a variety of tumor types. The use of CDK4 / 6 inhibitors in conjunction with endocrine therapy has been shown to be effective in treating human epidermal growth factor 2 (HER2)-negative, estrogen receptor (ER)-positive breast cancer. As a result, different CDK4 / 6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for use in combination with endocrine therapy in both first- and second-line settings (Cogliati, et al., Life, 2022;12:378). Most recently, abemaciclib has also been approved for the adjuvant treatment of early-stage breast cancer.

[0006] Despite the success of CDK4 / 6 inhibitors in the clinic, treatment-related adverse events, particularly hematological toxicities such as neutropenia, have prevented their continued administration. Currently, both palbociclib and ribociclib are administered on a 3-week on / 1-week off schedule. Mouse genetic and other emerging data suggest that the observed hematological toxicities may be associated with CDK6-cyclin D3 inhibition (Sicinska et al., Mol Cell Biol, 2006;26:8052-8060; Cooper et al., Nat Immunol, 2006;5:489-497). On the other hand, CDK6-cyclin D3 is expressed at very low levels in HR+ / HER2- breast cancer, and CDK4 has been identified as an oncogenic driver in this tumor type (Zhang et al., Cancer Res, 2022;epub). Summary of the Invention [Means for solving the problem]

[0007] Inhibitors specific to particular CDKs, such as CDK4, may have the advantage of an improved safety profile, may allow for improved administration schedules and higher doses, may result in deeper target inhibition, better efficacy, and may potentially overcome drug resistance. There remains a need in the clinic for CDK inhibitors, such as selective CDK4 inhibitors, including those with improved efficacy and reduced side effects.

[0008] In various embodiments, the present disclosure provides novel compounds capable of inhibiting CDKs, such as selectively inhibiting CDK4. The compounds and compositions herein are useful for treating various diseases or disorders associated with aberrant CDK4 activity, such as hormone receptor-positive, HER2-negative breast cancer.

[0009] Some embodiments of the present disclosure include a compound of Formula I, or a pharmaceutically acceptable salt thereof: [ka] wherein the variables are defined herein. In some embodiments, the compound of Formula I can have a structure according to any subformula provided herein, such as IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4, as defined herein. In some embodiments, the disclosure also provides a specific compound selected from any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions can typically be formulated for oral administration.

[0011] In some embodiments, the present disclosure also provides methods of inhibiting CDK activity, such as CDK4 activity, in a subject or biological sample. In some embodiments, the methods include contacting the subject or biological sample with an effective amount of one or more compounds of the present disclosure, e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0012] In some embodiments, the present disclosure provides methods for treating or preventing a CDK-mediated disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of one or more compounds of the present disclosure or a pharmaceutical composition herein. In some embodiments, the method comprises administering to the subject an effective amount of a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0013] In some embodiments, the present disclosure also provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described 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, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric (i.e., stomach) cancer, thyroid cancer, and combinations thereof. In some embodiments, the cancer is breast cancer 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 cancer is breast cancer. In some embodiments, the cancer is breast cancer selected from endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits inherited 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.

[0014] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, administration is oral. In some embodiments, administration is parenteral injection, such as intravenous injection.

[0015] The compounds of the present disclosure can be used as monotherapy or in combination therapy.In some embodiments of the methods described herein, one or more compounds of the present disclosure can be administered as the only active ingredient.In some embodiments, the methods herein further comprise administering to the subject an additional therapeutic agent, such as an additional anticancer agent described herein.

[0016] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION OF THE INVENTION

[0017] In various embodiments, the present disclosure provides compounds and compositions useful for inhibiting CDKs, such as CDK4, and / or treating or preventing various diseases or disorders described herein, e.g., cancer.

[0018] compound The compounds of the present disclosure are generally aminopyridine or aminopyrimidine derivatives having Formula I, as described herein. The compounds herein are generally capable of inhibiting a CDK, such as CDK4. In some embodiments, the compounds herein are capable of selectively inhibiting CDK4 over other CDKs.

[0019] Formula I In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L 1 is an optionally substituted phenylene, an optionally substituted 5- or 6-membered heteroarylene, an optionally substituted 4- to 8-membered heterocyclylene, or an optionally substituted C 3~8 is a carbocyclylene; R 1 is hydrogen, OH, NH2, NHCH3, or N(CH3)2; X is N or CR 10 and; R 2 is an optionally substituted ring system selected from a 10-membered heteroaryl, a 9-12 membered bicyclic heterocyclic ring, or a 12-16 membered heteroaryl or heterocyclic ring system having three or more rings, the ring system containing at least one phenyl or heteroaryl ring; R 2 is attached to the remainder of Formula I through a ring atom in the phenyl or heteroaryl portion of the ring system; R 3 is hydrogen, deuterium, halogen (e.g., F, Cl), CN, OR 11 , N.R. 12 R 13 , C(O)NR 12 R 13 , COOR A , C.O.R. B , optionally replaced by C 1~6 Alkyl, optionally substituted C 2~4 Alkenyl, optionally substituted C 2~4 Alkynyl, optionally substituted C 1~4 Heteroalkyl, optionally substituted C 3~8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; R 4 is hydrogen, deuterium, halogen (e.g., F), optionally substituted C 1~6 Alkyl or NR 12 R 13 and; During the ceremony, R 10 is hydrogen, halogen (e.g., F), CN, —OH, optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 Heteroalkyl, optionally substituted C 3~8 carbocyclyl or optionally substituted 4-10 membered heterocyclyl; R 11 is hydrogen, optionally substituted C 1~6Alkyl, optionally substituted C 3~8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or an oxygen protecting group; R in each occurrence 12 and R 13 each independently selected from hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or a nitrogen protecting group; or R 12 and R 13 can be linked to form an optionally substituted 4- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl; R A is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or an oxygen protecting group; R B is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 carbocyclyl, optionally substituted phenyl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl).

[0020] In one embodiment, R 2 wherein said phenyl or heteroaryl moiety (attached to the remainder of Formula I) is not fused to a 5-membered heteroaryl.

[0021] In some embodiments, compounds of Formula I (including any of the applicable subformulas as described herein) may contain one or more asymmetric centers and / or axial asymmetry and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. In some embodiments, compounds of Formula I, where applicable, may exist in the form of individual enantiomers and / or diastereomers, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, where applicable, compounds of Formula I (including any of the applicable subformulas as described herein) may have an enantiomeric excess ("ee") of greater than 60%, such as having greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, greater than 99% ee, or have undetectable amounts of the other enantiomer. In some embodiments, where applicable, compounds of Formula I (including any of the applicable subformulas as described herein) may also exist as mixtures of stereoisomers in any proportion, such as racemic mixtures.

[0022] In some embodiments, compounds of Formula I (including any of the applicable subformulas as described herein) may exist as isotopically labeled compounds, particularly deuterated analogs, in which one or more of the hydrogen atoms of a compound of Formula I are replaced with deuterium atoms at an abundance greater than its natural abundance, e.g., if the compound has a CH3 group, it is a CD3 analog. Without wishing to be bound by theory, deuterium substitution at certain positions (e.g., those explicitly specified herein) can result in compounds with superior pharmacokinetic profiles when compared to their hydrogen counterparts (i.e., at natural abundance), and therefore, superior pharmacokinetic outcomes in vivo. Compounds with specific deuterium substitutions can be prepared by methods using commercially available deuterium-enriched reagents such as deuterium gas, heavy water (DO), deuterated formic acid (DCOOD), deuterated methyl iodide (CD3I), deuterated methanol (CD3OD), sodium deuterated hydroxide (NaOD), sodium borodeuteride (NaBD4), and lithium aluminum deuteride (LiAlD4).

[0023] It should be apparent to those skilled in the art that in certain cases, compounds of Formula I may exist as a mixture of tautomers. The present disclosure is not limited to any particular tautomer. Moreover, the present disclosure encompasses all such tautomers, whether explicitly depicted or referenced.

[0024] Typically, X in formula I is N and the compound of formula I has formula IA: [ka] (In the formula, L 1 , R 1 , R 2 , R 3 , and R 4 may be characterized as having any of the following:

[0025] In some embodiments, X in formula I is CR10 (In the formula, R 10 is defined herein). For example, in some embodiments, R 10 may be hydrogen, and the compound of formula IB: [ka] (In the formula, L 1 , R 1 , R 2 , R 3 , and R 4 may be characterized as having any of the following:

[0026] Various groups can be represented by L in Formula I. 1 For example, in some embodiments, L in Formula I is suitable as 1 In some embodiments, L in Formula I can be an optionally substituted phenylene. 1 is an optionally substituted 5- or 6-membered heteroarylene, e.g., having 1 to 3 ring heteroatoms independently selected from N, O, and S; pyridylene, e.g., [ka] (optionally substituted), etc. For example, in some embodiments, L in Formula I 1 teeth, [ka] wherein the pyridylene is optionally substituted with a 5-membered heteroaryl, such as pyrazole or imidazole. In some embodiments, L in Formula I 1 teeth, [ka] Typically in such embodiments, R 1 In some embodiments, L in Formula I can be hydrogen. 1can be an optionally substituted 4-8 membered heterocyclylene, e.g., a monocyclic or bicyclic (e.g., fused, bridged, or spiro bicyclic) 4-8 membered heterocyclylene having 1-2 ring heteroatoms independently selected from N, O, and S. In some embodiments, L in Formula I 1 is an optionally substituted C 3~8 The carbocyclylene can be, for example, a monocyclic or bicyclic (eg, fused, bridged, or spiro bicyclic) carbocyclylene.

[0027] In some particular embodiments, the compounds of formula I herein have formula A: [ka] (In the formula, Q is (1)O; (2)NR 14 (In the formula, R 14 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 is); (3)CR 15 R 16 (In the formula, R 15 and R 16 are joined with the carbon atoms to which they are attached to form an optionally substituted 4- to 6-membered heterocyclic ring having 1 or 2 ring heteroatoms independently selected from O and N; or (4) non-existence; r1 is 1, 2, or 3; r2 is 0, 1, or 2; n is 0, 1, 2, 3, or 4, where valency allows; (i) R in each occurrence 100 are independently halogen (e.g., F or Cl), CN, OH, COOH, G A , O.G.A , N.G. B G C , N.G. B G C SO2G A , N.G. B G C SO2NG B G C , N.G. B G C S(O)(NH)G A , N.G. B G C COG A , N.G. B G C COOG A , N.G. 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 selected from; or (ii)R 100 two instances of R may be joined together with the intervening atoms to form an optionally substituted ring, such as an optionally substituted 3- to 6-membered ring, and any remaining R 100 is as defined in (i); During the ceremony, G in each existence A are independently optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), or optionally substituted 4- to 10-membered heterocyclyl; G in each existence B and G C each independently selected from hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or a nitrogen protecting group; or G B and G C can be linked to form an optionally substituted 4- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl; R 1 , R 2 , R 3 , and R 4 may be characterized as having a structure according to (including any of those described herein in any combination).

[0028] In some embodiments, the compound of formula A has formula A-S1 or A-S2: [ka] In some preferred embodiments, the compound of formula A may have an ee of greater than 60%, preferably greater than 80%, greater than 90%, greater than 95%, greater than 98%, greater than 99% or may exist as the stereoisomer of formula A-S1 with an undetectable amount of the enantiomer according to formula A-S2.

[0029] In some embodiments, the compound of formula A has formula A-S3 or A-S4: [ka] The compound may have the stereochemistry as shown in

[0030] In some embodiments according to Formula A, n is 0. In some embodiments according to Formula A, n is 1 or 2, and R at each occurrence is 100 are independently selected from the group consisting of C optionally substituted with F, Cl, CN, OH, F, 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, and C optionally substituted with F1~4 heteroalkyl.

[0031] In some embodiments according to Formula A, n is 1 and R 100 is F, Cl, CN, OH, methyl, fluorine-substituted methyl such as CF3, methoxy, or fluorine-substituted methoxy.

[0032] In some embodiments, in Formula A, 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.

[0033] In some embodiments, Q in formula A is absent (ie, Q is a bond connecting the two carbon atoms adjacent to Q in formula A).

[0034] In some embodiments, Q in formula A is O.

[0035] In some embodiments, in Formula A, r1 is 1, r2 is 1, and Q is O. For example, in some embodiments, in Formula A, [ka] The part is [ka] may be, preferably, [ka] In one embodiment, the moiety has the stereochemistry: [ka] In one embodiment, the moiety is [ka] is.

[0036] In some embodiments, the compound of formula A has formula A-1 or A-2: [ka] (In the formula, R 17 is an optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 The heterocyclic ring may be characterized as having a structure according to the formula: optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 8-membered heterocyclic ring, or optionally substituted 5- or 6-membered heteroaryl. For example, in some embodiments, R 17 teeth, (1) C optionally substituted with 1 to 3 substituents independently selected from deuterium, F, and OH, such as CHF2, CF3, etc. 1~4 alkyl; (2) Phenyl, pyridyl, or pyrimidyl, each of which is optionally substituted with deuterium, halogen, CN, OH, or F. 1~3 C optionally substituted with alkyl or F 1~3 phenyl, pyridyl, or pyrimidyl optionally substituted with 1 to 3 substituents independently selected from alkoxy; or (3) C optionally substituted with deuterium, halogen, CN, OH, or F 1~3 C optionally substituted with alkyl or F 1~3 and 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from alkoxy.

[0037] In some embodiments, R 17 is C 1~4 Alkyl, (C 1~4 alkylene) j -C 3~6 Cycloalkyl, (C 1~4 alkylene) j-(4-8 membered monocyclic heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S), or (C 1~4 alkylene) j -(5- or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S); j is 0 or 1, and C 1~4 Alkylene is a straight or branched alkenylene chain optionally substituted with F; C 1~4 Alkyl, C 3~6 Each of cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 8-membered monocyclic heterocyclyl may be selected from oxo (where valences allow), halo (e.g., F), G 1 , OH, OG 1 , NH2, NH(G 1 ), and N(G 1 )(G 1 Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from G in each existence 1 are independently: (1) F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or (2) F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 is cycloalkyl; If replaced, C 1~4 Alkyl, C 3~6 Cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 8-membered monocyclic heterocyclyl are preferably each independently selected from C optionally substituted with F, Cl, CN, OH, F 1~4 C optionally substituted with alkyl or F 1~4In some embodiments, j is 0. In some embodiments, j is 1 and C is substituted with 1, 2, or 3 substituents that are alkoxy, more preferably 1, 2, or 3 substituents that are each independently F, OH, methyl, fluorine-substituted methyl such as CF, methoxy, or fluorine-substituted methoxy. In some embodiments, j is 0. In some embodiments, j is 1 and C is substituted with ... 1~4 Alkylene is a straight or branched alkylene chain such as CH2.

[0038] In some embodiments, R 17 is C such as methyl, ethyl, isopropyl 1~4 In some embodiments, R 17 is C optionally replaced with F 1~4 It can be alkyl.

[0039] In some embodiments, R 17 is, for example, C optionally substituted with substituents described herein. 3~6 It may be cycloalkyl.

[0040] In some embodiments, R 17 can be, for example, a 4-8 membered monocyclic heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted with substituents described herein.

[0041] In some embodiments, R 17 is C 1~4 It may be an optionally substituted 5-membered heteroaryl such as alkyl, for example, R 17 teeth, [ka] may be selected from:

[0042] In some embodiments, R 17 may be phenyl or a 6-membered heteroaryl having 1 to 3 ring nitrogen atoms, and the phenyl or 6-membered heteroaryl may be selected from halo (e.g., F), G 1 , OH, OG1 , NH2, NH(G 1 ), and N(G 1 )(G 1 Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from G in each existence 1 are independently: (1) F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or (2) F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 is cycloalkyl, When substituted, phenyl or 6-membered heteroaryl preferably each independently represent C optionally substituted with F, Cl, CN, OH, F 1~4 alkyl, C optionally substituted with F 1~4 It is substituted with 1, 2, or 3 substituents that are alkoxy, more preferably 1 or 2 substituents that are each independently F or methyl. For example, in some embodiments, R 17 teeth, [ka] It could be.

[0043] In any of the embodiments herein, unless specified or contrary to context, R 1 can be OH.

[0044] In any of the embodiments herein, X may be N unless specified otherwise or to the contrary in context.

[0045] In any of the embodiments herein, unless specified or contrary to context, L in Formula I 1 -R 1 (or any applicable sub-formula as described herein, e.g., Formula A, IA, or IB) [ka] It could be.

[0046] In any of the embodiments herein, unless specified or contrary to context, L in Formula I 1 -R 1 (or any applicable sub-formula as described herein, e.g., Formula A, IA, or IB) [ka] It could be.

[0047] In some embodiments, L in Formula I 1 -R 1 (or any applicable sub-formula as described herein, e.g., Formula A, IA, or IB) [ka] and In the formula, R 17 teeth, (1) C optionally substituted with 1 to 3 substituents independently selected from deuterium, F, and OH, such as CHF2, CF3, etc. 1~4 alkyl; (2) Phenyl, pyridyl, or pyrimidyl (each of which is optionally substituted with deuterium, halogen, CN, OH, or F) 1~3 C optionally substituted with alkyl or F 1~3 optionally substituted with 1 to 3 substituents independently selected from alkoxy; or (3) C optionally substituted with deuterium, halogen, CN, OH, or F 1~3 C optionally substituted with alkyl or F 1~3 and 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from alkoxy. For example, in some embodiments, R 17 is C optionally substituted with 1 to 3 F1~4 In some embodiments, R 17 can be phenyl, pyridyl, or pyrimidyl (each unsubstituted or substituted with one or two substituents, each independently being F or methyl). In some embodiments, R 17 is a pyrazole, imidazole, or triazole (each of which is unsubstituted or optionally substituted with F); 1~3 In some particular embodiments, R 17 teeth, [ka] It could be.

[0048] In some embodiments, L in Formula I (e.g., Formula A, IA, or IB) 1 -R 1 teeth, [ka] may be selected from:

[0049] Various groups can be represented by R in Formula I 2 For example, in some embodiments, R 2 can be an optionally substituted 10-membered heteroaryl. In some embodiments, R 2 is an optionally substituted 9-12 membered bicyclic heterocyclic ring in which one of the two rings is a phenyl or heteroaryl ring; R 2 is linked to the remainder of Formula I through a ring atom of the phenyl or heteroaryl portion of the bicyclic ring system. 2 may be an optionally substituted 12-16 membered heteroaryl or heterocyclic ring system having three or more rings, in which at least one of the rings is a phenyl or heteroaryl ring, and R 2 is linked to the remainder of formula I through a ring atom in the phenyl or heteroaryl portion of the ring system. 2wherein said phenyl or heteroaryl moiety (attached to the remainder of Formula I) is not fused to a 5-membered heteroaryl.

[0050] In one embodiment, R 2 is an optionally substituted 10-membered heteroaryl, and R 2 is linked to the remainder of Formula I via a phenyl, which is fused to a 6-membered heteroaryl.

[0051] In one embodiment, R 2 is an optionally substituted 9- to 12-membered bicyclic heterocyclic ring, and R 2 is linked to the remainder of Formula I through a phenyl, which is fused to a 5- to 8-membered heterocyclic ring.

[0052] In one embodiment, R 2 is an optionally substituted tricyclic heteroaryl, and R 2 is linked to the remainder of Formula I via a phenyl (first ring), which is fused to a 6-membered heteroaryl (second ring), which is further fused to a 5- or 6-membered heteroaryl (third ring). In one embodiment, the third ring is a 5-membered heteroaryl. In one embodiment, the third ring is a 6-membered heteroaryl.

[0053] In one embodiment, R 2 is an optionally substituted tricyclic heterocyclic ring, and R 2 is linked to the remainder of Formula I via a phenyl (first ring), which is fused to a 6-membered heteroaryl (second ring), which is further fused to a 5- or 6-membered heteroaryl or a 5- or 6-membered carbocyclic ring (third ring). In one embodiment, the third ring is a 5-membered heterocyclic ring. In one embodiment, the third ring is a 6-membered heterocyclic ring. In one embodiment, the third ring is a 5-membered carbocyclic ring. In one embodiment, the third ring is a 6-membered carbocyclic ring.

[0054] In one embodiment, R 2 is an optionally substituted tricyclic heterocyclic ring, and R 2is linked to the remainder of Formula I through a phenyl (first ring), which is fused to a 5- to 7-membered heterocyclic ring (second ring), which is further fused to a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclic ring (third ring). In one embodiment, the second ring is a 6-membered heterocyclic ring and the third ring is a 6-membered heterocyclic ring. In one embodiment, the second ring is a 7-membered heterocyclic ring and the third ring is a 5-membered heteroaryl.

[0055] Usually, R 2 contains at least two heteroatoms that are nitrogen or oxygen. For example, in some embodiments, R 2 The total number of nitrogen and oxygen atoms in R can be 2, 3, 4, 5, or 6. 2 contains at least one hydrogen bond donor (e.g., an OH, NH, or NHR group) and at least one hydrogen bond acceptor (e.g., a C(=O) group, O, N (such as in a pyridine ring), etc.).

[0056] In some embodiments, R 2 is quinolinyl (preferably [ka] ), naphthyridinyl, and the like, which are 10-membered bicyclic heteroaryls having 1 to 4 ring nitrogen atoms, which are substituted with deuterium, halo (e.g., F, Cl), CN, G 1 , OH, COOH, C(O)-G 1 , O.G. 1 , C(O)-OG 1 , NH2, NH(G 1 ), N(G 1 )(G 1 ), C(O)-NH2, C(O)-NH(G 1 ), C(O)-N(G 1 )(G 1 ), G 2 , O.G. 2 , NH(G 2 ), N(G 1 )(G 2 ), C(O)-NH(G 2 ), and C(O)-N(G1 )(G 2 Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from G in each existence 1 are independently F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 is cycloalkyl; G in each existence 2 is independently a 4- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, each of which may be oxo (where applicable), halo (e.g., F), CN, G 1 , OH, OG 1 , NH2, NH(G 1 ), and N(G 1 )(G 1 Optionally substituted with 1 to 3 substituents independently selected from: The two optional substituents of a 10-membered bicyclic heteroaryl group, together with an intervening atom, can optionally be joined to form a fused ring structure.

[0057] In some embodiments, R 2 is a 9-12 membered bicyclic heterocyclic ring in which one of the two rings is a phenyl or heteroaryl ring, and R 2 is linked to the remainder of Formula I through a ring atom in the phenyl or heteroaryl portion of the bicyclic ring system, and the 9-12 membered bicyclic heterocyclic ring is selected from halo (e.g., F), CN, G 1 , OH, COOH, C(O)-G 1 , O.G. 1 , C(O)-OG 1 , NH2, NH(G 1 ), N(G 1 )(G 1 ), C(O)-NH2, C(O)-NH(G1 ), C(O)-N(G 1 )(G 1 ), G 2 , O.G. 2 , NH(G 2 ), N(G 1 )(G 2 ), C(O)-NH(G 2 ), and C(O)-N(G 1 )(G 2 Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from G in each existence 1 are independently F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 is cycloalkyl; G in each existence 2 is independently a 4- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, each of which may be oxo (where applicable), halo (e.g., F), CN, G 1 , OH, OG 1 , NH2, NH(G 1 ), and N(G 1 )(G 1 Optionally substituted with 1 to 3 substituents independently selected from: Two optional substituents of a 9- to 12-membered bicyclic heterocyclic ring, together with intervening atoms, can optionally be linked to form a ring structure.

[0058] In some embodiments, R 2 is a 12-16 membered heteroaryl or heterocyclic ring system having three or more rings, in which at least one of the rings is a phenyl or heteroaryl ring; R 2 teeth, [ka] and the 12-16 membered heteroaryl or heterocyclic ring is connected to the remainder of Formula I through a ring atom in the phenyl or heteroaryl portion of the ring system, such as deuterium, halo (e.g., F, Cl), CN, G 1 , OH, COOH, C(O)-G 1 , O.G. 1 , C(O)-OG 1 , NH2, NH(G 1 ), N(G 1 )(G 1 ), C(O)-NH2, C(O)-NH(G 1 ), C(O)-N(G 1 )(G 1 ), G 2 , O.G. 2 , NH(G 2 ), N(G 1 )(G 2 ), C(O)-NH(G 2 ), and C(O)-N(G 1 )(G 2 Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from G in each existence 1 are independently F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 is cycloalkyl; G in each existence 2 is independently a 4- to 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, each of which may be oxo (where applicable), halo (e.g., F), CN, G 1 , OH, OG 1 , NH2, NH(G 1 ), and N(G 1 )(G 1 Optionally substituted with 1 to 3 substituents independently selected from: Two optional substituents of a 12- to 16-membered heteroaryl or heterocyclic ring, together with intervening atoms, can optionally be linked to form a ring structure.

[0059] In some preferred embodiments, R in Formula I 2 is M-1: [ka] (In the formula, J 1 and J 2 are independently N or CR 30 and R in each existence 30 are independently hydrogen, halogen, C optionally substituted with F 1~4 C optionally substituted with alkyl or F 1~4 is heteroalkyl; R 20 is hydrogen, halogen (e.g., F or Cl), CN, C optionally substituted with F 1~4 alkyl, C optionally substituted with F 1~4 heteroalkyl or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R 21 , R 22 , and R 23 are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently: F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4heteroalkyl, or (6) C optionally substituted with oxo, halo (e.g., F), OH, NH, F. 1~4 C optionally substituted with alkyl or F 1~4 a 3- to 6-membered ring structure optionally substituted with 1-3 substituents that are heteroalkyl (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or R 21 and R 22 are, together with the intervening atoms, linked and independently represent C optionally substituted with oxo, deuterium, halo (e.g., F), OH, NH, F. 1~4 C optionally substituted with alkyl or F 1~4 forming a 5- to 8-membered ring (e.g., a 5- to 7-membered carbocyclic or heterocyclic ring) optionally substituted with 1 to 3 substituents that are heteroalkyl; R 23 is defined above; or R 22 and R 23 are, together with the intervening atoms, linked and independently represent C optionally substituted with oxo, deuterium, halo (e.g., F), OH, NH, F. 1~4 C optionally substituted with alkyl or F 1~4 forming a 5-8 membered ring (e.g., a 5-7 membered carbocyclic, aryl, heteroaryl, or heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R 21 may be a structure according to (as defined above).

[0060] J in M-1 1 is usually CR 30 and R 30 is defined herein, and preferably R 30 is hydrogen. However, in some embodiments, J 1 can be N.

[0061] J in M-1 2 is also usually 30 and R 30is defined herein, and preferably R 30 is hydrogen. However, in some embodiments, J 2 can also be N. Preferably, J 1 and J 2 are not both N.

[0062] In some preferred embodiments, both J in M-1 1 and J 2 is CH.

[0063] In one embodiment, R 2 is M-1-1: [ka] (In the formula, R 21 , R 22 , and R 23 are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently: F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 heteroalkyl, or (6) C optionally substituted with oxo, halo (e.g., F), OH, NH, F. 1~4 C optionally substituted with alkyl or F 1~4 It has a structure with a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocyclic ring, or a 5 membered heteroaryl) optionally substituted with 1-3 substituents that are heteroalkyl.

[0064] In some embodiments, the compound of formula I has formula I-1: [ka] (In the formula, R 3 , R 20 , R 21 , R 22 , and R 23 In some embodiments, the compound of formula I can have a structure according to, for example, formula I-1-D: [ka] (In the formula, R 3 , R 20 , R 21 , R 22 , and R 23 may be a deuterated analog of Formula I-1 having a structure according to (as defined herein).

[0065] In one embodiment, R 2 M-6-1: [ka] (In the formula, R 20 is hydrogen, halogen (e.g., F or Cl), CN, C optionally substituted with F 1~4 alkyl, C optionally substituted with F 1~4 heteroalkyl or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R 22 and R 23 are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently: F, OH, NH, 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 3~6cycloalkyl), or N(C 3~6 Cycloalkyl)(C 3~6 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 heteroalkyl, or (6) C optionally substituted with oxo, halo (e.g., F), OH, NH, F. 1~4 C optionally substituted with alkyl or F 1~4 It has a structure with a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocyclic ring, or a 5 membered heteroaryl) optionally substituted with 1-3 substituents that are heteroalkyl.

[0066] In some embodiments, R 20 is hydrogen. In some embodiments, R 20 is a halogen such as F (e.g., F or Cl) or CN. In some embodiments, R 20 is C optionally replaced with F 1~4 In some embodiments, R 20 is C optionally replaced with F 1~4 Heteroalkyl. Usually C 1~4 Heteroalkyl has 1 or 2 heteroatoms, which are independently N or O. In some embodiments, R 20 can also be an optionally substituted 3- to 6-membered ring structure (eg, cyclopropyl, cyclobutyl, a 4- to 6-membered heterocyclic ring, or a 5-membered heteroaryl).

[0067] R 20 is usually hydrogen, halogen, or C 1~4 For example, in some preferred embodiments, R 20 is hydrogen, F, Cl, methyl, or ethyl, more preferably F.

[0068] Preferably, R 21 , R 22 , and R 23At least one of R contains a hydrogen bond donor such as an OH, NH, or NHR group, and more preferably R 21 , R 22 , and R 23 contains a hydrogen bond donor, or R 21 and R 22 , or R 22 and R 23 The ring structure formed by contains a hydrogen bond donor.

[0069] If it does not contain a hydrogen bond donor, R 21 , R 22 , and R 23 is typically hydrogen, deuterium, halogen, or C, which may be optionally substituted with 1 to 3 suitable substituents as defined herein. 1~4 It can be alkyl.

[0070] In some embodiments, R 21 , R 22 , and R 23 One or more of the following may also be C optionally substituted with F: 1~4 It may also be a heteroalkyl, which contains one or two heteroatoms which are independently oxygen or nitrogen.

[0071] For example, in some embodiments, R 21 is C 1~4 In some embodiments, R 21 is NH(C 1~4 alkyl), N(C 1~3 Alkyl)(C 1~3 alkyl), and each C 1~3 The alkyls are independently selected, provided that the total number of carbons is 4 or less.

[0072] In some embodiments, R 22 is C 1~4 In some embodiments, R 22 is NH(C 1~4 alkyl), N(C 1~3 Alkyl)(C 1~3alkyl), and each C 1~3 The alkyls are independently selected, provided that the total number of carbons is 4 or less.

[0073] In some embodiments, R 23 is C 1~4 In some embodiments, R 23 is NH(C 1~4 alkyl), N(C 1~3 Alkyl)(C 1~3 alkyl), and each C 1~3 The alkyls are independently selected, provided that the total number of carbons is 4 or less.

[0074] In some embodiments, R 21 , R 22 , and R 23 One or more of may also be a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4- to 6-membered heterocyclic ring, or a 5-membered heteroaryl) that can be optionally substituted with 1 to 3 suitable substituents as defined herein. For example, in some embodiments, the 3- to 6-membered ring structure can be unsubstituted. In some embodiments, the 3- to 6-membered ring structure can each independently be oxo, OH, halo (e.g., F), or C. 1~4 For example, in some embodiments, R 21 , R 22 , and R 23 One of them is, [ka] It could be.

[0075] In some embodiments, R 21 are hydrogen, deuterium, and C 1~4 alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 In some embodiments, R 21 can be a halogen, such as F or Cl. In some preferred embodiments, R21 is hydrogen, deuterium, F, or methyl.

[0076] In some embodiments, R 21 has a hydrogen bond donor. For example, in some embodiments, R 21 is OH, NH2, or NH(C 1~4 C substituted with alkyl 1~4 Alkyl, preferably [ka] In some embodiments, R 21 is OH, NH2, or NH(C 1~4 C substituted with alkyl 3~4 Cycloalkyl, for example [ka] In such embodiments, typically R 22 and R 23 is also OH, NH2, or NH(C 1~4 alkyl) groups, for example, in some embodiments, R 22 and R 23 are each independently hydrogen, F, Cl, methyl, or ethyl.

[0077] In some embodiments, R 21 may be a 4- to 6-membered heterocyclic ring having one or two ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., and each of the 4- to 6-membered heterocyclic rings may independently be a C optionally substituted with oxo, F, OH, NH, F. 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 For example, in some embodiments, R 21 is azetidinyl or pyrrolidinyl, for example [ka] Typically, in such embodiments, R 22 and R 23 is not a heteroaryl or heterocyclic ring.

[0078] In some embodiments, R 21 may be a 5-membered heteroaryl ring having 2 to 4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., each of the 5-membered heteroaryl rings independently being C optionally substituted with F, OH, NH, F, 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 For example, in some embodiments, R 21 is one or two C such as methyl 1~4 imidazolyl or pyrazolyl optionally substituted with alkyl, for example [ka] Typically, in such embodiments, R 22 and R 23 is not a heteroaryl or heterocyclic ring.

[0079] Various groups also exist in R 22 For example, in some embodiments, R 22 is hydrogen, C 1~4 alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 In some embodiments, R 22 can be a halogen such as F or Cl.

[0080] In some preferred embodiments, R 22 has a hydrogen bond donor. For example, in some embodiments, R 22 is OH, NH2, or NH(C 1~4 C substituted with alkyl 1~4 Alkyl, preferably [ka] In some embodiments, R 22 is OH, NH2, or NH(C 1~4 C substituted with alkyl 3~4 Cycloalkyl, for example [ka] In some embodiments, R 22 teeth, [ka] In some embodiments, R 22 is a C substituted with NH-(3- to 7-membered ring) 1~4 The 3-7 membered ring may be alkyl, and the 3-7 membered ring is preferably a 3-, 4-, or 5-membered ring, such as cyclopropyl. For example, in some embodiments, R 22 is an NH-cyclopropyl-substituted C 1~4 In some embodiments, R 22 teeth, [ka] In some embodiments, R 22 teeth, [ka] In such embodiments, typically R 21 and R 23 is also OH, NH2, or NH(C 1~4 alkyl) groups, for example, in some embodiments, R 21 and R 23 are each independently hydrogen, deuterium, F, Cl, methyl, or ethyl.

[0081] In some embodiments, R 22may be a 4- to 6-membered heterocyclic ring having one or two ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., and each of the 4- to 6-membered heterocyclic rings may independently be a C optionally substituted with oxo, F, OH, NH, F. 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 For example, in some embodiments, R 22 is azetidinyl or pyrrolidinyl, for example [ka] In some embodiments, R 22 is C optionally replaced with F 1~4 Azetidinyl or pyrrolidinyl optionally substituted with alkyl, for example [ka] Typically, in such embodiments, R 21 and R 23 is not a heteroaryl or heterocyclic ring. For example, in some embodiments, R 21 and R 23 are each independently hydrogen, deuterium, F, Cl, methyl, or ethyl.

[0082] In some embodiments, R 22 may be a 5-membered heteroaryl ring having 2 to 4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., each of the 5-membered heteroaryl rings independently being C optionally substituted with F, OH, NH, F, 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 For example, in some embodiments, R 22 is one or two C such as methyl 1~4imidazolyl or pyrazolyl optionally substituted with alkyl, for example [ka] Typically, in such embodiments, R 21 and R 23 is not a heteroaryl or heterocyclic ring. For example, in some embodiments, R 21 and R 23 are each independently hydrogen, deuterium, F, Cl, methyl, or ethyl.

[0083] Various groups also exist in R 23 For example, in some embodiments, R 23 are hydrogen, deuterium, and C 1~4 alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 It can be heteroalkyl, for example, N(CH). In some embodiments, R 23 can be a halogen, such as F or Cl. In some preferred embodiments, R 23 is hydrogen, deuterium, F, Cl, or methyl.

[0084] In some embodiments, R 23 has a hydrogen bond donor. For example, in some embodiments, R 23 is OH, NH2, or NH(C 1~4 C substituted with alkyl 1~4 Alkyl, preferably [ka] In some embodiments, R 23 is OH, NH2, or NH(C 1~4 C substituted with alkyl 3~4 Cycloalkyl, for example [ka] In such embodiments, typically R21 and R 22 is also OH, NH2, or NH(C 1~4 alkyl) groups, for example, in some embodiments, R 21 and R 22 are each independently hydrogen, F, Cl, methyl, or ethyl.

[0085] In some embodiments, R 23 may be a 4- to 6-membered heterocyclic ring having one or two ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., and each of the 4- to 6-membered heterocyclic rings may independently be a C optionally substituted with oxo, F, OH, NH, F. 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 For example, in some embodiments, R 23 is azetidinyl or pyrrolidinyl, for example [ka] Typically, in such embodiments, R 21 and R 22 is not a heteroaryl or heterocyclic ring.

[0086] In some embodiments, R 23 may be a 5-membered heteroaryl ring having 2 to 4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., each of the 5-membered heteroaryl rings independently being C optionally substituted with F, OH, NH, F, 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 For example, in some embodiments, R 23 is one or two C such as methyl 1~4 imidazolyl or pyrazolyl optionally substituted with alkyl, for example [ka] Typically, in such embodiments, R 21 and R 22 is not a heteroaryl or heterocyclic ring.

[0087] In some embodiments, R 21 and R 22 are joined together with the intervening atoms to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, each independently selected from the group consisting of C, optionally substituted with F, OH, NH, F, 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 alkyl), preferably one of the substituents is OH, NH, or NH(C 1~4 In such embodiments, R 23 is typically hydrogen, halogen (e.g., F or Cl), C 1~4 alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 It is heteroalkyl.

[0088] In some embodiments, R 22 and R 23 are joined together with the intervening atoms to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, each independently selected from the group consisting of C, optionally substituted with F, OH, NH, F, 1~4 alkyl, C optionally substituted with F 1~4 Alkoxy, or NH(C 1~4 alkyl), preferably one of the substituents is OH, NH, or NH(C 1~4 In such embodiments, R 21 is typically hydrogen, halogen (e.g., F or Cl), C 1~4alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 It is heteroalkyl.

[0089] For example, in some embodiments, R 2 teeth, [ka] may be selected from:

[0090] In some preferred embodiments, R 22 contains a hydrogen bond donor, such as one having an OH, NH, or NH group / moiety. For example, in some embodiments, R 2 teeth, [ka] may be selected from:

[0091] In some preferred embodiments, R in Formula I 2 teeth, [ka] may be selected from:

[0092] In some preferred embodiments, R in Formula I 2 teeth, [ka] may be selected from:

[0093] In some embodiments, R 21 or R 23 contains a hydrogen bond donor, such as one having an OH, NH, or NH group / moiety. For example, in some embodiments, R 2 teeth, [ka] may be selected from:

[0094] In some embodiments, R in Formula I 2 M-2 or M-5: [ka] (In the formula, J 1 and J 2 are independently N or CR 30 and R in each existence 30 are independently hydrogen, halogen, C optionally substituted with F 1~4 C optionally substituted with alkyl or F 1~4 is heteroalkyl; Ring C is a heterocyclic or heteroaryl ring, which is 110 optionally substituted with 1 to 5 instances of R in each occurrence 110 are independently (1) oxo, (2) halogen (e.g., F or Cl), (3) OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), (4) each independently F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 (6) R is heteroalkyl; 110 Two examples of C, optionally substituted with oxo, halo (e.g., F), OH, NH, F, are linked together with an intervening atom. 1~4 C optionally substituted with alkyl or F 1~4forming a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; J 3 and J 4 are independently N and NR 31 , C.R. 32 R 33 , or CR 34 and R in each occurrence 31 are independently hydrogen, C optionally substituted with F 1~4 alkyl, or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R in each occurrence 32 and R 33 each independently being (1) hydrogen or deuterium, (2) halogen (e.g., F or Cl), (3) OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), (4) each independently F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or (7) R 32 and R 33 are joined together with the carbon atom to which they are both attached to form a carbonyl (CO) or a C optionally substituted with, each independently, oxo, halo (e.g., F), OH, NH, F 1~4C optionally substituted with alkyl or F 1~4 form a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4- to 6-membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; or R 32 Two examples of R 32 One example of R 100 One example of is C, which together with the intervening atoms are linked and each independently optionally substituted with oxo, halo (e.g., F), OH, NH, F. 1~4 C optionally substituted with alkyl or F 1~4 forming a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R in each occurrence 34 are independently (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), (4) each independently F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 heteroalkyl, or (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R 20A and R 21A are each independently hydrogen, deuterium, halogen (e.g., F or Cl), CN, C optionally substituted with F 1~4alkyl, C optionally substituted with F 1~4 It can be a heteroalkyl, or an optionally substituted 3- to 6-membered ring structure (eg, cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl).

[0095] Ring C in M-2 or M-5 can typically be a 5- or 6-membered heterocyclic ring having one ring nitrogen atom, such as a tetrahydropyridine ring or a dihydropyrrole ring, for example, a heterocyclic ring having one or two ring heteroatoms. In some embodiments, ring C in M-2 or M-5 can be a 5-membered heteroaryl, preferably having one or two ring heteroatoms, for example, a heteroaryl ring such as an imidazole or pyrazole ring. R 110 These two examples are linked together with the intervening atoms to form a 3- to 6-membered ring structure, and Ring C may be combined with the 3- to 6-membered ring structure to form a spiro, bridged, or fused ring structure.

[0096] J in M-2 or M-5 1 is usually CR 30 and R 30 is defined herein, and preferably R 30 is hydrogen. However, in some embodiments, J 1 can be N.

[0097] J in M-2 or M-5 2 is also usually 30 and R 30 is defined herein, and preferably R 30 is hydrogen. However, in some embodiments, J 2 may also be N. Preferably, J in M-2 or M-5 1 and J 2 are not both N.

[0098] In some preferred embodiments, both J in M-2 or M-5 1 and J 2is CH. For example, in some embodiments, the compound of formula I has formula I-2: [ka] (In the formula, R 3 , R 20A , R 21A , J 3 , J 4 ,p,R 110 and ring C is as defined herein). In some embodiments, the compound of formula I can have a structure according to, for example, formula I-2-D: [ka] (In the formula, R 3 , R 20A , R 21A , J 3 , J 4 ,p,R 110 and ring C is as defined herein).

[0099] In some embodiments, R 20A is hydrogen. In some embodiments, R 20A is a halogen such as F (e.g., F or Cl) or CN. In some embodiments, R 20A is C optionally replaced with F 1~4 In some embodiments, R 20A is C optionally replaced with F 1~4 Heteroalkyl. Usually C 1~4 Heteroalkyl has 1 or 2 heteroatoms, which are independently N or O. In some embodiments, R 20A can also be an optionally substituted 3- to 6-membered ring structure (eg, cyclopropyl, cyclobutyl, a 4- to 6-membered heterocyclic ring, or a 5-membered heteroaryl).

[0100] R 20A is usually hydrogen, halogen, or C 1~4 For example, in some preferred embodiments, R20A is hydrogen, F, Cl, methyl, or ethyl, preferably R 20A is F.

[0101] In some embodiments, R 21A is hydrogen. In some embodiments, R 21A is deuterium. In some embodiments, R 21A is a halogen such as F (e.g., F or Cl) or CN. In some embodiments, R 21A is C optionally replaced with F 1~4 In some embodiments, R 21A is C optionally replaced with F 1~4 Heteroalkyl. Usually C 1~4 Heteroalkyl has 1 or 2 heteroatoms, which are independently N or O. In some embodiments, R 21A can also be an optionally substituted 3- to 6-membered ring structure (eg, cyclopropyl, cyclobutyl, a 4- to 6-membered heterocyclic ring, or a 5-membered heteroaryl).

[0102] R 21A is usually hydrogen, halogen, or C 1~4 For example, in some preferred embodiments, R 21A is hydrogen, F, Cl, methyl, or ethyl. In some preferred embodiments, R 21A is hydrogen, deuterium, or methyl.

[0103] In some embodiments, the integer p is 0. In some embodiments, the integer p is 1 and R 110 are OH, NH2, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), or C 1~4 It is alkyl.

[0104] In some embodiments, the integer p is 2. In such embodiments, typically, R 110independently, C 1~4 alkyl (e.g., methyl, ethyl); or two R 110 is linked together with the intervening atom to form a 3- to 6-membered ring such as a cyclopropyl ring.

[0105] In some embodiments, the integer p is 2, 3, or 4, and R 110 Two examples of R are linked together with the intervening atoms to form a 5- or 6-membered ring, 110 Any remaining instances of R are defined herein. For example, in some embodiments, R at each occurrence 110 Any remaining non-ring-forming example of 1~4 Alkyl (eg, methyl, ethyl).

[0106] J 3 and J 4 are independently N and NR 31 , C.R. 32 R 33 , or CR 34 For example, in some embodiments, J 3 is NR 31 and R 31 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 3 is N. In some embodiments, J 3 is CR 34 and R 34 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 3 is CR 32 R 33 and R 32 is hydrogen, deuterium, F, or C 1~4 alkyl (e.g., methyl or ethyl), and R 33 is hydrogen, deuterium, F, or C 1~4 alkyl (e.g., methyl or ethyl), e.g., J 3 is CH, CD, CF, CH(CH), or C(CH). In some embodiments, J 3is CR 32 R 33 and R 32 and R 33 taken together with the carbon atoms to which they are both attached form a 3-4 membered ring, such as cyclopropyl. 4 is NR 31 and R 31 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 4 is N. In some embodiments, J 4 is CR 34 and R 34 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 4 is CR 32 R 33 and R 32 is hydrogen, deuterium, F, or C 1~4 alkyl (e.g., methyl or ethyl), and R 33 is hydrogen, deuterium, F, or C 1~4 alkyl (e.g., methyl or ethyl), e.g., J 4 is CH, CD, CF, CH(CH), or C(CH). In some embodiments, J 4 is CR 32 R 33 and R 32 and R 33 taken together with the carbon atoms to which they are both attached form a 3-4 membered ring, such as cyclopropyl. 4 can be C(O). Usually, J 3 or J 4 is N or CR 34 If J 3 or J 4 means to form a double bond with another ring atom in Ring C, such as those exemplified herein, where applicable.

[0107] In one embodiment, R 32 One example of R 100One example of J is, taken together with the intervening atoms, linked to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring) that is optionally substituted as described herein. In one embodiment, J 4 is CR 32 R 33 and R 32 is R 100 One example of (J 4 on a ring atom not adjacent to R) forms a bridge (e.g., an -NH- bridge), 33 is hydrogen, deuterium, F, or C 1~4 alkyl (for example, methyl or ethyl).

[0108] For example, in some embodiments, R 2 is of the formula F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, F-10, F-11, F-12, F-13, or F-14: [ka] (In the formula, p1 is 0, 1, 2, or 3, where valency allows; R 111 is hydrogen or R 110 and Variable Element J 1 , J 2 , R 20A , R 21A , R 31 , R 32 , R 33 , R 34 , and R 110 are as defined herein. For example, in some embodiments, J in F-1 through F-12 are 1 and J 2 In some embodiments, in F-1 to F-12, R 20A and R 21A are each independently hydrogen, halogen, or C 1~4 alkyl, preferably R 20A and R 21Aare each independently hydrogen, F, Cl, methyl, or ethyl, for example, in some preferred embodiments, R 20A can be F. In some embodiments, in F-1 to F-9, R 31 , R 32 , R 33 , and R 34 are each independently hydrogen, halogen, or C 1~4 alkyl, preferably hydrogen, methyl, or ethyl, or R 32 and R 33 One or both pairs of are joined together with the carbon atoms to which they are both attached to form a cyclopropyl ring. 2 is characterized as having a structure according to formula F-1.

[0109] In one embodiment, R 2 is of formula F-1-1, F-2-1, F-3-1, F-4-1, F-5-1, F-6-1, F-7-1, F-8-1, F-9-1, F-10-1, F-11-1, F-12-1, F-13-1, or F-14-1: [ka] It is characterized as having a structure according to

[0110] In some embodiments, in F-1 or F-2 (or a subformula thereof), p1 is 0, or p1 is 1, and R 110 is C 1~4 In some embodiments, in F-1 or F-2 (or a subformula thereof), p is 2 and R at each occurrence is alkyl. 110 independently, C 1~4 alkyl (e.g., methyl, ethyl); or two R 110 is linked together with the intervening atom to form a 3- to 6-membered ring such as a cyclopropyl ring.

[0111] In some embodiments, in F-3, F-4, F-5, F-6, or F-7 (or subformulas thereof), R111 is hydrogen or C 1~4 It is alkyl.

[0112] In some embodiments, in F-4, F-5, F-6, or F-7 (or subformulas thereof), R 111 is NH2 or NH(C 1~4 alkyl).

[0113] For example, in some particular embodiments, ring C in M-2 is a heterocyclic ring, and R in formula I 2 teeth, [ka] may be selected from:

[0114] In some particular embodiments, ring C in M-2 is a heterocyclic ring, and R in formula I 2 teeth, [ka] may be selected from:

[0115] In some particular embodiments, ring C in M-2 is a 5-membered heterocyclic ring or heteroaryl ring, and R in formula I 2 teeth, [ka] may be selected from:

[0116] In some particular embodiments, ring C in M-2 is R 110 can be linked together to form a bridged heterocyclic ring, e.g., R in Formula I 2 teeth, [ka] It could be.

[0117] In some embodiments, R in Formula I 2 M-3 or M-4: [ka] (In the formula, J 1 and J 2 are independently N or CR 30 and R in each existence 30 are independently hydrogen, halogen, C optionally substituted with F 1~4 C optionally substituted with alkyl or F 1~4 is heteroalkyl; Ring C is a heterocyclic or heteroaryl ring, which is 110 optionally substituted with 1 to 5 instances of R in each occurrence 110 are independently (1) oxo, (2) halogen (e.g., F or Cl), (3) OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), (4) each independently F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 (6) R is heteroalkyl; 110 Two examples of C, optionally substituted with oxo, halo (e.g., F), OH, NH, F, are linked together with an intervening atom. 1~4 C optionally substituted with alkyl or F 1~4 forming a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; U is O or C(=O); W and V are independently C, N, or CR. 34 and; t is 0, 1, 2, or 3; and each Z is independently O, N, or NR. 31 , C.R. 32 R 33 , or CR 34 and; the bond between W and V, between W and Z, or between two consecutive Zs, is a single or double bond, if valence allows; J 3 and J 4 are independently N and NR 31 , C.R. 32 R 33 , or CR 34 and R in each occurrence 31 are independently hydrogen, C optionally substituted with F 1~4 alkyl, or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R in each occurrence 32 and R 33 each independently being (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), (4) each independently F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4(6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or (7) R 32 and R 33 are joined together with the carbon atom to which they are both attached to form a carbonyl (CO) or a C optionally substituted with, each independently, oxo, halo (e.g., F), OH, NH, F 1~4 C optionally substituted with alkyl or F 1~4 forming a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4- to 6-membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R in each occurrence 34 are independently (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), (4) each independently F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 heteroalkyl, or (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or J 3 and R 110 One example of J 4 and R 110 An example of is linked together with intervening atoms to form a ring structure; R 20Ais hydrogen, halogen (e.g., F or Cl), CN, C optionally substituted with F 1~4 alkyl, C optionally substituted with F 1~4 heteroalkyl or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R 22A and R 23A are each independently: (1) hydrogen; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently: F, OH, NH, 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl 1~4 alkyl, (5) C optionally substituted with F 1~4 heteroalkyl, or (6) C optionally substituted with oxo, halo (e.g., F), OH, NH, F. 1~4 alkyl, C optionally substituted with F 1~4 It can be a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocyclic ring, or a 5 membered heteroaryl) optionally substituted with 1-3 substituents that are heteroalkyl.

[0118] Ring C in M-3 can typically be a 5- or 6-membered heterocyclic ring having one ring nitrogen atom, such as a tetrahydropyridine ring or a dihydropyrrole ring, for example, a heterocyclic ring having one or two ring heteroatoms. In some embodiments, ring C in M-3 can be a 5-membered heteroaryl, preferably one having one or two ring heteroatoms, for example, a heteroaryl ring such as an imidazole or pyrazole ring.

[0119] The bond between W and V may be a single or double bond, where valence allows. Similarly, the bond between W and Z may be a single or double bond, where valence allows. Also, two consecutive Z's may be joined via a single or double bond, where valence allows.

[0120] J in M-3 or M-4 1 is usually CR 30 and R 30 is defined herein, and preferably R 30 is hydrogen. However, in some embodiments, J 1 can be N.

[0121] J in M-3 or M-4 2 is also usually 30 and R 30 is defined herein, and preferably R 30 is hydrogen. However, in some embodiments, J 2 may also be N. Preferably, J in M-3 or M-4 1 and J 2 are not both N.

[0122] In some preferred embodiments, both J in M-3 or M-4 1 and J 2 is CH. For example, in some embodiments, the compound of Formula I has Formula I-3 or I-4: [ka] (In the formula, R 3 , R 20A , R 22A , R 23A , J 3 , J 4 ,p,R 110 , t, U, V, W, Z, and ring C can have a structure according to the formula:

[0123] In some embodiments, R 20Ais hydrogen. In some embodiments, R 20A is a halogen such as F (e.g., F or Cl) or CN. In some embodiments, R 20A is C optionally replaced with F 1~4 In some embodiments, R 20A is C optionally replaced with F 1~4 Heteroalkyl. Usually C 1~4 Heteroalkyl has 1 or 2 heteroatoms, which are independently N or O. In some embodiments, R 20A can also be an optionally substituted 3- to 6-membered ring structure (eg, cyclopropyl, cyclobutyl, a 4- to 6-membered heterocyclic ring, or a 5-membered heteroaryl).

[0124] R 20A is usually hydrogen, halogen, or C 1~4 For example, in some preferred embodiments, R 20A is hydrogen, F, Cl, methyl, or ethyl.

[0125] In some embodiments, the integer p is 0. In some embodiments, the integer p is 1 and R 110 are OH, NH2, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 alkyl), or C 1~4 It is alkyl.

[0126] In some embodiments, the integer p is 2. In such embodiments, typically, R 110 independently, C 1~4 alkyl (e.g., methyl, ethyl); or two R 110 is linked together with the intervening atom to form a 3- to 6-membered ring such as a cyclopropyl ring.

[0127] J 3 and J 4 are independently N and NR 31 , C.R. 32 R33 , or CR 34 For example, in some embodiments, J 3 is NR 31 and R 31 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 3 is N. In some embodiments, J 3 is CR 34 and R 34 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 3 is CR 32 R 33 and R 32 is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl), and R 33 is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl), e.g., J 3 is CH, CH(CH), or C(CH). In some embodiments, J 3 is CR 32 R 33 and R 32 and R 33 taken together with the carbon atoms to which they are both attached form a 3-4 membered ring, such as cyclopropyl. 4 is NR 31 and R 31 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 4 is N. In some embodiments, J 4 is CR 34 and R 34 is hydrogen or C 1~4 In some embodiments, J is alkyl (e.g., methyl or ethyl). 4 is CR 32 R 33 and R 32 is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl), and R 33is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl), e.g., J 4 is CH, CH(CH), or C(CH). In some embodiments, J 4 is CR 32 R 33 and R 32 and R 33 together with the carbon atoms to which they are both attached form a 3- or 4-membered ring, such as cyclopropyl. 3 or J 4 is N or CR 34 If J 3 or J 4 means to form a double bond with another ring atom in Ring C, such as those exemplified herein.

[0128] U in M-3 or M-4 is typically O. In some embodiments, U can also be C(=O).

[0129] The integer t is usually 1 or 2.

[0130] Typically, Z in each occurrence independently 32 R 33 and R 32 is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl), and R 33 is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl), for example, Z is CH, CH(CH), or C(CH). In some embodiments, one example of Z is CR. 32 R 33 and R 32 and R 33 together with the carbon atoms to which they are both attached form a 3- or 4-membered ring, such as cyclopropyl; any remaining instances of Z may independently be CR 32 R 33 and R 32 is hydrogen or C 1~4 alkyl (e.g., methyl or ethyl) and R 33 is hydrogen or C1~4 alkyl (e.g., methyl or ethyl), for example, the remaining instances of Z are independently CH2, CH(CH3), or C(CH3)2.

[0131] In some embodiments, W is C and Z directly linked to W is CR 34 and R 34 is hydrogen or C 1~4 alkyl (eg, methyl or ethyl) and the bond between Z and W is a double bond.

[0132] In some embodiments, W is C. In some embodiments, W is CH.

[0133] In some embodiments, V is C. In some embodiments, V is CH. In some embodiments, V is N.

[0134] For example, in some embodiments, M-3 or M-4 is [ka] wherein the variables are defined herein.

[0135] In one embodiment, R 2 is M-3-A-1, M-3-A-2, M-3-A-3, M-4-A-1, M-3-B-1, M-3-B-2, or M-3-C-1: [ka] (In the formula, R 111 is hydrogen or R 110 (In the formula, R 110 has a structure according to) where (is) as defined herein or elsewhere.

[0136] R in M-4 22A is usually hydrogen, C 1~4alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 For example, in some embodiments, R 22A can be hydrogen or methyl.

[0137] In some embodiments, R in M-4 (e.g., M-4-D) 22A is OH, NH2, or NH(C 1~4 C substituted with alkyl 1~4 Alkyl, for example, [ka] It could be.

[0138] R in M-4 23A is usually hydrogen, C 1~4 alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen 1~4 For example, in some embodiments, R 23A can be hydrogen or methyl.

[0139] In some embodiments, R in M-4 23A is OH, NH2, or NH(C 1~4 C substituted with alkyl 1~4 It can be alkyl.

[0140] In some embodiments, R 22A and R 23A One of the groups is a group containing a hydrogen bond donor.

[0141] In some particular embodiments, ring C in M-3 is a 5-membered heteroaryl, and R 2 teeth, [ka] may be selected from:

[0142] In some particular embodiments, ring C in M-3 is a heterocyclic ring structure, and R 2 teeth, [ka] may be selected from:

[0143] In some preferred embodiments, R 2 teeth, [ka] may be selected from:

[0144] Various groups can be represented by R in Formula I 3 For example, in some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen (e.g., F). In some embodiments, R 3 is CN. In some embodiments, R 3 is C(O)NR 11 R 12 and R 11 and R 12 is defined herein, for example, R 11 and R 12 and R may be hydrogen. 3 is an optionally substituted C 3~8 In some embodiments, R 3 is an optionally substituted 4-10 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S. In some embodiments, R 3 is an optionally substituted 5-10 membered heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S.

[0145] In any of the embodiments herein, unless specified or contrary to context, R in Formula I 3(or any subformula provided herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) can be any of C optionally substituted with hydrogen, F, Cl, Br, F 1~4 It can be alkyl, or CN.

[0146] In some embodiments, R in Formula I 3 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) may include an optionally substituted C 1~4 In some embodiments, R 3 is deuterium, F, CN, or OR C C optionally substituted with one or more, such as 1 to 3 substituents independently selected from 1~4 R at each occurrence may be alkyl. C are independently hydrogen, deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 For example, in some embodiments, R 3 can be methyl, CD, CH-OMe, CH-OCD, ethyl, CHF, CFCH, CHCHF, CHCFH, or CF. In some embodiments, R 3 can be CF2CF3. In some preferred embodiments, R 3 can be F or Cl.

[0147] In some embodiments, R in Formula I 3(or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) may include an optionally substituted C 2~4 Alkenyl, for example [ka] It could be.

[0148] In some embodiments, R in Formula I 3 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) may include an optionally substituted C 2~4 Alkynyl, for example [ka] It could be.

[0149] In some embodiments, R in Formula I 3 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) may be expressed as OR A For example, in some embodiments, R 3 is OR A and R A are hydrogen, deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 It is cycloalkyl.

[0150] In some embodiments, R in Formula I 3 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) is a C(O)R B For example, in some embodiments, R 3 is C(O)R B and R B are hydrogen, deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 It is cycloalkyl.

[0151] In some embodiments, R in Formula I 3 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) may also be C 3~6 It may be cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S, such as oxetanyl, tetrahydrofuranyl, or 5-6 membered heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S, such as thiazolyl, each of which may be 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) optionally substituted with 1 to 3 substituents independently selected from 1 are independently deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 1~4 Alkyl, or deuterium, F, CN, OH, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl 3~6 It is cycloalkyl.

[0152] In any of the embodiments herein, unless specified or contrary to context, R in Formula I 3 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) [ka] may be selected from:

[0153] R in Formula I 4 (or any of the applicable sub-formulas as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-2, I-3, or I-4) is typically hydrogen. In some embodiments, R in Formula I 4 In some embodiments, R in Formula I can be deuterium. 4 may also be halogen (e.g., F), optionally substituted C 1~6 Alkyl or NR 11 R 12 For example, in some embodiments, R in Formula I can be 4 is NH2.

[0154] In some embodiments, in Formula I (or any of the applicable subformulas as described herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, or A-2), R 3 and R 4 can also be joined together with intervening atoms to form an optionally substituted 4- to 8-membered ring structure, such as a 4- to 8-membered heterocyclic structure or a 5- or 6-membered heteroaryl structure. For example, in any of the embodiments herein, unless specified otherwise or contrary to context, in Formula I (or any applicable subformula as described herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, or A-2), R 3 and R 4 can be linked together with intervening atoms to form one of the following: [ka]

[0155] In some embodiments, R 21 , R 22 , R 23 , R 110 , R 32 , R 33 , R 34 , R 22A , or R 23A Each C 1~4 Alkyl is independently F, OH, NH, NH(C 1~4 alkyl), or N(C 1~4 Alkyl)(C 1~4 and optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, aryl, aryl, aryl substituted with ...

[0156] In some embodiments, the present disclosure also provides a compound selected from Table 1 below, a deuterated analog thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] TIFF2025527170000076.tif191170TIFF2025527170000077.tif196170TIFF2025527170000078.tif189170TIFF2025527170 000079.tif189170TIFF2025527170000080.tif221170TIFF2025527170000081.tif221170TIFF2025527170000082.tif22917 0TIFF2025527170000083.tif228170TIFF2025527170000084.tif190170TIFF2025527170000085.tif190170TIFF202552717 0000086.tif193170TIFF2025527170000087.tif196170TIFF2025527170000088.tif189170TIFF2025527170000089.tif2061 70TIFF2025527170000090.tif193170TIFF2025527170000091.tif188170TIFF2025527170000092.tif197170TIFF20255271 70000093.tif193170TIFF2025527170000094.tif192170TIFF2025527170000095.tif192170TIFF2025527170000096.tif193 The compounds in Table 1 may exist in various stereoisomeric forms, such as individual isomers, individual enantiomers and / or diastereomers, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers, where applicable. In some embodiments, where applicable, the compounds set forth in Table 1 may have an enantiomeric excess ("ee") of greater than 60%, such as having greater than 80% ee, greater than 90% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, greater than 99% ee, or have an undetectable amount of the other enantiomer.In some embodiments, where applicable, the compounds shown in Table 1 may also exist as mixtures of stereoisomers in any proportion, such as racemic mixtures.

[0157] In some embodiments, to the extent applicable, the genera of compounds described herein also exclude any specifically known single compounds prior to the present disclosure. In some embodiments, to the extent applicable, any subgenera or species of compounds prior to the present disclosure that are entirely included in the genera of compounds described herein may also be excluded from such genera herein.

[0158] The compounds of the present disclosure may be readily synthesized by one of ordinary skill in the art in light of the present disclosure. Exemplary syntheses are also provided in the Examples section.

[0159] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis", 4 thed. P.G.M.Wuts; T.W. Greene, John Wiley, 2007, and the references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial manufacturers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others are available from 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 Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7 th These compounds may be prepared by procedures described in standard reference texts such as "The Organic Synthesis of Benzyl Alcohols" (Wiley-VCH, 1999), "The Organic Synthesis of Benzyl Alcohols," and "The Organic Synthesis of Benzyl Alcohols," (Wiley-VCH, 1999), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any updates available at the time of this filing, or obvious modifications thereof.

[0160] Pharmaceutical Composition Certain embodiments are directed to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0161] The pharmaceutical composition may optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting examples of suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavorings, humectants, lubricants, flavorings, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0162] Pharmaceutical compositions can include any one or more of the compounds of the present disclosure. For example, in some embodiments, pharmaceutical compositions include, for example, a therapeutically effective amount of a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition can include a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical compositions may comprise a compound selected from the compounds according to Examples 1-111 having a CDK4 / cyclin D1 IC50 level designated as "A" or "B" in Table 2 herein, preferably "A."

[0163] The pharmaceutical compositions herein may be formulated for delivery via any of the known routes of delivery, including, but not limited to, oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal or parenteral administration.

[0164] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be provided as discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. Excipients for preparing compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, lactic acid bacteria ... Ingredients include cellulose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0165] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations can be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral formulations are known in the art. Non-limiting examples of suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, 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.

[0166] The compounds of the present disclosure may be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, such as additional anti-cancer therapeutic agents, including, for example, antimitotic agents, alkylating agents, antimetabolites, antitumor antibiotics, angiogenesis inhibitors, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, e.g., inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, cancer immunotherapy agents, and the like. In some embodiments, one or more compounds of the present disclosure 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 an immunomodulatory agent such as a PD-1 or PD-L1 antagonist, an OX40 agonist, or a 4-1BB agonist. In some embodiments, one or more compounds of the present disclosure may be used in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable additional anticancer therapeutic agents include any known in the art, such as those approved for the appropriate cancer by regulatory agencies, such as the U.S. Food and Drug Administration. Some examples of suitable additional anticancer therapeutic agents also include those described as suitable for use in combination with CDK inhibitors in International Publication Nos. WO 2019 / 207463, WO 2020 / 224568, and the like, the contents of each of which are incorporated herein by reference in their entireties.

[0167] When used in combination with one or more additional therapeutic agents, the compounds of the present disclosure or pharmaceutical compositions herein can be administered to a subject simultaneously or sequentially in any order with such additional therapeutic agents. In some embodiments, a pharmaceutical composition can contain one or more compounds of the present disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition containing one or more compounds of the present disclosure can be included in a kit that also contains a separate pharmaceutical composition containing one or more additional therapeutic agents.

[0168] Pharmaceutical compositions may contain varying amounts of the compounds of the present disclosure, depending on various factors, such as the intended use and efficacy and selectivity of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, such as breast cancer or ovarian cancer, which may depend on the recipient of the 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 the treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0169] Method of Treatment / Use The compounds of the present disclosure have various uses.For example, the compounds of the present disclosure can be used as therapeutically active substances for the treatment and / or prevention of CDK4-mediated diseases or disorders.Therefore, some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure or pharmaceutical compositions herein for treating or preventing CDK4-mediated diseases or disorders in a subject in need thereof, for example, for treating cancer in a subject in need thereof.

[0170] In some embodiments, the present disclosure provides a method of inhibiting abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the abnormal cell growth is a cancer associated with CDK4.

[0171] In some embodiments, the present disclosure also provides methods of inhibiting CDK activity in a subject or biological sample. In some embodiments, the present disclosure provides methods of inhibiting CDK activity in a subject or biological sample, comprising contacting the subject or biological sample with an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein.

[0172] In some embodiments, the present disclosure provides methods of treating or preventing a CDK-mediated, particularly a CDK4-mediated, disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the CDK4-mediated disease or disorder is, for example, a cancer described herein.

[0173] In some embodiments, the present disclosure also provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described 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, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric (i.e., stomach) cancer, thyroid cancer, and combinations thereof. In some embodiments of the methods 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.

[0174] In some embodiments of the methods herein, 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 can be endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits inherent or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer can be advanced or metastatic breast cancer.

[0175] In some embodiments of the methods herein, the cancer is ovarian cancer.

[0176] In some embodiments, a compound of the present disclosure is administered as a first-line therapy. In other embodiments, a compound of the present disclosure is administered as a second (or later) line therapy. In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy after treatment with an endocrine therapeutic agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy after treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM, or a SERD. In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy after treatment with a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy after treatment with one or more chemotherapy regimens, e.g., including a taxane or platinum agent. In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy after treatment with a HER2-targeting agent, e.g., trastuzumab.

[0177] In some embodiments, the disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described 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 that exhibits inherent or acquired resistance to CDK4 / CDK6 inhibition, hi some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0178] In some preferred embodiments, the compounds of the disclosure for the methods herein have a CDK4 / cyclin D1 IC50 of less than 100 nM, more preferably less than 10 nM, as measured / calculated according to Biological Example 1 herein. In some preferred embodiments, the compounds of the disclosure for the methods herein are selected from compounds according to Examples 1-111 having a CDK4 / cyclin D1 IC50 level designated as "A" or "B" in Table 2 herein, preferably "A."

[0179] In some preferred embodiments, the compounds of the disclosure for the methods herein are selective for CDK4 over CDK6. In some embodiments, the compounds of the disclosure for the methods herein may be selective for CDK4 over other CDKs.

[0180] In some embodiments, the present disclosure provides a method of inhibiting cancer cell growth in a subject, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell growth.

[0181] In some embodiments, the present disclosure provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell invasiveness.

[0182] In some embodiments, the present disclosure provides a method of inducing apoptosis of cancer cells in a subject, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis.

[0183] In some embodiments, the present disclosure provides a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

[0184] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, administration is oral. In some embodiments, administration is parenteral injection, such as intravenous injection.

[0185] The compounds of the present disclosure may be used as monotherapy or in combination therapy. In some embodiments of the methods described herein, one or more compounds of the present disclosure may be administered as the sole active ingredient. In some embodiments of the methods described herein, one or more compounds of the present disclosure may also be co-administered to a subject in need thereof with an additional therapeutic agent, either simultaneously or sequentially in any order. The additional therapeutic agent may typically be an additional anti-cancer therapeutic agent, such as a mitotic inhibitor, an alkylating agent, an antimetabolite, an antitumor antibiotic, an angiogenesis inhibitor, a topoisomerase I and II inhibitor, a plant alkaloid, a hormone agent and antagonist, a growth factor inhibitor, radiation, a signal transduction inhibitor, e.g., an inhibitor of protein tyrosine kinase and / or serine / threonine kinase, a cell cycle inhibitor, a biological response modifier, an enzyme inhibitor, an antisense oligonucleotide or oligonucleotide derivative, a cytotoxic agent, or an immuno-oncology agent. In some embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD, or a SERM. In some embodiments, one or more compounds of the present disclosure may be administered in combination with one or more targeted agents such as an inhibitor 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 an immunomodulatory agent such as a PD-1 or PD-L1 antagonist, an OX40 agonist, or a 4-1BB agonist. In some embodiments, one or more compounds of the present disclosure may be administered in combination with a standard of care agent such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable additional anti-cancer therapeutic agents include any known in the art, including those approved for the appropriate cancer by regulatory authorities, such as the U.S. Food and Drug Administration.Some examples of suitable additional anti-cancer therapeutic agents also include those described as suitable for use in combination with CDK inhibitors in WO 2019 / 207463, WO 2020 / 224568, etc., the contents of each of which are incorporated herein by reference in their entireties.

[0186] Dosage regimens, including dosages, for the methods described herein may vary and be adjusted, and may depend on the recipient of the 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 rate of clearance, and whether another drug is co-administered.

[0187] definition It is to be understood that appropriate atomic valences are maintained for all moieties and combinations thereof.

[0188] It is also to be understood that a particular embodiment of a variable element moiety herein may be the same as or different from another particular embodiment having the same identifier.

[0189] Suitable groups for the variables in compounds of Formula I, or subformulas thereof, are independently selected, where applicable. Non-limiting useful groups for the variables in compounds of Formula I, or subformulas thereof, where applicable, include any of the respective groups individually or in any combination as shown in the Examples or specific compounds described in Table 1 herein. Examples of the variable R 1 In some embodiments, compounds of Formula I can be prepared using the R shown in the specific compounds described in the Examples or Table 1 herein, regardless of the other variables shown in the specific compound. 1 R by any of the groups 1 In some embodiments, the compound of Formula I may contain at least one other variable (e.g., L) according to the Examples or specific compounds described in Table 1 herein. 1) in combination with the R 1 R by any of the groups 1 may contain a group, R 1 and at least one other variable may be from the same compound or a different compound. Any such combination is contemplated and is within the scope of the present disclosure. Unless otherwise specified, the description of a variable in connection with a formula also applies to any other overlapping formulas (e.g., sub-formulas), if said variable exists.

[0190] The described embodiments of the present disclosure may be combined. Such combinations are contemplated and within the scope of the present disclosure. For example, L of Formula I (or any subformula provided herein, e.g., Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) 1 , R 1 , R 2 , R 3 , R 4 , and any one or more definitions of X, L, 1 , R 1 , R 2 , R 3 , R 4 and any one or more other definitions of X, and compounds resulting from such combinations are contemplated to be within the scope of the present disclosure.

[0191] Symbols displayed perpendicular to or otherwise intersecting a bond [ka] ,for example, [ka] indicates the point at which the indicated moiety is attached to the remainder of the molecule. One or more groups that are directly linked will be identified by the symbol indicating the linkage, as will be understood by one of skill in the art. [ka] Note that the number of vertices may be greater than 1.

[0192] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in the Handbook of Chemistry and Physics, 75 th The elements are identified according to the CAS Periodic Table of the Elements, which is located on the inside cover of the Ed., and specific functional groups are generally defined as set forth therein. Further, general principles of organic chemistry and specific functional moieties and reactivities are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the list of exemplary substituents set forth herein.

[0193] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may exist in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), chiral supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers, including racemic mixtures. When stereochemistry is specifically depicted, it is to be understood that, unless contradicted by context, with respect to that particular chiral center or axial asymmetry, the compound may exist predominantly as the stereoisomer depicted, with less than 20%, less than 10%, less than 5%, less than 1% or an undetectable amount of other stereoisomers by weight, HPLC or SFC area, or both.For example, in some embodiments, a compound may exist predominantly as the depicted stereoisomer with an enantiomeric excess ("ee") of greater than 80%, such as having an ee of 90% or greater, 95% or greater, 98% or greater, 99% or greater, or may have undetectable amounts of other enantiomers. The presence and / or amount of stereoisomers may be determined by one of skill in the art in light of this disclosure, including through the use of chiral HPLC or chiral SFC. As will be understood by one of skill in the art, when an "*" appears in a chemical structure herein, unless contradicted by context, it indicates that the corresponding chiral center is enantiomerically pure or enriched in either configuration, or enantiomerically pure or enriched in the depicted configuration by less than 20%, less than 10%, less than 5%, less than 1%, etc., by weight, HPLC or SFC area, or both, or with an undetectable amount of the other stereoisomer. Additionally, when stereochemistry is not specifically depicted and "*" is not used in a chemical structure, unless contradicted by context, such structure is to be understood to include the corresponding compound in any stereoisomeric form, including individual isomers and mixtures of various isomers substantially free of other isomers, including racemic mixtures.

[0194] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 ” is 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 is intended to encompass:

[0195] As used herein, the term "compound" of the present disclosure refers to any of the compounds described herein according to Formula I (or any subformula provided herein, e.g., Formulas IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4), any of Examples 1-111, or any of the specific compounds disclosed in Table 1 herein, isotopically labeled compounds thereof (such as deuterated analogs ( The term "compound" refers to a compound in which one or more hydrogen atoms are replaced with deuterium atoms in an abundance above their natural abundance, e.g., when the compound has a CH group (e.g., a CD analog), its possible positional isomers, possible geometric isomers, its possible stereoisomers (including diastereoisomers, enantiomers, and racemic mixtures), its tautomers, its stereoisomers, its pharmaceutically acceptable esters, and / or its possible pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). For clarity, the compounds of Examples 1-111 refer to compounds in the Examples section that are labeled with integers alone or with integers appended with "a," "b," etc. to indicate different stereoisomers of the compounds labeled with integers such as 1, 2, etc., 15a, 15b, up to 111a and 111b. See, e.g., Exemplary Examples 1-27 herein. Hydrates and solvates of the compounds of the present disclosure are contemplated compositions of the present disclosure, where the compounds are associated with water or solvent, respectively. In some embodiments, the compounds of the present disclosure can be any of those according to the claims provided herein.

[0196] The compounds of the present disclosure may be present in isotopically labeled or isotopically enriched forms containing one or more atoms with atomic masses or mass numbers different from the atomic masses or mass numbers of the most abundant atoms found in nature.Isotopes may be radioactive or non-radioactive.Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18F, 36 Cl, and 125 Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0197] As used herein, the phrase "administration" of a compound, "administering" a compound, or other variations thereof, means providing a compound or a prodrug of a compound to an individual in need of treatment.

[0198] As used herein, the term "alkyl," when used alone or as part of another group, refers to a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, alkyl refers to an alkyl group having 1 to 12 carbon atoms (i.e., C 1~12 In one embodiment, the alkyl group may be a straight chain C 1~10 In another embodiment, the alkyl group is a branched C 3~10 In another embodiment, the alkyl group is a straight-chain C 1~6 In another embodiment, the alkyl group is a branched C 3~6 In another embodiment, the alkyl group is a straight-chain C 1~4 It is an alkyl group. For example, C 1~4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene," when used alone or as part of another group, refers to a divalent radical derived from an alkyl group. For example, non-limiting straight-chain alkylene groups include -CH-CH-CH-CH-, -CH-CH-CH-, -CH-CH-, and the like. Unless otherwise specified, alkyl groups are optionally substituted.

[0199] As used herein, the term "alkenyl," when used alone or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, an alkenyl group is 2~6 In another embodiment, the alkenyl group is C 2~4 Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl. Unless otherwise specified, alkenyl groups are optionally substituted.

[0200] As used herein, the term "alkynyl," when used alone or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one to three, carbon-carbon triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, an alkynyl group is C 2~6 In another embodiment, the alkynyl group is C 2~4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butenyl, 2-butynyl, pentynyl, and hexynyl groups. Unless otherwise specified, alkynyl groups are optionally substituted.

[0201] As used herein, the term "alkoxy" when used alone or as part of another group refers to a group of the formula OR a1 refers to the radical of R a1 is alkyl as defined herein.

[0202] As used herein, the term "cycloalkoxy" when used alone or as part of another group refers to a group of the formula OR a1 refers to the radical of R a1 is cycloalkyl as defined herein.

[0203] As used herein, the term "haloalkyl," when used alone or as part of another group, refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In preferred embodiments, a haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is selected from the group consisting of C 1~10 In one embodiment, the haloalkyl group is C 1~6 In one embodiment, the haloalkyl group is C 1~4 It is a haloalkyl group.

[0204] As used herein, the term "heteroalkyl," alone or in combination with another term, means, unless otherwise stated, a stable straight- or branched-chain alkyl group having 2 to 14 carbons, e.g., 2 to 10 carbons in the chain, wherein one or more of the carbons are replaced by a heteroatom selected from S, O, P, and N; the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized; and the nitrogen heteroatom may optionally be quaternized. The heteroatoms S, O, P, and N may be replaced at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When a heteroalkyl is said to be substituted, a substituent can replace one or more hydrogen atoms bonded to a carbon atom and / or heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C 1~4 C refers to heteroalkyl, which refers to heteroalkyl as defined herein having 1 to 4 carbon atoms. 1~4Examples of heteroalkyl include, but are not limited to, C4 heteroalkyl such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)-CH3, C2 heteroalkyl such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3, and C1 heteroalkyl such as -CH2-OH, -CH2-NH2, -O-CH3. 1~4 Heteroalkyl preferably has one or two heteroatoms, such as one having one oxygen, one oxygen and one nitrogen, two oxygen atoms, or two nitrogen atoms. Similarly, the term "heteroalkylene," alone or as part of another substituent, means a divalent radical derived from heteroalkyl, as exemplified but not limited by -CH-CH-O-CH-CH- and -O-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. When "heteroalkyl" is recited, followed by a specific heteroalkyl group (e.g., -NR'R ’’ When a heteroalkyl group such as -NR'R is mentioned, it is understood that the term heteroalkyl and -NR'R ’’ It will be understood that the terms "heteroalkyl" and "heteroalkyl-" are not redundant or mutually exclusive. Furthermore, specific heteroalkyl groups are listed for added clarity. Thus, the term "heteroalkyl" is used herein to refer to a specific heteroalkyl group (e.g., -NR'R ’’ Unless otherwise specified, heteroalkyl groups are optionally substituted.

[0205] "Carbocyclyl" or "carbocyclic", when used alone or as part of another group, refers to a ring system having at least three carbon atoms, e.g., 3 to 10 ring carbon atoms ("C 3~10 "carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 1 or 2 carbon atoms, and 0 heteroatoms. A carbocyclyl group can be monocyclic ("monocyclic carbocyclyl") or contain fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene," when used alone or as part of another group, refers to a divalent radical derived from a carbocyclyl group, as defined herein. Unless otherwise specified, a carbocyclyl group is optionally substituted.

[0206] In some embodiments, a "carbocyclyl" is fully saturated, which is also referred to as a cycloalkyl. In some embodiments, a cycloalkyl has 3 to 10 ring carbon atoms ("C 3~10 In a preferred embodiment, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene," when used alone or as part of another group, refers to a divalent radical derived from a cycloalkyl group, such as [ka] Refers to...

[0207] "Heterocyclyl" or "heterocyclic," used alone or as part of another group, refers to a radical of three or more members, such as a 3- to 14-membered non-aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings, and the point of attachment may be on any ring. As used herein, the term "heterocyclylene," when used alone or as part of another group, refers to a divalent radical derived from a heterocyclyl group, as defined herein. The heterocyclyl or heterocyclylene can be optionally linked to the remainder of the molecule through a carbon or nitrogen atom. Unless otherwise specified, the heterocyclyl group is optionally substituted.

[0208] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0209] "Aryl" when used alone or as part of another group refers to, for example, an aromatic ring system ("C 6~14 "C6 aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in the ring arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms, as provided in "aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C6 aryl"; e.g., phenyl). 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "aryl"; e.g., anthracyl). As used herein, the term "arylene" when used alone or as part of another group refers to a divalent radical derived from an aryl group, as defined herein. Unless otherwise specified, an aryl group is optionally substituted.

[0210] "Aralkyl," when used alone or as part of another group, refers to an alkyl substituted with one or more aryl groups, preferably one aryl group. Examples of aralkyls include benzyl, phenethyl, and the like. Unless otherwise specified, an aralkyl group is optionally substituted. When an aralkyl is said to be optionally substituted, either the alkyl or aryl portion of the aralkyl can be optionally substituted.

[0211] "Heteroaryl," used alone or as part of another group, refers to the radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in the ring arrangement) having ring carbon atoms and at least one, preferably 1 to 4, ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In one embodiment, a heteroaryl group has 5 to 14 ring atoms ("5-14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, if valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, etc.), the point of attachment can be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene," when used alone or as part of another group, refers to a divalent radical derived from a heteroaryl group, as defined herein. Unless specified otherwise or contrary to context, when a heteroaryl group is fused to a non-aromatic ring, the resulting fused ring system is referred to as a heterocyclyl group. Unless otherwise specified, a heteroaryl group is optionally substituted.

[0212] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. 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 tetrazinyl, 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, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0213] "Heteroaralkyl," when used alone or as part of another group, refers to an alkyl substituted with one or more heteroaryl groups, preferably one heteroaryl group. Unless otherwise specified, a heteroaralkyl group is optionally substituted. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0214] As used herein, and unless otherwise specified, the term “amino” refers to —N(R # )(R # ) and each R # may independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. # )(R # ) group is a group consisting of two R # , they may be combined with the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms is a heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. The term "amino" also refers to an N-oxide (-N + (R # )(R # )O - In certain embodiments, each R # or -N(R # )(R # ) may independently be unsubstituted or substituted with one or more substituents.

[0215] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the respective groups that are unsubstituted or substituted. Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position is substituted in any given structure, the substituent may be the same or different at each position. Typically, when substituted, the optionally substituted groups herein may be substituted with 1 to 5 substituents. Substituents, where applicable, may be carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituents, each of which may be optionally isotopically labeled, such as by deuteration. Two of the optional substituents may be linked to form a ring structure, such as an optionally substituted cycloalkyl, heterosilyl, aryl, or heteroaryl ring. Substitutions may occur on any available carbon, oxygen, or nitrogen atom, and may form a spirocyclic ring. Generally, substitutions herein do not result in OO, ON, SS, SN (excluding SO-N bonds), heteroatom-halogen, or -C(O)-S bonds or three or more consecutive heteroatoms, with the exception of O-SO-O, O-SO-N, and N-SO-N, except that some such bonds or linkages may be tolerated if they result in a stable aromatic system.

[0216] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl, each of which can be substituted, if appropriate.

[0217] Exemplary substituents include alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halo, -NO, -CN, -SF, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)-alkyl, -S(O)-aryl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heteroaryl, -S-alkenyl Examples of alkyl groups include, but are not limited to, alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)-alkylene-aryl, -S(O)-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH, -C(=NH)-NH, -C(=NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y1)(Y2), -C(O)N(Y1)(Y2) and -S(O)N(Y1)(Y2), where Y1 and Y2 may be the same or different and are independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0218] Some examples of suitable substituents include (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10) cycloalkyl groups, halogens (F, Cl, Br, or I), halogenated (C1-C8) alkyl groups (such as, 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) groups, -NH2, -C(O)NH2, -C(O)NH(C1-C8) alkyl groups, -C(O)N((C1-C8) alkyl) groups, -NHC(O)H, -NHC(O)(C1-C8) alkyl groups, -NHC(O)(C3-C8) cycloalkyl groups, -N((C -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((C1-C8)alkyl), -C(O)H, -C(O)(C1-C8)alkyl group, -CN, -NO2, -S(O)(C1-C8)alkyl group, -S(O)2(C1-C8) alkyl group, -S(O)2N((C1-C8) alkyl)2 group, -S(O)2NH(C1-C8) alkyl group, -S(O)2NH(C3-C8) cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1-C8) alkyl group, -N((C1-C8) alkyl)S(O)2(C1-C8) alkyl group, -(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(C -C1-C8) alkyl groups, -O-halogenated (C1-C8) alkyl groups (such as, but not limited to, -OCF3), -S(O)2-halogenated (C1-C8) alkyl groups (such as, but not limited to, -S(O)2CF3), -S-halogenated (C1-C8) alkyl groups (such as, but not limited to, -SCF3), -(C1-C6) heterocycles (such as, but not limited to, pyrrolidine, tetrahydrofuran, pyran, or morpholine), -(C1-C6) heteroaryls (such as, but not limited to, tetrazole, imidazole, furan, pyrazine, or pyrazole),Examples of alkyl groups include, but are not limited to, -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, and -C(=NO-(C1-C6)alkyl)-(C1-C6)alkyl group.

[0219] Exemplary carbon atom substituents include deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amido, sulfonamido, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3~10 Carbocyclyl, C 6~10 Examples of carbon atom substituents include, but are not limited to, aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, etc. For example, exemplary carbon atom substituents are F, Cl, —CN, —SOH, —SOH, —OH, —OC 1~6 Alkyl, -NH2, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), -SH, -SC 1~6 Alkyl, -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -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), -NHC(=O)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6alkyl)2, -SO2NH(C 1~6 alkyl), -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, C 3~10 Carbocyclyl, C 6~10 It may include aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal substituents may be linked to form =0.

[0220] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 or two substituents attached to the nitrogen atom may be linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, each of which may be further substituted as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3004, pp. 111-114, which is incorporated herein by reference. rdedition, John Wiley & Sons, 1999. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates such as carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), Troc, 9-fluorenylmethyloxycarbonyl (Fmoc) groups, those that form amides such as acetyl, benzoyl, those that form benzylic amines such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, those that form sulfonamides such as tosyl, nosyl, and others such as p-methoxyphenyl.

[0221] Exemplary oxygen atom substituents include acyl groups, esters, sulfonates, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14

[0033] Examples of suitable protecting groups include, but are not limited to, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and 5- to 14-membered heteroaryl, each of which may be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 399-402, incorporated herein by reference. rdedition, John Wiley & Sons, 1999. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, etc.; substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), those that form silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), those that form acetals or ketals such as tetrahydropyranyl (THP), those that form esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, and those that form carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0222] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain intact or essentially unchanged for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0223] In some embodiments, an "optionally substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocycle, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein can each independently be unsubstituted, or can be substituted with deuterium, F, Cl, -OH, protected hydroxyl, oxo (where applicable), NH, protected amino, NH(C 1~4 alkyl) or its protected derivatives, N(C 1~4 Alkyl ((C1~4 alkyl), C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6 and cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, —OH, oxo (where applicable), C 1~4 Alkyl, fluoro-substituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy and fluoro-substituted C 1~4 In some embodiments, the "optionally substituted" aryl, arylene, heteroaryl, or heteroarylene groups herein can each independently be unsubstituted, or can be substituted with deuterium, F, Cl, -OH, -CN, NH, protected amino, NH(C 1~4 alkyl) or its protected derivatives, 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, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6and cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, —OH, oxo (where applicable), C 1~4 Alkyl, fluoro-substituted C 1~4 Alkyl, C 1~4 Alkoxy and fluoro-substituted C 1~4 Optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0224] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0225] The term "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salts" includes both acid and base addition salts.

[0226] Examples of pharmaceutically acceptable acid addition salts include those with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as those with acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamenic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerin, glycerol ... Examples of suitable organic acids include, but are not limited to, phosphonic acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, 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, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0227] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared from the addition of an inorganic or organic base to a free acid compound. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In one embodiment, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. In one embodiment, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0228] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerization is known to those skilled in the art. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerizations.

[0229] The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0230] As used herein, and unless otherwise specified, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treat" and cognates contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0231] As used herein, and unless otherwise specified, the terms "prevent," "preventing," "prevention," and the like refer to reducing the likelihood of development of a disease or condition in a subject who does not have the development or redevelopment of the disease or condition or the recurrence of the disease or condition, but is at risk of or susceptible to it, reducing the likelihood of redevelopment of the disease or condition, or reducing the likelihood of recurrence of a previously controlled disease or condition.

[0232] The term "effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to effect the intended application, including, but not limited to, disease prevention or treatment. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a specific response in target cells and / or tissues. The specific dose will vary depending on the particular compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0233] As used herein, the singular forms "a," "an," and "the" include plural references unless it is expressly stated otherwise or it is clearly clear from the context that this is not intended.

[0234] As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the stated feature or component as referenced, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Consequently, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments.

[0235] As used herein, the term "or" should be interpreted as an inclusive "or," meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will occur only when combinations of elements, functions, steps, or acts exist in some manner that is inherently mutually exclusive.

[0236] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B; A or B:A alone; and B alone. Similarly, the term "and / or" when used in phrases such as "A, B, and / or C" is intended to encompass 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.

[0237] It should be noted that if there is a discrepancy between a depicted structure and the name associated with that structure, the depicted structure should be given more weight.

[0238] As used herein, and unless otherwise specified, the term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means 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.

[0239] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and should not be referenced in connection with interpreting the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined with features described under other headings or subheadings in various embodiments. Furthermore, not all features under a single heading or a single subheading may be used together in an embodiment. [Example]

[0240] The various starting materials, intermediates, and compounds of the embodiments herein may be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds may be performed using conventional methods such as melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Abbreviations used in the Examples section should be understood to have their ordinary meaning in the art unless specifically indicated otherwise or clearly contrary to the context. The Examples are merely illustrative and do not limit the claimed invention in any way.

[0241] Exemplary embodiments of steps for carrying out the synthesis of the products described herein are described in more detail below. Some of the examples discussed herein can be prepared by separation from the corresponding racemic mixture. As will be understood by those skilled in the art, the compounds described in the Examples section exist in racemic and / or stereoisomeric mixture form immediately prior to the chiral separation step, for example, by supercritical fluid chromatography (SFC), and bold bonds that are not wedge bonds are used in chemical structure diagrams to indicate relative stereochemistry. The enantiomeric excess ("ee") and / or diastereomeric excess ("de") reported for these examples are merely representative of the procedures exemplified herein and are not intended to be limiting; those skilled in the art will understand that such enantiomers with different ee and / or de, such as higher ee and / or higher de, can be obtained in light of the present disclosure.

[0242] In some illustrative examples, the synthesis of deuterated compounds is shown. To the extent applicable, it should be understood that the corresponding non-deuterated (i.e., natural abundance) compounds were prepared by the same methods, except using the corresponding non-deuterated starting materials or intermediates.

[0243] Synthesis of borate intermediates 4,4,7-trifluoro-3,3-dimethyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (Int-1) As a starting material, S-1.1 is obtained according to the procedure of Example 24 in the Examples section, which undergoes substitution, hydrolysis, and fluorination to provide S-1.4. Int-1 is then synthesized from S-1.4 by reduction and boronation. [ka]

[0244] 7-Fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-1,1-d2 (Int-2) Int-2 is synthesized starting from S-2.1 according to the synthetic route below: First, S-2.9 is obtained via a similar procedure to Example 24 in the Examples section. Then, Int-2 is obtained from S-2.9 by reduction and boronation via a similar procedure to Example 27 in the Examples section. [ka]

[0245] 4,7-Difluoro-3,3-dimethyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (Int-3) Int-3 is synthesized starting from S-1.3 according to the synthetic route below. [ka]

[0246] 4,7-Difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane] (Int-4) Int-4 is synthesized starting from S-2.9 according to the synthetic route below. [ka]

[0247] 4,4,7-Trifluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane] (Int-5) Int-5 is synthesized starting from S-4.2 according to the synthetic route below. [ka]

[0248] Example 1. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (1) [ka] To a solution of 2-amino-5-bromo-3-fluorobenzoic acid (1.1, 1.00 g, 4.27 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.32 g, 8.55 mmol) in portions at 0° C., and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was slowly quenched with sodium sulfate decahydrate (1.20 g) and diluted with ethyl acetate (20 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (2-amino-5-bromo-3-fluorophenyl)methanol (1.2, 750 mg, 80%) as a yellow solid. LC-MS (ESI): m / z 220.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.16(dd,J=10.3,2.2Hz,1H),7.07-7.04(m,1H),4.70(s,2H),4.28(brs,2H).

[0249] A mixture of (2-amino-5-bromo-3-fluorophenyl)methanol (1.2, 750 mg, 3.41 mmol) and manganese dioxide (5.93 g, 68.2 mmol) in dichloromethane (20 mL) was stirred at 25° C. for 12 hours. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (30 mL). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-amino-5-bromo-3-fluorobenzene-1-carbaldehyde (1.3, 560 mg, 75%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.87(d,J=2.0Hz,1H),7.51-7.45(m,1H),7.33(dd,J=10.6,2.2Hz,1H),6.20(brs,2H).

[0250] A mixture of 2-amino-5-bromo-3-fluorobenzene-1-carbaldehyde (1.3, 470 mg, 2.16 mmol), ethyl prop-2-inoate (254 mg, 2.59 mmol), and L-proline (74.5 mg, 0.65 mmol) in ethanol (20 mL) was stirred at 90° 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-8-fluoroquinoline-3-carboxylate (1.4, 620 mg, 96%) as a yellow solid. LC-MS (ESI): m / z 298.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.52(d,J=1.9Hz,1H),8.84-8.78(m,1H),7.98-7.94(m,1H),7.69(dd,J=9.5,1.9Hz,1H),4.53(q,J=7.1Hz,2H),1.50(t,J=7.2Hz,3H).

[0251] To a solution of ethyl 6-bromo-8-fluoroquinoline-3-carboxylate (1.4, 300 mg, 1.06 mmol) in tetrahydrofuran (10 mL), methylmagnesium bromide (1.68 mL, 5.03 mmol, 3 M in 2-methyltetrahydrofuran) was added dropwise at 0° C. under a nitrogen atmosphere, and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), 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 2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-ol (1.5, 270 mg, 94%) as a yellow solid. LC-MS (ESI): m / z 284.0 [M+H] + .

[0252] A mixture of 2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-ol (1.5, 200 mg, 0.70 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (215 mg, 0.84 mmol), potassium acetate (207 mg, 2.11 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (57.6 mg, 0.07 mmol) in dioxane (4 mL) was stirred at 90°C under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (1.6, 160 mg, 68%) as a yellow solid. LC-MS (ESI): m / z 332.2 [M+H] + .

[0253] A mixture of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (1.6, 80.0 mg, 0.24 mmol), 2,4,5-trichloropyrimidine (1.7, 40.0 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (25.2 mg, 0.02 mmol), and potassium carbonate (60.3 mg, 0.43 mmol) in dioxane (1 mL) and water (0.25 mL) was stirred at 90 °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 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-ol (1.8, 40.0 mg, 52%) as a yellow solid. LC-MS(ESI):m / z 352.0[M+H] + .

[0254] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-ol (1.8, 40.0 mg, 0.11 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 34.9 mg, 0.23 mmol), potassium fluoride (26.4 mg, 0.45 mmol), 18-crown-6 (30.0 mg, 0.11 mmol) and potassium carbonate (30.0 mg, 0.11 mmol) in dimethyl sulfoxide (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 (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (1, 16.2 mg, 33%) as a white solid. LC-MS (ESI): m / z 433.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.21(d,J=2.1Hz,1H),8.56(s,1H),8.49(s,1H),8.30(s,1H),7.87(d,J=11.6Hz,1H),7.57(d,J=8.1Hz,1H),5.51(s,1H),4.95(d,J=5.4Hz) ,1H),3.94-3.75(m,3H),3.57-3.47(m,1H),3.40-3.38(m,1H),3.08(t,J=10.4Hz,1H),2.04-1.92(m,1H),1.61(s,6H),1.58-1.46(m,1H).

[0255] Example 2. Synthesis of 4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carbonitrile (2) [ka] To a solution of (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 500 mg, 3.26 mmol) and N,N-diisopropylethylamine (841 mg, 6.51 mmol) in tert-butanol (10 mL) was added 2,4-dichloropyrimidine-5-carbonitrile (2.1, 849 mg, 4.88 mmol) at 25° C., and the mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC to give 4-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carbonitrile (2.2, 480 mg, 58%) as a yellow solid. LC-MS (ESI): m / z 255.1 [M+H] + .

[0256] A mixture of 2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (1.6, 28.6 mg, 0.08 mmol), 4-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carbonitrile (2.2, 20.0 mg, 0.08 mmol), tetrakis(triphenylphosphine)palladium (18.2 mg, 0.02 mmol), and potassium carbonate (21.7 mg, 0.16 mmol) in dioxane (1 mL) and water (0.25 mL) was stirred at 90° C. for 4 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give 4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carbonitrile (2, 5.50 mg, 16%) as a white solid. LC-MS (ESI): m / z 424.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.24(d,J=2.1Hz,1H),8.85(d,J=24.4Hz,1H),8.58(d,J=7.9Hz,1H),8.55 -8.40(m,2H),8.05-7.91(m,1H),5.55(d,J=3.0Hz,1H),5.06-4.96(m,1H) ,4.14-3.97(m,1H),3.90-3.79(m,2H),3.59-3.52(m,1H),3.43-3.40(m,1 H),3.16-3.03(m,1H),2.02-1.87(m,1H),1.61(s,6H),1.60-1.53(m,1H).

[0257] Example 3. Synthesis of (3S,4R)-4-((5-chloro-4-(4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (3) [ka] To a solution of methyl 6-bromoquinoline-4-carboxylate (3.1, 800 mg, 3.00 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise methylmagnesium bromide (4 mL, 3 M in diethyl ether) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl (20 mL) solution at 0 °C and extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(6-bromoquinolin-4-yl)propan-2-ol (3.2, 564 mg, 71%). LC-MS (ESI): m / z 266.0 [M+H] + .

[0258] To a mixture of 2-(6-bromoquinolin-4-yl)propan-2-ol (3.2, 230 mg, 0.87 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (209 mg, 0.82 mmol) in dioxane (4 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.0 mg, 0.04 mmol) and potassium acetate (255 mg, 2.60 mmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)propan-2-ol (3.3, 168 mg, 62%) as a yellow oil. LC-MS (ESI): m / z 314.2 [M+H] + .

[0259] To a mixture of 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)propan-2-ol (3.3, 168 mg, 0.54 mmol) and 2,4,5-trichloropyrimidine (1.7, 76.0 mg, 0.41 mmol) in dioxane / water (4 mL / 1 mL), tetrakis(triphenylphosphine)palladium(0) (48.0 mg, 0.04 mmol) and potassium carbonate (114 mg, 0.83 mmol) were added, and the mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL×2). 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 2-(6-(2,5-dichloropyrimidin-4-yl)quinolin-4-yl)propan-2-ol (3.4, 103 mg, 75%). LC-MS (ESI): m / z 334.0 [M+H] + .

[0260] To a mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)quinolin-4-yl)propan-2-ol (3.4, 50.0 mg, 0.15 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 69.0 mg, 0.45 mmol) in anhydrous dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (125 μL, 0.75 mmol) was added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (3, 10.6 mg, 17%) as a white solid. LC-MS(ESI):m / z 415.1[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.31(s,1H),8.89(d,J=4.6Hz,1H),8.45(s,1H),8.13(d,J=8.6Hz,1H),8.0 9-8.00(m,1H),7.59(d,J=4.7Hz,1H),7.49(d,J=6.5Hz,1H),5.60(s,1H),4. 93(d,J=5.3Hz,1H),3.88-3.76(m,3H),3.56-3.46(m,1H),3.31-3.29(m,1H) ,3.02(t,J=10.4Hz,1H),2.05-1.91(m,1H),1.72(s,6H),1.57-1.43(m,1H).

[0261] Example 4. Synthesis of (3S,4R)-4-((5-chloro-4-(4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (4) [ka] To a solution of 5-bromoindoline-2,3-dione (4.1, 2.00 g, 8.80 mmol) in acetone / water (10 mL / 8 mL) was added potassium hydroxide (4.00 g, 71.0 mmol), and the mixture was stirred at 60 °C for 8 h. The reaction mixture was cooled to room temperature and adjusted to pH 5-6 with 10% HCl, followed by filtration. The filter cake was washed with hot water (10 mL) and dried in vacuo to give 6-bromo-2-methylquinoline-4-carboxylic acid (4.2, 1.76 g, 75%). LC-MS (ESI): m / z 266.0 [M+H] + .

[0262] To a solution of 6-bromo-2-methylquinoline-4-carboxylic acid (4.2, 1.76 g, 6.63 mmol) in anhydrous methanol (25 mL) was added thionyl chloride (963 uL, 13.2 mmol) dropwise at 0 °C, and the mixture was then stirred at 60 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give methyl 6-bromo-2-methylquinoline-4-carboxylate (4.3, 1.90 g, crude). LC-MS (ESI): m / z 280.0 [M+H] +.

[0263] To a solution of methyl 6-bromo-2-methylquinoline-4-carboxylate (4.3, 1.90 g, crude) in anhydrous tetrahydrofuran (20 mL) was added methylmagnesium bromide (8.84 mL, 26.5 mmol, 3 M in diethyl ether) under nitrogen atmosphere at 0 °C, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl (20 mL) solution at 0 °C and extracted with ethyl acetate (15 mL × 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(6-bromo-2-methylquinolin-4-yl)propan-2-ol (4.4, 1.07 g). LC-MS (ESI): m / z 280.0 [M+H] + .

[0264] To a mixture of 2-(6-bromo-2-methylquinolin-4-yl)propan-2-ol (4.4, 600 mg, 2.15 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (655 mg, 2.58 mmol) in dioxane (10 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (88.0 mg, 0.11 mmol) and potassium acetate (632 mg, 6.45 mmol). The mixture was stirred at 90°C under a nitrogen atmosphere for 2 hours. The resulting mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (10 mL), and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)propan-2-ol (4.5, 583 mg, 83%). LC-MS (ESI): m / z 328.2 [M+H] + .

[0265] To a mixture of 2-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)propan-2-ol (4.5, 425 mg, 1.30 mmol) and 4,5-dichloro-2-(methylthio)pyrimidine (4.6, 195 mg, 1.00 mmol) in dioxane / water (4 mL / 1 mL) was added tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.10 mmol) and potassium carbonate (276 mg, 2.00 mmol). The mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layer was 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 2-(6-(5-chloro-2-(methylthio)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (4.7, 237 mg, 66%). LC-MS (ESI): m / z 360.1 [M+H] + .

[0266] To a solution of 2-(6-(5-chloro-2-(methylthio)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (4.7, 237 mg, 0.66 mmol) in dichloromethane (5 mL) was added 3-chloroperbenzoic acid (137 mg, 0.79 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with dichloromethane (30 mL), washed with saturated sodium carbonate solution (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 2-(6-(5-chloro-2-(methylsulfinyl)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (4.8, 143 mg, crude) as a brown oil. LC-MS (ESI): m / z 376.1 [M+H] + .

[0267] To a mixture of 2-(6-(5-chloro-2-(methylsulfinyl)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (4.8, 60.0 mg, crude) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 74.0 mg, 0.48 mmol) in anhydrous dimethyl sulfoxide (2 mL) was added N,N-diisopropylethylamine (130 uL, 0.80 mmol), and the resulting mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (4, 5.40 mg, 8%) as a white solid. LC-MS (ESI): m / z 429.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.23(s,1H),8.44(s,1H),8.01(d,J=6.5Hz,2H),7.50-7.44(m,2H),5.54(s,1H),4.93(d,J=5.3Hz,1H),3.86-3.77(m,3H),3 .55-3.48(m,1H),3.34-3.32(m,1H),3.02(t,J=10.4Hz,1H),2.67(s,3H),2.04-1.94(m,1H),1.71(s,6H),1.56-1.43(m,1H).

[0268] Example 5. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (5) [ka] A mixture of 2-amino-5-bromo-3-fluorobenzene-1-carbaldehyde (1.3, 400 mg, 1.83 mmol), ethyl but-2-inoate (617 mg, 5.51 mmol), and L-proline (127 mg, 1.10 mmol) in ethyl alcohol (10 mL) was stirred at 90° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl 6-bromo-8-fluoro-2-methylquinoline-3-carboxylate (5.1, 544 mg, 95%) as a yellow solid. LC-MS (ESI): m / z 312.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.67(s,1H),7.88(s,1H),7.63(dd,J=9.8,2.0Hz,1H),4.49(q,J=7.1Hz,2H),3.04(s,3H),1.49(t,J=7.1Hz,3H).

[0269] To a solution of ethyl 6-bromo-8-fluoro-2-methylquinoline-3-carboxylate (5.1, 600 mg, 1.92 mmol) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (3.20 mL, 9.61 mmol, 3 M in 2-methyltetrahydrofuran) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), diluted with water (20 mL), and extracted with ethyl acetate (15 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 2-(6-bromo-8-fluoro-2-methylquinolin-3-yl)propan-2-ol (5.2, 360 mg, 63%) as a yellow solid. LC-MS (ESI): m / z 298.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.19(s,1H),7.78(s,1H),7.51(dd,J=9.8,2.0Hz,1H),3.04(s,3H),1.81(s,6H).

[0270] A mixture of 2-(6-bromo-8-fluoro-2-methylquinolin-3-yl)propan-2-ol (5.2, 340 mg, 1.14 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (347 mg, 1.37 mmol), potassium acetate (336 mg, 3.42 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (93.0 mg, 0.11 mmol) in dioxane (10 mL) was stirred at 90° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (5.3, 360 mg, 91%) as a yellow solid. LC-MS (ESI): m / z 346.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.27(s,1H),8.11(s,1H),7.72(d,J=11.1,1H),3.08(s,3H),1.80(s,6H),1.42(s,12H).

[0271] A mixture of 2-(8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (5.3, 122 mg, 0.35 mmol), 2,4,5-trichloropyrimidine (1.7, 59.0 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (37.2 mg, 0.03 mmol) and potassium carbonate (88.9 mg, 0.64 mmol) in dioxane / water (1 mL / 0.25 mL) was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2-methylquinolin-3-yl)propan-2-ol (5.4, 100 mg, 85%) as a yellow solid. LC-MS (ESI): m / z 366.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.75(s,1H),8.39(s,1H),8.30(s,1H),7.97(d,J=11.3Hz,1H),3.11(s,3H),1.84(s,6H).

[0272] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2-methylquinolin-3-yl)propan-2-ol (5.4, 50.0 mg, 0.14 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 41.9 mg, 0.27 mmol), potassium fluoride (31.7 mg, 0.55 mmol), 18-crown-6 (36.1 mg, 0.14 mmol) and potassium carbonate (18.9 mg, 0.14 mmol) in dimethyl sulfoxide (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 (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (5, 21.1 mg, 33%) as a white solid. LC-MS (ESI): m / z 447.2 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ 8.50(s,1H),8.48(s,1H),8.27(s,1H),7.83(d,J=11.7Hz,1H),7.60-7.48(m,1H),5.35(s,1H),4.94(d,J=5.4Hz,1H),3.94-3.78 (m,3H),3.56-3.47(m,1H),3.40-3.34(m,1H),3.12-3.03(m,1H),2.98(s,3H),2.04-1.91(m,1H),1.67(s,6H),1.58-1.48(m,1H).

[0273] Example 6. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (6) [ka] To a solution of ethyl 6-bromoquinoline-3-carboxylate (6.1, 400 mg, 1.43 mmol) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (2.38 mL, 7.14 mmol, 3 M in 2-methyltetrahydrofuran) under a nitrogen atmosphere at 0° C., and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), diluted with water (20 mL), and extracted with ethyl acetate (15 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 2-(6-bromoquinolin-3-yl)propan-2-ol (6.2, 360 mg, 1.35 mmol, 95%) as a yellow oil. LC-MS (ESI): m / z 266.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.08(d,J=2.2Hz,1H),8.19(d,J=2.2Hz,1H),8.02(d,J=2.2Hz,1H),8.00(d,J=9.0Hz,1H),7.79(dd,J=9.0,2.2Hz,1H),1.74(s,6H).

[0274] A mixture of 2-(6-bromoquinolin-3-yl)propan-2-ol (6.2, 360 mg, 1.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (412 mg, 1.62 mmol), potassium acetate (398 mg, 4.06 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (111 mg, 0.13 mmol) in dioxane (10 mL) was stirred at 90° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (6.3, 310 mg, 73%) as a yellow oil. LC-MS (ESI): m / z 314.2 [M+H] + .

[0275] A mixture of 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (6.3, 310 mg, 0.99 mmol), 2,4,5-trichloropyrimidine (1.7, 150 mg, 0.82 mmol), tetrakis(triphenylphosphine)palladium (94.5 mg, 0.08 mmol), and potassium carbonate (226 mg, 1.64 mmol) in dioxane (0.8 mL) and water (0.2 mL) was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(6-(2,5-dichloropyrimidin-4-yl)quinolin-3-yl)propan-2-ol (6.4, 220 mg, 0.66 mmol, 88%) as a yellow oil. LC-MS(ESI):m / z 334.1[M+H] + .

[0276] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)quinolin-3-yl)propan-2-ol (6.4, 50.0 mg, 0.14 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 41.9 mg, 0.27 mmol), potassium fluoride (31.7 mg, 0.54 mmol), 18-crown-6 (36.1 mg, 0.14 mmol) and potassium carbonate (18.9 mg, 0.14 mmol) in dimethyl sulfoxide (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 (3S,4R)-4-((5-chloro-4-(3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (6, 16.4 mg, 26%) as a white solid. LC-MS (ESI): m / z 415.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.16(d,J=2.3Hz,1H),8.48(s,1H),8.47(d,J=2.2Hz,1H),8.40(s,1H),8. 12(d,J=8.7Hz,1H),8.03(d,J=8.8Hz,1H),7.53(s,1H),5.43(s,1H),4.94( d,J=5.4Hz,1H),3.93-3.76(m,3H),3.59-3.46(m,1H),3.40-3.35(m,1H), 3.07(t,J=10.3Hz,1H),2.02-1.92(m,1H),1.60(s,6H),1.57-1.47(m,1H).

[0277] Example 7. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (7) [ka] To a solution of 2-amino-3-fluorobenzene-1-carbonitrile (7.1, 1.00 g, 7.35 mmol) in dichloromethane (20 mL) was added N-bromosuccinimide (1.37 g, 7.71 mmol), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-amino-5-bromo-3-fluorobenzene-1-carbonitrile (7.2, 1.40 g, 89%) as a purple solid. LC-MS (ESI): m / z 215.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.40-7.31(m,2H),4.57(brs,2H).

[0278] To a solution of 2-amino-5-bromo-3-fluorobenzene-1-carbonitrile (7.2, 400 mg, 1.86 mmol) in tetrahydrofuran (5 mL), methylmagnesium bromide (3.10 mL, 9.30 mmol, 3 M in 2-methyltetrahydrofuran) was added dropwise at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), diluted with water (20 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 1-(2-amino-5-bromo-3-fluorophenyl)ethan-1-one (7.3, 330 mg, 76%) as a yellow solid. LC-MS (ESI): m / z 232.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.78(s,1H),7.57(dd,J=11.0,2.2Hz,1H),7.21(s,2H),2.57(s,3H).

[0279] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)ethan-1-one (7.3, 300 mg, 1.29 mmol), ethyl prop-2-inoate (1.02 g, 10.34 mmol), and copper divalent bis(trifluoromethanesulfonate) (187 mg, 0.52 mmol) in ethanol (4 mL) was stirred at 90 °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-8-fluoro-4-methylquinoline-3-carboxylate (7.4, 120 mg, 30%) as a yellow solid. LC-MS (ESI): m / z 312.0 [M+H] + .

[0280] To a solution of ethyl 6-bromo-8-fluoro-4-methylquinoline-3-carboxylate (7.4, 300 mg, 1.07 mmol) in tetrahydrofuran (5 mL) was added dropwise methylmagnesium bromide (1.44 mL, 4.33 mmol, 3 M in 2-methyltetrahydrofuran) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), diluted with water (20 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 2-(6-bromo-8-fluoro-4-methylquinolin-3-yl)propan-2-ol (7.5, 70 mg, 27%) as a yellow oil. LC-MS (ESI): m / z 298.0 [M+H] + .

[0281] A mixture of 2-(6-bromo-8-fluoro-4-methylquinolin-3-yl)propan-2-ol (7.5, 70.0 mg, 0.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (71.6 mg, 0.28 mmol), potassium acetate (69 mg, 0.704 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (19.2 mg, 0.02 mmol) in dioxane (10 mL) was stirred at 90°C under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(8-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (7.6, 40.0 mg, 49%) as a yellow oil. LC-MS (ESI): m / z 346.2 [M+H] + .

[0282] A mixture of 2-(8-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (7.6, 37.6 mg, 0.11 mmol), 2,4,5-trichloropyrimidine (1.7, 20.0 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium (12.6 mg, 0.01 mmol) and potassium carbonate (30.1 mg, 0.22 mmol) in dioxane (1 mL) and water (0.2 mL) was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-methylquinolin-3-yl)propan-2-ol (7.7, 30.0 mg, 75%) as a yellow oil. LC-MS (ESI): m / z 366.1 [M+H] + .

[0283] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-methylquinolin-3-yl)propan-2-ol (7.7, 30.0 mg, 0.08 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 19.0 mg, 0.12 mmol), potassium fluoride (19.0 mg, 0.33 mmol), 18-crown-6 (21.7 mg, 0.08 mmol) and potassium carbonate (11.3 mg, 0.08 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120 °C for 2 h. The reaction mixture was filtered and the filtrate was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (7, 5.50 mg, 15%) as a white solid. LC-MS (ESI): m / z 447.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.14(s,1H),8.56-8.38(m,2H),7.88(d,J=11.1Hz,1H),7.58(s,1H),5.43(s,1H),4.96(d,J=5.4Hz,1H),3.95-3.77(m,3H),3 .61-3.47(m,1H),3.44-3.37(m,1H),3.07(t,J=10.4Hz,1H),2.98(s,3H),2.07-1.87(m,1H),1.70(s,6H),1.61-1.46(m,1H).

[0284] Example 8. Synthesis of (3S,4R)-4-((5-chloro-4-(7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (8) [ka] To a mixture of 1-(tert-butyl)3-ethyl 4-oxopiperidine-1,3-dicarboxylate (8.1, 15.0 g, 55.3 mmol) and N,N-diisopropylethylamine (21.4 g, 166 mmol, 28.9 mL) in dichloromethane (400 mL) was added a solution of trifluoromethanesulfonic anhydride (18.7 g, 66.4 mmol, 11 mL) in dichloromethane (50 mL) dropwise at 0 °C, and the resulting mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (100 mL × 3). The combined 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 1-(tert-butyl)3-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (8.2, 17.0 g, 69%) as a yellow oil. LC-MS (ESI): m / z 404.1 [M+H] + .

[0285] To a solution of 1-(tert-butyl)3-ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (8.2, 17.0 g, 42.1 mmol) in dioxane (300 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (11.8 g, 46.4 mmol), potassium acetate (12.4 g, 126 mmol) and Pd(dppf)Cl 2·CHCl (3.44 g, 4.21 mmol) was added, and the mixture was stirred at 110° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×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-(tert-butyl)3-ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (8.3, 11.0 g, 58%) as a yellow oil. LC-MS (ESI): m / z 382.2 [M+H] + .

[0286] To a solution of 4-bromo-2-fluoro-6-iodoaniline (9.11 g, 28.9 mmol) and 1-(tert-butyl)3-ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-pyridine-1,3(2H)-dicarboxylate (8.3, 11.0 g, 28.9 mmol) in dioxane (150 mL) and water (15 mL), sodium carbonate (9.17 g, 86.6 mmol) and Pd(dppf)Cl (1.06 g, 1.44 mmol) were added, and the resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl alcohol (60 mL) at 25° C. for 1 hour to give tert-butyl 9-bromo-7-fluoro-5-oxo-1,4,5,6-tetrahydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.4, 4.50 g, 33%) as a white solid. LC-MS (ESI): m / z 397.1 [M+H] + . 1 H NMR(400MHz CDCl3)δ 9.96-9.50(m,1H),7.56(s,1H),7.40(d,J=12.5Hz,1H),4.48(s,2H),3.85-3.75(m,2H),2.89(s,2H),1.49(s,9H).

[0287] To a solution of tert-butyl 9-bromo-7-fluoro-5-oxo-1,4,5,6-tetrahydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.4, 4.50 g, 11.3 mmol) in dioxane (55 mL) were added phosphorus oxychloride (8.68 g, 56.6 mmol) and N,N-diisopropylethylamine (7.32 g, 56.6 mmol), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with tetrahydrofuran (4 mL) and concentrated HCl (40 mL, 12 M). The resulting mixture was then stirred at 100° C. for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was triturated with saturated sodium bicarbonate solution (50 mL). The filter cake was dried in vacuo, diluted with phosphorus oxychloride (20 mL), and subsequently stirred at 100° C. for an additional 2 hours. The mixture was concentrated under reduced pressure and triturated with acetonitrile / methyl tert-butyl ether = 10 / 1 (50 mL) at 25 ° C. for 1 hour. The filter cake was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (20 mL) at 25 ° C. for 1 hour, and the filter cake was dried in vacuo to give 9-bromo-5-chloro-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine (8.5, 2.50 g, 56%) as a yellow solid. LC-MS (ESI): m / z 315.0 [M+H] + .

[0288] To a solution of 9-bromo-5-chloro-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine (8.5, 1.00 g, 3.17 mmol) in trifluoroacetic acid (10 mL), zinc powder (2.07 g, 31.7 mmol) was added in small portions, and the mixture was stirred at 40 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and dichloromethane (30 mL), adjusted to pH 11 with sodium hydroxide (solid), and then filtered. The filtrate was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-bromo-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine (8.6, 750 mg, crude) as a yellow solid. LC-MS(ESI):m / z 281.1[M+H] + .

[0289] To a solution of 9-bromo-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine (8.6, 3.00 g, crude) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (4.14 g, 32.0 mmol) and di-tert-butyl dicarbonate (2.79 g, 12.8 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL × 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 and further purified by preparative TLC to give tert-butyl 9-bromo-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.7, 0.50 g) as a pale yellow solid. LC-MS(ESI):m / z 381.1[M+H] + .

[0290] To a solution of tert-butyl 9-bromo-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.7, 0.50 g, 1.31 mmol) in dioxane (1 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (366 mg, 1.44 mmol), potassium acetate (386 mg, 3.93 mmol), and Pd(dppf)Cl (96.0 mg, 131 mmol) were added, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 tert-butyl 7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.8, 0.35 g, 58%) as a white solid. LC-MS (ESI): m / z 429.0 [M+H] + .

[0291] To a mixture of tert-butyl 7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.8, 100 mg, 0.23 mmol) and 2,4,5-trichloropyrimidine (1.7, 26.8 μL, 0.23 mmol) in dioxane (1 mL) and water (0.2 mL), Pd(PPh3)4 (54.0 mg, 0.05 mmol) and potassium carbonate (64.5 mg, 0.47 mmol) were added, and the reaction was stirred at 90 °C under a nitrogen atmosphere for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). 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 tert-butyl 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.9, 72.0 mg, 68%) as a white solid. LC-MS (ESI): m / z 449.1 [M+H] + .

[0292] A mixture of tert-butyl 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.9, 110 mg, 0.25 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 37.6 mg, 0.25 mmol), potassium carbonate (33.8 mg, 0.25 mmol), potassium fluoride (42.7 mg, 0.73 mmol), and 18-crown-6 (6.47 mg, 0.02 mmol) in dimethyl sulfoxide (1 mL) was stirred at 120 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was 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 tert-butyl 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.10, 100 mg, 77%) as a white solid. LC-MS (ESI): m / z 530.2 [M+H] + .

[0293] To a solution of tert-butyl 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.10, 100 mg, 0.19 mmol) in methanol (1 mL) was added hydrochloric acid (1 mL, 4 M in dioxane), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7 with saturated sodium bicarbonate solution (5 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (8, 52.0 mg, 64%) as a white solid. LC-MS (ESI): m / z 430.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.76(s,1H),8.47(s,1H),8.21(s,1H),7.87(d,J=11.4Hz,1H),7.64-7.49(m,1H),4.16(s,2H),3.83-3.79(m,3H),3. 53-3.50(m,1H),3.37-3.30(m,1H),3.24-3.11(m,4H),3.05(t,J=10.4Hz,1H),2.02-1.89(m,1H),1.58-1.44(m,1H).

[0294] Example 9. Synthesis of (3S,4R)-4-((5-chloro-4-(7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (9) [ka] A mixture of 1-(tert-butyl)4-ethyl 3-oxopiperidine-1,4-dicarboxylate (9.1, 25.0 g, 92.2 mmol) and N,N-diisopropylethylamine (35.7 g, 276 mmol, 48.2 mL) in dichloromethane (600 mL) was added dropwise to a solution of trifluoromethanesulfonic anhydride (31.2 g, 111 mmol, 18.2 mL) in dichloromethane (70 mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (200 mL×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-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (9.2, 35.0 g, 85%) as a yellow oil. LC-MS (ESI): m / z 304.1 [M-100+H] + .

[0295] To a solution of 1-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (9.2 g, 35.0 g, 86.8 mmol) in dioxane (500 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (24.2 g, 95.5 mmol), potassium acetate (25.6 g, 260 mmol), and Pd(dppf)Cl.CHCl (7.09 g, 8.68 mmol), and the mixture was stirred at 110 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (700 mL) and extracted with ethyl acetate (300 mL × 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-(tert-butyl)4-ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (9.3, 30.0 g, 77%) as a yellow oil. LC-MS (ESI): m / z 282.2 [M-100+H] + .

[0296] To a mixture of 4-bromo-2-fluoro-6-iodoaniline (8.29 g, 26.2 mmol) and 1-(tert-butyl)4-ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (9.3, 10.0 g, 26.2 mmol) in dioxane (100 mL) and water (10 mL), sodium carbonate (8.34 g, 78.7 mmol) and Pd(dppf)Cl (960 mg, 1.31 mmol) were added under a nitrogen atmosphere, and the resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl alcohol (50 mL) at 25° C. for 1 hour, followed by filtration. The filter cake was dried in vacuo to give tert-butyl 9-bromo-7-fluoro-5-oxo-3,4,5,6-tetrahydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.4, 8.00 g, 65%) as an off-white solid. LC-MS (ESI): m / z 397.0 [M+H] + .

[0297] A mixture of tert-butyl 9-bromo-7-fluoro-5-oxo-3,4,5,6-tetrahydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.4, 8.00 g, 20.1 mmol) and hydrochloric acid (100 mL, 4 M in dioxane) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution (100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 9-bromo-7-fluoro-2,3,4,6-tetrahydrobenzo[c][2,6]naphthyridin-5(1H)-one (9.5, 5.00 g, crude) as a yellow solid. LC-MS (ESI): m / z 297.0 [M+H] + .

[0298] A mixture of 9-bromo-7-fluoro-2,3,4,6-tetrahydrobenzo[c][2,6]naphthyridin-5(1H)-one (9.5, 5.00 g, crude) and phosphorus oxychloride (50 mL) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with acetonitrile (10 mL) and then triturated with methyl tert-butyl ether (100 mL) at 25° C. for 30 minutes. The resulting mixture was filtered, and the filter cake was dried in vacuo to obtain a residue. The residue was diluted with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane / methanol = 10 / 1 (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-bromo-5-chloro-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (9.6, 2.70 g, crude) as a yellow solid. LC-MS (ESI): m / z 314.9 [M+H] + .

[0299] To a solution of 9-bromo-5-chloro-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (9.6, 50.0 mg, crude) in trifluoroacetic acid (1 mL) was added zinc powder (73.0 mg, 1.11 mmol), and the mixture was stirred at 40 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and dichloromethane (100 mL), and then adjusted to pH 11 with 10 M sodium hydroxide solution. The resulting mixture was filtered, and the filtrate was extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 9-bromo-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (9.7, 1.60 g, crude) as a yellow solid. LC-MS (ESI): m / z 281.1 [M+H] + .

[0300] To a solution of 9-bromo-7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (9.7, 1.60 g, crude) in dichloromethane (20 mL) were added di-tert-butyl dicarbonate (1.49 g, 6.83 mmol, 1.57 mL) and N,N-diisopropylethylamine (2.21 g, 17.1 mmol, 2.97 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and further purified by preparative TLC to give tert-butyl 9-bromo-7-fluoro-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.8, 0.45 g) as a white solid. LC-MS (ESI): m / z 381.0 [M+H] + .

[0301] To a solution of tert-butyl 9-bromo-7-fluoro-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.8, 0.44 g, 1.15 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (322 mg, 1.27 mmol), potassium acetate (340 mg, 3.46 mmol), and Pd(dppf)Cl (84.5 mg, 115 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined 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 tert-butyl 7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.9, 390 mg, 63%) as a yellow solid. LC-MS (ESI): m / z 429.2 [M+H]+.

[0302] To a mixture of tert-butyl 7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.9, 100 mg, 0.29 mmol) and 2,4,5-trichloropyrimidine (1.7, 33 μL, 0.29 mmol) in water (0.2 mL) and dioxane (1 mL) was added Pd(PPh3)4 (67.0 mg, 0.06 mmol) and potassium carbonate (120 mg, 0.87 mmol). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 4 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined 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 tert-butyl 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.10, 130 mg, crude) as a yellow solid. LC-MS (ESI): m / z 449.3 [M+H] + .

[0303] A mixture of tert-butyl 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.10, 130 mg, crude), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 44.0 mg, 0.29 mmol), potassium carbonate (40.0 mg, 0.29 mmol), potassium fluoride (50.0 mg, 0.87 mmol), and 18-crown-6 (8 mg, 0.03 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined 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 tert-butyl 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.11, 150 mg, crude) as a white solid. LC-MS (ESI): m / z 530.2 [M+H] + .

[0304] To a solution of tert-butyl 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-3,4-dihydrobenzo[c][2,6]naphthyridine-2(1H)-carboxylate (9.11, 150 mg, crude) in methanol (2 mL) was added hydrochloric acid (1 mL, 4 M in dioxane), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated sodium bicarbonate solution (5 mL), and subsequently extracted with ethyl acetate (20 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(7-fluoro-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (9, 19.2 mg) as a white solid. LC-MS (ESI): m / z 430.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.75(s,1H),8.47(s,1H),8.16(s,1H),7.84(d,J=11.5Hz,1H),7.56(s,1H),4.92(d,J=5.4Hz,1H),4.29(s,2H),3.89-3.76 (m,3H),3.54-3.47(m,1H),3.38-3.35(m,1H),3.08-3.00(m,3H),2.92-2.84(m,2H),2.02-1.88(m,1H),1.58-1.44(m,1H).

[0305] Example 10. Synthesis of (3S,4R)-4-((5-chloro-4-(2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (10) [ka] A mixture of 4-bromo-2-methyl-1H-imidazole-5-carbaldehyde (10.1, 1.00 g, 5.29 mmol), 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.34 g, 5.29 mmol), potassium carbonate (2.19 g, 15.9 mmol), and Pd(dppf)Cl (387 mg, 529 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-chloro-2-methyl-3H-imidazo[4,5-c]quinoline (10.2, 680 mg, 54%) as a yellow solid. LC-MS (ESI): m / z 218.1 [M+H] + .

[0306] To a solution of 8-chloro-2-methyl-3H-imidazo[4,5-c]quinoline (10.2, 580 mg, 2.66 mmol) in dimethyl sulfoxide (5 mL) were added potassium carbonate (368 mg, 2.66 mmol) and 1-(chloromethyl)-4-methoxybenzene (417 mg, 2.66 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinoline (10.3, 510 mg, 57%) as a white solid. LC-MS(ESI):m / z 338.1[M+H] + .

[0307] A mixture of 8-chloro-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinoline (10.3, 510 mg, 1.51 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (958 mg, 3.77 mmol), tris(dibenzylideneacetone)dipalladium (138 mg, 151 µmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (124 mg, 302 µmol), and potassium acetate (445 mg, 4.53 mmol) in dioxane (5 mL) was stirred at 100° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)boronic acid (10.4, 315 mg, 60%) as a white solid. LC-MS (ESI): m / z 348.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.16(s,1H),8.96(s,1H),8.27(s,2H),8.00(s,2H),7.20(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),5.62(s,2H),3.70(s,3H),2.69(s,3H).

[0308] To a mixture of (3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)boronic acid (10.4, 100 mg, 0.23 mmol) and 2,4,5-trichloropyrimidine (1.7, 27 μL, 0.23 mmol) in dioxane (1 mL) and water (0.2 mL), Pd(PPh3)4 (54 mg, 0.05 mmol) and potassium carbonate (64.0 mg, 0.46 mmol) were added, and the mixture was stirred at 90 °C for 4 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinoline (10.5, 100 mg, crude) as a yellow solid. LC-MS (ESI): m / z 450.2 [M+H] + .

[0309] A mixture of 8-(2,5-dichloropyrimidin-4-yl)-3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinoline (10.5, 100 mg, crude), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 38.0 mg, 0.24 mmol), potassium carbonate (31.0 mg, 0.22 mmol), potassium fluoride (39.0 mg, 0.66 mmol), and 18-crown-6 (6.00 mg, 0.02 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120° C. for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (3S,4R)-4-((5-chloro-4-(3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (10.6, 100 mg, crude) as a yellow solid. LC-MS (ESI): m / z 531.2 [M+H] + .

[0310] A mixture of (3S,4R)-4-((5-chloro-4-(3-(4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (10.6, 100 mg, crude) and trifluoroacetic acid (1 mL) was stirred at 100° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (15 mL) and adjusted to pH 8 with saturated sodium carbonate solution, followed by extraction with dichloromethane (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (10, 27.1 mg) as a white solid. LC-MS (ESI): m / z 411.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.13(s,1H),8.75(s,1H),8.45(s,1H),8.16(d,J=8.5Hz,1H),7.96(d,J=8.7Hz,1H),7.48(s,1H),4.93(s,1H),3 .88-3.75(m,3H),3.52-3.45(m,2H),3.03(t,J=10.4Hz,1H),2.63(s,3H),2.02-1.90(m,1H),1.57-1.41(m,1H).

[0311] Example 11. Synthesis of (3S,4R)-4-((5-chloro-4-(1-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (11) [ka] To a mixture of ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate (11.1, 7.85 g, 33.7 mmol) in tetrahydrofuran (80 mL) was added lithium aluminum hydride (1.28 g, 33.7 mmol) in portions at 0° C., and the mixture was then stirred at 0° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was slowly quenched with saturated sodium chloride solution (6 mL) at 0° C. and stirred for 10 minutes. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-bromo-5-methyl-1H-pyrazole-3-carbaldehyde (11.2, 1.80 g, 28%) as a white solid. LC-MS (ESI): m / z 189.1 [M+H] + .

[0312] To a mixture of 4-bromo-5-methyl-1H-pyrazole-3-carbaldehyde (11.2 g, 0.90 g, 4.76 mmol), 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.21 g, 4.76 mmol), and cesium carbonate (4.65 g, 14.3 mmol) in N,N-dimethylacetamide (70 mL) and water (15 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (389 mg, 476 mmol), and the resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL x 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 8-chloro-1-methyl-2H-pyrazolo[3,4-c]quinoline (11.3, 470 mg, 45%) as a yellow solid. LC-MS (ESI): m / z 218.2 [M+H] + .

[0313] To a mixture of 8-chloro-1-methyl-2H-pyrazolo[3,4-c]quinoline (11.3, 455 mg, 2.09 mmol) in dichloromethane (10 mL) were added 3,4-dihydro-2H-pyran (352 mg, 4.18 mmol) and p-toluenesulfonic acid monohydrate (79.5 mg, 418 μmol), and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with dichloromethane (15 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 8-chloro-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinoline (11.4, 530 mg, 84%) as a yellow solid. LC-MS(ESI):m / z 302.2[M+H] + .

[0314] To a mixture of 8-chloro-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinoline (11.4, 510 mg, 1.69 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (858 mg, 3.38 mmol), potassium acetate (498 mg, 5.07 mmol), and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (161 mg, 338 mmol) in tetrahydrofuran (10 mL) was added palladium(II) acetate (38.0 mg, 169 mmol), and the resulting mixture was stirred at 70°C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative HPLC to give (1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinolin-8-yl)boronic acid (11.5, 169 mg, 29%) as a white solid. LC-MS (ESI): m / z 312.1 [M+H] + .

[0315] To a mixture of (1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinolin-8-yl)boronic acid (11.5, 80.0 mg, 0.26 mmol) and 2,4,5-trichloropyrimidine (1.7, 30 μL, 0.26 mmol) in water (0.2 mL) and dioxane (1 mL), tetrakis(triphenylphosphine)palladium(0) (59.0 mg, 0.05 mmol) and potassium carbonate (107 mg, 0.77 mmol) were added, and the resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinoline (11.6, 100 mg, crude) as a white solid. LC-MS (ESI): m / z 414.1 [M+H] + .

[0316] A mixture of 8-(2,5-dichloropyrimidin-4-yl)-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinoline (11.6, 100 mg, crude), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 37.0 mg, 0.24 mmol), potassium carbonate (34.0 mg, 0.24 mmol), potassium fluoride (42.0 mg, 0.72 mmol), and 18-crown-6 (6.40 mg, 0.02 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120° C. for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (3S,4R)-4-((5-chloro-4-(1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (11.7, 119 mg, crude) as a white solid. LC-MS (ESI): m / z 495.2 [M+H]+ .

[0317] A mixture of (3S,4R)-4-((5-chloro-4-(1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[3,4-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (11.7, 119 mg, crude) and hydrogen chloride (2 mL, 4 M in methanol) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (15 mL) and adjusted to pH 8 with saturated sodium carbonate solution, followed by extraction with dichloromethane (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(1-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (11, 39.9 mg) as a white solid. LC-MS (ESI): m / z 411.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.72(s,1H),9.28(s,1H),8.98-8.60(m,1H),8.47(s,1H),8.32-8.16(m,1H),8.15-7.83(m,1H),7.52(s,1H),4.94(d,J=5.3Hz,1H) ,3.94-3.76(m,3H),3.58-3.48(m,1H),3.39-3.33(m,1H),3.05(t,J=10.4Hz,1H),2.85(s,3H),2.10-1.88(m,1H),1.62-1.43(m,1H).

[0318] Example 12. Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol (12) [ka] To a mixture of 4-bromo-5-chloro-2-fluoropyridine (12.1, 58.1 mg, 0.28 mmol) in dioxane (4 mL) and water (1 mL) was added 2-(4-fluoro-1-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)propan-2-ol (12.2, 100 mg, 0.27 mmol), Pd(PPh) (31.9 mg, 0.03 mmol), and potassium carbonate (76.3 mg, 0.55 mmol), and the resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 3 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with brine (15 mL × 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(6-(5-chloro-2-fluoropyridin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol (12.3, 98.0 mg, 97%) as a white solid. LC-MS (ESI): m / z 366.1 [M+H] + .

[0319] To a solution of 2-(6-(5-chloro-2-fluoropyridin-4-yl)-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol (12.3, 98.0 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL) were added cesium carbonate (180 mg, 0.55 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 85.0 mg, 0.55 mmol), and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (20 mL×3). The combined organic layer was washed with brine (10 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol (12, 15.0 mg, 12%) as a white solid. LC-MS (ESI): m / z 463.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.06(s,1H),7.56(s,1H),7.05(d,J=8.0Hz,1H),6.80(d,J=8.0Hz,1H),6.64(s,1H),5.79(s,1H),5.76-5.71(m,1H),5.03(d,J= 8.0Hz,1H),3.83-3.77(m,3H),3.54-3.43(m,2H),3.08(t,J=12.0Hz,1H),2.07-1.96(m,1H),1.66(s,6H),1.58(d,J=7.2Hz,7H).

[0320] Example 13. Synthesis of (3S,4R)-4-((5-chloro-4-(1-methyl-3,4-dihydrochromeno[3,4-c]pyrazol-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (13) [ka] To a mixture of ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate (13.1, 5.00 g, 21.5 mmol) and p-toluenesulfonic acid monohydrate (816 mg, 4.29 mmol) in dichloromethane (85 mL), 3,4-dihydro-2H-pyran (4.00 mL, 42.9 mmol) was added, and the mixture was stirred at 25 °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 4-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (13.2, 5.40 g, 79%) as a yellow solid. LC-MS (ESI): m / z 317.1 [M+H] + .

[0321] To a mixture of ethyl 4-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (13.2, 4.20 g, 13.2 mmol) in 2-methyltetrahydrofuran (75 mL) was added lithium borohydride (1.15 g, 53.0 mmol) under a nitrogen atmosphere at 0° C., and the mixture was stirred at 25° C. under a nitrogen atmosphere for 14 hours. The reaction mixture was poured into ice water (200 mL), which was stirred for 10 minutes, and then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (4-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (13.3, 3.60 g, crude) as a white solid. LC-MS(ESI):m / z 275.2[M+H] + .

[0322] To a mixture of (4-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (13.3, 3.60 g, crude), (2-(benzyloxy)-5-chlorophenyl)boronic acid (3.43 g, 13.1 mmol), and potassium phosphate (8.33 g, 39.3 mmol) in dioxane (90 mL) and water (18 mL), XPhos Pd G3 (1.11 g, 1.31 mmol) was added, and the resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layer was 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 (4-(2-(benzyloxy)-5-chlorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (13.4, 3.80 g, 70%) as a yellow oil. LC-MS (ESI): m / z 413.2 [M+H] + .

[0323] To a solution of (4-(2-(benzyloxy)-5-chlorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (13.4, 1.00 g, 2.42 mmol) in tetrahydrofuran (20 mL) was added palladium (1.00 g, 10% on carbon). The resulting mixture was degassed and recharged with hydrogen three times, and then it was stirred at room temperature under a hydrogen atmosphere (1 atm) for 15 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-chloro-2-(5-(hydroxymethyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenol (13.5, 770 mg, crude) as a yellow solid. LC-MS (ESI): 323.2 [M+H] + .

[0324] To a mixture of 4-chloro-2-(5-(hydroxymethyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenol (13.5, 770 mg, crude) and triphenylphosphine (939 mg, 3.58 mmol) in tetrahydrofuran (20 mL) was added diethyl azodicarboxylate (0.66 mL, 3.58 mmol) at 0° C., and the mixture was stirred at 25° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8-chloro-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrochromeno[3,4-c]pyrazole (13.6, 520 mg) as a yellow solid. LC-MS (ESI): 305.2 [M+H] + .

[0325] To a mixture of 8-chloro-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrochromeno[3,4-c]pyrazole (13.6, 450 mg, 1.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (750 mg, 2.95 mmol), potassium acetate (435 mg, 4.43 mmol), and XPhos (141 mg, 0.30 mmol) in dioxane (15.0 mL) was added Pd(dba) (136 mg, 0.15 mmol), and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-methyl-3-(tetrahydro-2H-pyran-2-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrochromeno[3,4-c]pyrazole (13.7, 366 mg, 26%) as a yellow solid. LC-MS (ESI): 397.3 [M+H] + .

[0326] A mixture of 1-methyl-3-(tetrahydro-2H-pyran-2-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrochromeno[3,4-c]pyrazole (13.7, 100 mg, 0.25 mmol), 2,4,5-trichloropyrimidine (1.7, 55.5 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium (29.2 mg, 0.02 mmol) and potassium carbonate (69.8 mg, 0.50 mmol) in dioxane (1 mL) and water (0.25 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-(2,5-dichloropyrimidin-4-yl)-1-methyl-3-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-4H-chromeno[3,4-c]pyrazole (13.8, 102 mg, 96%) as a yellow solid. LC-MS (ESI): m / z 417.2 [M+H] + .

[0327] A mixture of 8-(2,5-dichloropyrimidin-4-yl)-1-methyl-3-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-4H-chromeno[3,4-c]pyrazole (13.8, 100 mg, 0.24 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 73.6 mg, 0.48 mmol), potassium fluoride (55.7 mg, 0.96 mmol), 18-crown-6 (63.3 mg, 0.24 mmol) and potassium carbonate (33.1 mg, 0.24 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give (3S,4R)-4-((5-chloro-4-(1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrochromeno[3,4-c]pyrazol-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (13.9, 102 mg, 85%) as a white solid. LC-MS (ESI): m / z 498.3 [M+H] + .

[0328] To a solution of (3S,4R)-4-((5-chloro-4-(1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrochromeno[3,4-c]pyrazol-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (13.9, 102 mg, 0.205 mmol) in dioxane (2 mL), hydrochloric acid (1 mL, 4 M in dioxane) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated sodium bicarbonate solution (5 mL), and subsequently extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(1-methyl-3,4-dihydrochromeno[3,4-c]pyrazol-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (13, 42.0 mg, 49%) as a white solid. LC-MS (ESI): m / z 414.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.75(s,1H),8.36(s,1H),7.91(s,1H),7.57(s,1H),7.37(d,J=7.8Hz,1H),7.04(d,J=8.4Hz,1H),5.25(s,2H),4.92(d,J=5.3Hz,1H) ,3.91-3.72(m,3H),3.57-3.44(m,1H),3.37-3.25(m,1H),3.03(t,J=10.4Hz,1H),2.47(s,3H),2.06-1.89(m,1H),1.58-1.43(m,1H).

[0329] Example 14. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-((R)-1-hydroxyethyl)-2,4-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (14) [ka] To a solution of 2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-ol (1.5, 1.00 g, 3.52 mmol) in acetonitrile (15 mL), sulfuric acid (1.5 mL, 28.2 mmol) was added dropwise at 0° C., and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into water (20 mL) and adjusted to pH 9 with 1 M aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (20 mL×3). The combined organic layer was 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 N-(2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-yl)acetamide (14.1, 810 mg, 71%) as a white solid. LC-MS (ESI): m / z 325.0 [M+H] + .

[0330] A mixture of N-(2-(6-bromo-8-fluoroquinolin-3-yl)propan-2-yl)acetamide (14.1, 670 mg, 2.06 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (628 mg, 2.47 mmol), potassium acetate (607 mg, 6.18 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (169 mg, 0.20 mmol) in dioxane (5 mL) was stirred at 90°C under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, 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 give N-(2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-yl)acetamide (14.2, 525 mg, 68%) as a yellow oil. LC-MS (ESI): m / z 373.2 [M+H] + .

[0331] A mixture of N-(2-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-yl)acetamide (14.2, 525 mg, 1.41 mmol), 2,4,5-trichloropyrimidine (1.7, 259 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium (163 mg, 0.14 mmol) and potassium carbonate (390 mg, 2.82 mmol) in dioxane (6 mL) and water (1 mL) was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give N-(2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-yl)acetamide (14.3, 450 mg, 81%) as a yellow oil. LC-MS (ESI): m / z 393.1 [M+H] + .

[0332] A mixture of N-(2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-yl)acetamide (14.3, 450 mg, 1.14 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 264 mg, 1.72 mmol), potassium fluoride (266 mg, 4.57 mmol), potassium carbonate (237 mg, 1.72 mmol), and 18-crown-6 (302 mg, 1.14 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120° C. for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was 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 N-(2-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-yl)acetamide (14.4, 487 mg, 90%) as a white solid. LC-MS (ESI): m / z 474.2 [M+H] + .

[0333] A mixture of N-(2-(6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-yl)acetamide (14.4, 487 mg, 1.03 mmol) and concentrated hydrochloric acid (5 mL, 12 M) in ethanol (5 mL) was stirred at 90° C. for 48 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and adjusted to pH 9 with 1 M aqueous sodium hydroxide solution. The resulting mixture was 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 (3S,4R)-4-((4-(3-(2-aminopropan-2-yl)-8-fluoroquinolin-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (14, 79.0 mg, 18%) as a white solid. LC-MS (ESI): m / z 432.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 9.29(d,J=2.3Hz,1H),8.57(s,1H),8.48(s,1H),8.26(s,1H),7.84(d,J=11.6Hz,1H),7.56(s,1H),4.93(d,J=5.4Hz,1 H),3.98-3.75(m,3H),3.58-3.44(m,1H),3.38-3.33(m,1H),3.12-3.01(m,1H),2.07-1.87(m,1H),1.61-1.43(m,7H).

[0334] Example 15. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-((R)-1-hydroxyethyl)-2,4-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (15a) and (3S,4R)-4-((5-chloro-4-(8-fluoro-3-((S)-1-hydroxyethyl)-2,4-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (15b) [ka] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)ethan-1-one (7.3, 300 mg, 1.29 mmol), pentane-2,4-dione (0.14 mL, 1.42 mmol), and p-toluenesulfonic acid monohydrate (49.2 mg, 0.26 mmol) in ethanol (5 mL) was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(6-bromo-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-one (15.2, 270 mg, 64%) as a yellow solid. LC-MS (ESI): m / z 296.0 [M+H] + .

[0335] To a solution of 1-(6-bromo-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-one (15.2, 200 mg, 0.67 mmol) in methanol (3 mL) was added sodium borohydride (204 mg, 5.40 mmol) at 0° C., and the mixture was stirred at 25° C. for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(6-bromo-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-ol (15.3, 190 mg, 94%) as a yellow oil. LC-MS (ESI): m / z 298.0 [M+H] + .

[0336] A mixture of 1-(6-bromo-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-ol (15.3 mg, 190 mg, 0.63 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (194 mg, 0.76 mmol), potassium acetate (187 mg, 1.91 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (52.2 mg, 0.06 mmol) in dioxane (4.0 mL) was stirred at 90° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, 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 give 1-(8-fluoro-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)ethan-1-ol (15.4, 210 mg, 95%) as a yellow oil. LC-MS (ESI): m / z 346.2 [M+H] + .

[0337] A mixture of 1-(8-fluoro-2,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)ethan-1-ol (15.4, 210 mg, 0.61 mmol), 2,4,5-trichloropyrimidine (1.7, 112 mg, 0.61 mmol), tetrakis(triphenylphosphine)palladium (70.3 mg, 0.06 mmol) and potassium carbonate (168 mg, 1.22 mmol) in dioxane (1 mL) and water (0.2 mL) was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 1-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-ol (15.5, 110 mg, 46%) as a yellow oil. LC-MS (ESI): m / z 366.1 [M+H] + .

[0338] A mixture of 1-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-ol (15.5, 200 mg, 0.54 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 109 mg, 0.71 mmol), potassium fluoride (127 mg, 2.18 mmol), 18-crown-6 (144 mg, 0.54 mmol) and potassium carbonate (75.5 mg, 0.54 mmol) in dimethyl sulfoxide (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 (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(1-hydroxyethyl)-2,4-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (15, 49.0 mg, 20%) as a white solid, which was further separated by chiral SFC to give:

[0339] Isomer 1: (15a, 100%ee); retention time: 0.522 min. LC-MS(ESI):m / z 447.2[M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ 8.47(s,1H),8.37(s,1H),7.83(s,1H),7.56(s,1H),5.47-5.36(m,2H),4.94(d,J=5.5Hz,1H),3.92-3.77(m,3H),3.51(s,1H),3.39-3.33(m ,1H),3.11-3.02(m,1H),2.83(s,3H),2.81(s,3H),1.97(s,1H),1.59-1.44(m,4H).

[0340] Isomer 2: (15b, 100%ee); Retention time: 1.280 min; LC-MS (ESI): m / z 447.2[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 8.47(s,1H),8.37(s,1H),7.83(s,1H),7.56(s,1H),5.48-5.37(m,2H),4.94(d,J=5.2Hz,1H),3.94-3.75(m,3H) ),3.51(s,1H),3.39-3.33(s,1H),3.10-3.00(m,1H),2.83(s,3H),2.80(s,3H),1.96(s,1H),1.60-1.43(m,4H).

[0341] Analytical separation method: Column: CHIRALPAK IH-3, 4.6 x 50 mm, 3.0 um; A on MTBE (0.1% DEA) and B on MeOH; Gradient: 3.6 min @ 50% B; Flow rate: 1.67 mL / min; High pressure: 76 bar; Column temperature: 25°C.

[0342] Preparative separation method: Instrument: GILSON-03; Column: CHIRALPAK IH-3, 20 x 250 mm, 5 um; Mobile phase: A for MTBE (0.1% DEA) and B for MeOH; Gradient: B 50%; Flow rate: 20 mL / min; High pressure: 78 bar; Column temperature: 25°C.

[0343] Example 16. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(1-hydroxycyclobutyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (16) [ka] To a solution of 6-bromo-8-fluoroquinoline (16.1, 10.0 g, 44.2 mmol) in acetic acid (80 mL) was added N-iodosuccinimide (49.8 g, 221 mmol), and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and then poured into water (100 mL). The resulting mixture was adjusted to pH 8 with saturated sodium bicarbonate (300 mL) and extracted with ethyl acetate (50 mL×5). The combined 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 6-bromo-8-fluoro-3-iodoquinoline (16.2, 9.00 g, 57%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 9.12(d,J=2.00Hz,1H),8.94(t,J=1.69Hz,1H),8.10-8.05(m,1H),7.93(dd,J=10.19,2.06Hz,1H).

[0344] To a solution of 6-bromo-8-fluoro-3-iodoquinoline (16.2, 2.00 g, 5.68 mmol) in tetrahydrofuran (30 mL) was added isopropylmagnesium chloride (5.25 mL, 1.30 M in tetrahydrofuran) dropwise at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 1 hour, and then a solution of cyclobutanone (597 mg, 8.52 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture was stirred at −78° C. for 3 hours, then slowly warmed to 25° C. and stirred for an additional 8 hours. The reaction mixture was poured into saturated ammonium chloride (100 mL) and extracted with ethyl acetate (40 mL×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-(6-bromo-8-fluoroquinolin-3-yl)cyclobutan-1-ol (16.3, 950 mg, 45%) as a yellow solid. LC-MS (ESI): m / z 296.0 [M+H] + .

[0345] To a mixture of 1-(6-bromo-8-fluoroquinolin-3-yl)cyclobutan-1-ol (16.3, 880 mg, 2.97 mmol), bis(pinacolato)diboron (1.51 g, 5.94 mmol), and potassium acetate (875 mg, 8.91 mmol) in dioxane (10.0 mL) was added XPhos (283 mg, 0.59 mmol) and tris(dibenzylideneacetone)dipalladium (272 mg, 0.30 mmol), and the mixture was stirred at 100° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 1-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)cyclobutan-1-ol (16.4, 750 mg, 73%) as a purple oil. LC-MS (ESI): m / z 344.3 [M+H] + .

[0346] To a mixture of 1-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)cyclobutan-1-ol (16.4, 260 mg, 0.76 mmol) and 2,4,5-trichloropyrimidine (1.7, 107 mg, 0.58 mmol) in dioxane / water (4 mL / 1 mL) was added tetrakis(triphenylphosphine)palladium (67.0 mg, 0.06 mmol) and potassium carbonate (160 mg, 1.16 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL×2). 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-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)cyclobutan-1-ol (16.5, 168 mg, 80%). LC-MS (ESI): m / z 364.0 [M+H] + .

[0347] To a mixture of 1-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)cyclobutan-1-ol (16.5, 168 mg, 0.46 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 107 mg, 0.69 mmol) in anhydrous dimethyl sulfoxide (2 mL) was added potassium fluoride (107 mg, 1.84 mmol), potassium carbonate (95.0 mg, 0.69 mmol), and 18-crown-6 (121 mg, 0.46 mmol). The resulting mixture was stirred at 110° C. for 1 hour. The reaction mixture was filtered and the filtrate was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(1-hydroxycyclobutyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (16, 40.0 mg, 20%) as a white solid. LC-MS (ESI): m / z 445.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 9.18(d,J=2.2Hz,1H),8.59(t,J=1.9Hz,1H),8.48(s,1H),8.32(s,1H),7.86(d,J=1 2.6Hz,1H),7.56(s,1H),5.97(s,1H),4.92(d,J=5.5Hz,1H),3.91-3.78(m,3H),3.54 -3.45(m,1H),3.35(dd,J=11.9,2.3Hz,1H),3.05(dd,J=11.1,9.6Hz,1H),2.62-2.52 (m,2H),2.45-2.36(m,2H),2.03-1.93(m,2H),1.82-1.69(m,1H),1.56-1.44(m,1H).

[0348] Example 17. Synthesis of (3S,4R)-4-((5-chloro-4-(4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (17) [ka] To a solution of 4-bromo-2-fluoroaniline (9.46 g, 49.8 mmol) in toluene (40 mL) was added diethyl 2-(ethoxymethylene)malonate (17.2, 11.6 g, 53.9 mmol), and the mixture was heated to reflux and stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give diethyl 2-(((4-bromo-2-fluorophenyl)amino)methylene)malonate (17.2, 10.5 g, 59%). LC-MS (ESI): m / z 360.0 [M+H] + and 362.0[M+2+H] + .

[0349] A mixture of Eaton's reagent (6 mL) and diethyl 2-(((4-bromo-2-fluorophenyl)amino)methylene)malonate (17.2, 2.74 g, 7.61 mmol) was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was subjected to silica gel column chromatography to give ethyl 6-bromo-8-fluoro-4-hydroxyquinoline-3-carboxylate (17.3, 400 mg, 17%). LC-MS (ESI): m / z 314.0 [M+H] + and 316.1[M+2+H] + .

[0350] A mixture of ethyl 6-bromo-8-fluoro-4-hydroxyquinoline-3-carboxylate (17.3, 400 mg, 1.27 mmol) and phosphorus oxychloride (3 mL) was stirred at 90° C. for 2 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-chloro-8-fluoroquinoline-3-carboxylate (17.4, 350 mg, 83%). LC-MS (ESI): m / z 331.9 [M+H] + and 334.0[M+2+H] + .

[0351] To a solution of ethyl 6-bromo-4-chloro-8-fluoroquinoline-3-carboxylate (17.4, 190 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (3 mL, 1 M in tetrahydrofuran) at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), 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 2-(6-bromo-4-chloro-8-fluoroquinolin-3-yl)propan-2-ol (17.5, 182 mg, 52%). LC-MS (ESI): m / z 318.0 [M+H] + and 319.9[M+2+H] + .

[0352] To a solution of 2-(6-bromo-4-chloro-8-fluoroquinolin-3-yl)propan-2-ol (17.5, 85.0 mg, 0.27 mmol) in dioxane (2 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (84.0 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) (7.7 mg, 0.01 mmol), and potassium acetate (110 mg, 1.12 mmol). The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give (4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)boronic acid (17.6, 36.0 mg, 48%). LC-MS (ESI): m / z 283.8 [M+H] + .

[0353] To a mixture of (4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)boronic acid (17.6, 36.0 mg, 0.10 mmol) and 2,4,5-trichloropyrimidine (1.7, 54.0 mg, 0.29 mmol) in dioxane (1 mL) and water (0.1 mL) was added tetrakis(triphenylphosphine)palladium (2.00 mg, 0.002 mmol) and potassium carbonate (35.0 mg, 0.25 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(4-chloro-6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-ol (17.7, 25.0 mg, 65%). LC-MS (ESI): m / z 386.0 [M+H] + and 388.1[M+2+H] + .

[0354] To a solution of 2-(4-chloro-6-(2,5-dichloropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-ol (17.7, 24.6 mg, 0.06 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (1.9, 19.2 mg, 0.13 mmol) in anhydrous dimethyl sulfoxide (1.0 mL) was added N,N-diisopropylethylamine (0.15 mL), and the resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (17, 14.0 mg, 47%). LC-MS(ESI):m / z 467.1[M+H] + and 469.0[M+2+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.43(s,1H),8.59(s,1H),8.50(s,1H),8.05(d,J=10.0Hz,1H),7.64(s,1H),5.82(s,1H),4.94(d,J=5.5Hz,1H),3.88-3.7 9(m,3H),3.54-3.49(m,1H),3.36-3.33(m,1H),3.05(t,J=10.0Hz,1H),2.03-1.94(m,1H),1.75(s,6H),1.55-1.48(m,1H).

[0355] Example 18. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(5-methyl-1H-imidazol-4-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (18) [ka] To a mixture of 4-iodo-5-methyl-1H-imidazole (18.1, 4.00 g, 19.2 mmol) and 3,4-dihydro-2H-pyran (4.85 g, 57.7 mmol) in N,N-dimethylformamide (50 mL) was added p-toluenesulfonic acid (331 mg, 1.92 mmol), and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to 25 °C, poured into water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazole (18.2, 2.50 g, 44%) as a yellow oil. LC-MS(ESI):m / z 293.1[M+H] + .

[0356] To a solution of 4-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazole (18.2, 1.00 g, 3.42 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride (2.57 mL, 5.14 mmol) at 0° C. After the mixture was stirred at 0° C. for 1 hour, tributyl(chloro)stannane (1.25 mL, 4.64 mmol) was added and the resulting mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(tributylstannyl)-1H-imidazole (18.3, 1.50 g, crude) as a yellow oil. LC-MS (ESI): m / z 457.3 [M+H] + .

[0357] To a mixture of 6-bromo-8-fluoro-3-iodoquinoline (16.2, 900 mg, 2.56 mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(tributylstannyl)-1H-imidazole (18.3, 1.50 g, crude) in N,N-dimethylformamide (15 mL) was added tetrakis(triphenylphosphine)palladium (296 mg, 0.26 mmol) and cuprous iodide (97.4 mg, 0.51 mmol), and the resulting mixture was stirred at 60 °C for 12 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and then poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6-bromo-8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)quinoline (18.4, 800 mg) as a yellow solid. LC-MS (ESI): m / z 390.2 [M+H] + .

[0358] 6-Bromo-8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)quinoline (18.4, 800 mg, 2.05 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl) in 1,4-dioxane (10 mL) To a mixture of xaborolane (1.04 g, 4.10 mmol) and potassium acetate (604 mg, 6.15 mmol) were added 2-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl (XPhos, 195 mg, 0.41 mmol) and tris(dibenzylideneacetone)dipalladium (188 mg, 0.21 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (18.5, 550 mg, 31%) as a yellow solid. LC-MS (ESI): m / z 438.2 [M+H] + .

[0359] To a mixture of 8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (18.5, 200 mg, 0.46 mmol) and 2,4,5-trichloropyrimidine (1.7, 251 mg, 1.37 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added tetrakis(triphenylphosphine)palladium (53.1 mg, 0.05 mmol) and potassium carbonate (127 mg, 0.92 mmol), and the reaction was stirred at 90° C. for 16 hours under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). 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 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)quinoline (18.6, 190 mg, 91%) as a yellow solid. LC-MS (ESI): m / z 458.1 [M+H] + .

[0360] A mixture of 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)quinoline (18.6, 190 mg, 0.42 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 76.8 mg, 0.50 mmol), potassium carbonate (69.0 mg, 0.50 mmol), potassium fluoride (72.3 mg, 1.25 mmol), and 18-crown-6 (11.1 mg, 0.04 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120° C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layer was 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 (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (18.7, 100 mg, 45%) as a yellow solid. LC-MS (ESI): m / z 539.2 [M+H] + .

[0361] To a solution of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-4-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (18.7, 100 mg, 0.19 mmol) in methanol (3 mL) was added hydrochloric acid (3 mL, 4 M in dioxane) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(5-methyl-1H-imidazol-4-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (18, 21.7 mg, 26%) as a white solid. LC-MS (ESI): m / z 455.3 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 12.29(s,1H),9.42(s,1H),8.64(s,1H),8.48(s,1H),8.31(s,1H),7.81(d,J=10 .9Hz,1H),7.73(s,1H),7.56(s,1H),4.93(d,J=5.4Hz,1H),3.86(dd,J=10.6,4. 3Hz,1H),3.82(dd,J=10.9,4.6Hz,2H),3.53-3.48(m,1H),3.36(s,1H),3.05(t, J=10.4Hz,1H),2.54(s,3H),1.96(d,J=9.0Hz,1H),1.50(qd,J=12.2,4.5Hz,1H).

[0362] Example 19. Synthesis of (3S,4R)-4-((5-chloro-4-((R)-7-fluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (19) [ka] To a solution of (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (19.1, 5.00 g, 23.1 mmol) in tetrahydrofuran (80 mL) and water (80 mL), sodium carbonate (3.68 g, 34.7 mmol) and 2,5-dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl)carbonate (5.39 g, 20.8 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was 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 (R)-4-(tert-butyl)1-(2,2,2-trichloroethyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate (19.2, 4.00 g, 48%) as a colorless oil. LC-MS(ESI):m / z 391.0[M+H] + .

[0363] To a mixture of (R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate 4-(tert-butyl)1-(2,2,2-trichloroethyl) (19.2 g, 4.00 g, 11.1 mmol), triphenylphosphine (3.78 g, 14.4 mmol), and 4-bromo-2,6-difluorophenol (2.32 g, 11.1 mmol) in tetrahydrofuran (60 mL), diisopropyl azodiformate (2.92 g, 14.4 mmol, 2.54 mL) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water (100 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 (R)-4-(tert-butyl)1-(2,2,2-trichloroethyl)2-((4-bromo-2,6-difluorophenoxy)methyl)piperazine-1,4-dicarboxylate (19.3, 3.20 g, 52%) as a colorless oil. LC-MS (ESI): m / z 525.0 [M-56+H] + .

[0364] To a solution of (R)-4-(tert-butyl)1-(2,2,2-trichloroethyl)2-((4-bromo-2,6-difluorophenoxy)methyl)piperazine-1,4-dicarboxylate (19.3, 3.20 g, 5.80 mmol) in acetonitrile (40 mL) was added cesium fluoride (4.40 g, 29.0 mmol), and the mixture was stirred at 90° C. for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give tert-butyl (R)-9-bromo-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.4, 1.60 g, 71%) as a white solid. LC-MS (ESI): m / z 387.1 [M+H] + .

[0365] To a solution of (R)-9-bromo-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.4, 1.00 g, 2.58 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (787 mg, 3.10 mmol), potassium acetate (760 mg, 7.74 mmol), and Pd(dppf)Cl (191 mg, 0.25 mmol). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 6 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain tert-butyl (R)-7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.5, 340 mg, 30%) as a yellow solid. LC-MS (ESI): m / z 435.2 [M+H] + .

[0366] To a mixture of (R)-7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.5, 340 mg, 0.78 mmol) and 2,4,5-trichloropyrimidine (1.7, 100 µL, 0.86 mmol) in water (0.5 mL) and dioxane (2 mL), Pd(PPh3)4 (135 mg, 0.11 mmol) and potassium carbonate (216 mg, 1.56 mmol) were added. The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 15 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). 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 tert-butyl (R)-9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.6, 261 mg, 73%) as a yellow solid. LC-MS (ESI): m / z 399.1 [M-56+H] + .

[0367] A mixture of (R)-9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.6, 261 mg, 0.57 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (1.9, 105 mg, 0.68 mmol), potassium carbonate (79.2 mg, 0.57 mmol), potassium fluoride (100 mg, 1.72 mmol), and 18-crown-6 (30.0 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120° C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined 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 tert-butyl (R)-9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.7, 210 mg, 68%) as a white solid. LC-MS (ESI): m / z 536.2 [M+H] + .

[0368] To a solution of tert-butyl (R)-9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (19.7, 120 mg, 0.22 mmol) in methanol (2 mL) was added hydrochloric acid (1 mL, 4 M in dioxane), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated sodium bicarbonate solution (5 mL), and subsequently extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-((R)-7-fluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (19, 60.0 mg, 61%) as a white solid. LC-MS (ESI): m / z 436.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.34(s,1H),7.38(d,J=8.0Hz,1H),7.16-7.01(m,2H),4.88(brs,1H),4.38(dd,J=10.8,2.8H z,1H),3.98(dd,J=10.8,8.7Hz,1H),3.82-3.76(m,3H),3.67-3.63(m,1H),3.51-3.47(m,1H) ,3.31(td,J=11.7,2.3Hz,1H),3.13-3.01(m,4H),2.78(td,J=12.1,3.1Hz,1H),2.67(td,J=1 1.8,3.2Hz,1H),2.40(t,J=11.4Hz,1H),1.93(d,J=13.2Hz,1H),1.48(qd,J=11.8,4.5Hz,1H).

[0369] Example 20. Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinolin-2-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (20a) and (3S,4R)-4-((5-chloro-4-(4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinolin-2-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (20b) [ka] To a mixture of diethyl 2-(diethoxyphosphoryl)acetate (20.5 g, 91.5 mmol) in tetrahydrofuran (80 mL) was added sodium hydride (3.46 g, 86.4 mmol, 60% dispersion in mineral oil) in small portions at 0 °C. The mixture was stirred under a nitrogen atmosphere at 0 °C for 3 hours, after which a solution of ethyl 5-formyl-1H-pyrrole-2-carboxylate (20.1 g, 8.50 g, 50.8 mmol) in tetrahydrofuran (30 mL) was added. The resulting mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), and the aqueous layer was extracted with ethyl acetate (50 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 purified by recrystallization from petroleum ether to give ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate (20.2, 12.0 g, 99%). LC-MS (ESI): m / z 238.1 [M+H] + .

[0370] To a solution of (E)-ethyl 5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate (20.2, 12.0 g, 50.5 mmol) in ethyl alcohol (100 mL) was added Raney nickel (1.11 g, 5.06 mmol). The resulting mixture was degassed and recharged with hydrogen three times, and then stirred under a hydrogen atmosphere (1 atm) at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give ethyl 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate (20.3, 11.50 g, 95%) as a yellow oil. LC-MS (ESI): 240.1 [M+H] + .

[0371] To a mixture of ethyl 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate (20.3 g, 11.5 g, 48.0 mmol), 4-dimethylaminopyridine (0.59 g, 4.81 mmol), and triethylamine (20 mL, 144 mmol) in acetonitrile (100 mL), di-tert-butyl dicarbonate (21.0 g, 96.2 mmol) was added, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and washed with 1N hydrochloric acid (25 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1-(tert-butyl)-2-ethyl 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-1,2-dicarboxylate (20.4, 10.0 g, 61%) as a white solid. LC-MS (ESI): m / z 240.3 [M-100+H] + .

[0372] To a solution of 1-(tert-butyl)2-ethyl 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-1,2-dicarboxylate (20.4, 10.0 g, 29.4 mmol) in methanol (100 mL) was added palladium (1.00 g, 10% on carbon). The resulting mixture was degassed and recharged with hydrogen three times, and then stirred under a hydrogen atmosphere (1 atm) at room temperature for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-(tert-butyl)2-ethyl-5-(3-ethoxy-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (20.5, 9.00 g, 89%) as a yellow oil. LC-MS (ESI): 244.1 [M-100+H] + .

[0373] To a solution of 1-(tert-butyl)2-ethyl-5-(3-ethoxy-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (20.5, 8.50 g, 24.7 mmol) in tetrahydrofuran (160 mL) was added potassium tert-butoxide (4.17 g, 37.1 mmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), and the aqueous phase was extracted with ethyl acetate (80 mL × 2). 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 8-(tert-butyl)3-ethyl 2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (20.6, 5.50 g, 75%) as a white solid. LC-MS(ESI):242.3[M-56+H] + .

[0374] To a solution of 8-(tert-butyl)3-ethyl 2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (20.6, 5.00 g, 16.8 mmol) in tetrahydrofuran (50 mL) were added sodium hydride (2.02 g, 50.4 mmol, 60% dispersion in mineral oil) and N-phenyl-bis(trifluoromethanesulfonimide) (12.0 g, 33.6 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). 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 8-(tert-butyl)3-ethyl 2-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-3,8-dicarboxylate (20.7, 6.30 g, crude). LC-MS (ESI): m / z 374.0 [M-56+H] + .

[0375] To a solution of 8-(tert-butyl)3-ethyl 2-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-3,8-dicarboxylate (20.7, 6.30 g, crude) in dioxane (80 mL) and water (14 mL) was added (2-amino-5-chloro-3-fluorophenyl)boronic acid (3.43 g, 14.6 mmol), potassium carbonate (6.08 g, 44.0 mmol), and tetrakis(triphenylphosphine)palladium (1.70 g, 1.47 mmol). The mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×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 tert-butyl 2-chloro-4-fluoro-6-oxo-6,7,8,9,10,11-hexahydro-5H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.8, 1.30 g) as a yellow solid. LC-MS (ESI): 323.0 [M-56+H]+ .

[0376] To a solution of tert-butyl 2-chloro-4-fluoro-6-oxo-6,7,8,9,10,11-hexahydro-5H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.8 g, 1.30 g, 3.43 mmol) in tetrahydrofuran (20 mL), sodium hydride (0.34 g, 8.58 mmol, 60% dispersion in paraffin liquid) and N-phenyl-bis(trifluoromethanesulfonimide) (3.06 g, 8.58 mmol) were added, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 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 tert-butyl 2-chloro-4-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.9, 1.74 g, 99%) as a yellow oil. LC-MS (ESI): m / z 511.2 [M+H] + .

[0377] To a solution of tert-butyl 2-chloro-4-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.9g, 1.00g, 1.96mmol) in tetrahydrofuran (10mL) was added tetrakis(triphenylphosphine)palladium (0.23g, 0.20mmol), pyridine (1.6mL, 19.6mmol), and triethylsilane (2.28g, 19.6mmol). The mixture was stirred at 50°C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (30mL 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 tert-butyl 2-chloro-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.10, 0.30 g, 38%) as a white solid. LC-MS (ESI): m / z 363.0 [M+H] + .

[0378] To a mixture of tert-butyl 2-chloro-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.10, 300 mg, 0.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (315 mg, 1.24 mmol), potassium acetate (243 mg, 2.48 mmol), and X-Phos (39 mg, 0.08 mmol) in dioxane (5 mL) was added tris(dibenzylideneacetone)dipalladium (76.0 mg, 0.08 mmol). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 15 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.11, 0.38 g, crude). LC-MS (ESI): 455.1 [M+H] + .

[0379] A mixture of tert-butyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.11, 380 mg, crude), 2,4,5-trichloropyrimidine (1.7, 153 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (97.0 mg, 0.08 mmol) and potassium carbonate (347 mg, 2.51 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give tert-butyl 2-(2,5-dichloropyrimidin-4-yl)-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.12, 364 mg, crude) as a white solid. LC-MS (ESI): m / z 475.0 [M+H] + .

[0380] A mixture of tert-butyl 2-(2,5-dichloropyrimidin-4-yl)-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.12, 364 mg, crude), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 141 mg, 0.92 mmol), potassium carbonate (106 mg, 0.77 mmol), 18-crown-6 (20 mg, 0.08 mmol), and potassium fluoride (178 mg, 3.06 mmol) in dimethyl sulfoxide (2 mL) was stirred at 110 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was 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 tert-butyl 2-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.13, 0.16 g) as a white solid. LC-MS (ESI): m / z 556.1 [M+H] + .

[0381] To a solution of tert-butyl 2-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinoline-12-carboxylate (20.13, 160 mg, 0.29 mmol) in dioxane (1 mL), hydrochloric acid (1 mL, 4 M in dioxane) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated sodium bicarbonate solution (5 mL), and subsequently extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4R)-4-((5-chloro-4-(4-fluoro-8,9,10,11-tetrahydro-7H-8,11-epiminocyclohepta[c]quinolin-2-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (20, 118 mg, 91%) as a white solid, which was further separated by chiral SFC to give:

[0382] Isomer 1: (20a, 99.0%ee); Retention time: 0.763 min. LC-MS(ESI):m / z 456.2[M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.70(s,1H),8.48(s,1H),8.34(s,1H),7.84(s,1H),7.58(s,1H),4.92(dd,J=19 .6,5.8Hz,2H),3.93-3.76(m,4H),3.51(s,1H),3.36(s,1H),3.24(dd,J=17.0,4 .6Hz,1H),3.05(t,J=10.4Hz,1H),2.69(d,J=17.1Hz,1H),2.09(dt,J=17.6,5.7 Hz,1H),2.05-1.90(m,2H),1.84(t,J=9.8Hz,1H),1.55(dt,J=20.0,9.7Hz,2H).

[0383] Isomer 2: (20b, 99.3%ee); Retention time: 1.130 min; LC-MS (ESI): m / z 456.2 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 8.70(s,1H),8.48(s,1H),8.34(s,1H),7.84(s,1H),7.58(s,1H),4.92(dd,J=15.8,5.8Hz,2H),3.95-3.74(m,4H),3.51(s,1H),3.36(s,1H) ,3.24(dd,J=17.0,4.5Hz,1H),3.05(t,J=10.4Hz,1H),2.69(d,J=17.0Hz,1H),2.16-1.92(m,3H),1.84(t,J=9.7Hz,1H),1.63-1.43(m,2H).

[0384] Analytical separation method: Column: CHIRAL ART Cellulose-SB, 4.6 x 50 mm, 3.0 um; Mobile phase: A with MTBE (0.1% DEA) and B with EtOH; Gradient: B 30%; Flow rate: 1.67 mL / min; High pressure: 114 bar; Column temperature: 25°C; Wavelength: 254 nm.

[0385] Preparative separation method: Column: CHIRAL ART Cellulose-SB, 20 x 250 mm, 5 um; Mobile phase: A with MTBE (10 mM NH3) and B with EtOH; Gradient: B 30%; Flow rate: 20 mL / min; High pressure: 63 bar; Column temperature: 25 °C; Wavelength: 256 nm / 234 nm; Cycle time: approximately 12 min.

[0386] Example 21. Synthesis of (3S,4R)-4-((5-chloro-4-(7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropan]-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (21) [ka] To a suspension of tert-butyl (1-formylcyclopropyl)carbamate (10.0 g, 54.0 mmol) in tetrahydrofuran (200 mL) was added 2-(triphenyl-λ 5Ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)acrylate (21.1, 37.6 g, 108 mmol) was added portionwise and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was triturated with petroleum ether (150 mL). Precipitation occurred after 10 minutes and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)acrylate (21.2, 12.0 g, 87%) as a white solid. LC-MS (ESI): m / z 156.2 [M-100+H] + .

[0387] To a solution of ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)acrylate (21.2, 12.00 g, 47.0 mmol) in ethyl acetate (80 mL) was added palladium (1.00 g, 10% on carbon). The resulting mixture was degassed and recharged with hydrogen three times, and then it was stirred under a hydrogen atmosphere (1 atm) at room temperature for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoate (21.3, 11.0 g, crude) as a white solid. LC-MS (ESI): m / z 158.2 [M-100+H] + .

[0388] To a solution of ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)propanoate (21.3, 11.0 g, crude) in ethanol (60 mL) was added hydrochloric acid (50 mL, 4 M in dioxane) and the mixture was stirred at 40° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give ethyl 3-(1-aminocyclopropyl)propanoate hydrochloride (21.4, 8.56 g, crude) as an off-white solid. LC-MS (ESI): m / z 158.1 [M+H] + .

[0389] To a mixture of ethyl 3-(1-aminocyclopropyl)propanoate hydrochloride (21.4, 8.56 g, crude) and potassium carbonate (12.2 g, 88.4 mmol) in acetonitrile (80 mL) was added ethyl 2-bromoacetate (8.85 g, 53.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give ethyl 3-(1-((2-ethoxy-2-oxoethyl)amino)cyclopropyl)propanoate (21.5, 5.74 g) as a colorless oil. LC-MS (ESI): m / z 244.2 [M+H] + .

[0390] To a mixture of ethyl 3-(1-((2-ethoxy-2-oxoethyl)amino)cyclopropyl)propanoate (21.5, 5.74 g, 23.6 mmol) and triethylamine (4.92 mL, 35.4 mmol) in dichloromethane (50 mL) was added 4-dimethylaminopyridine (144 mg, 1.18 mmol) and di-tert-butyl dicarbonate (6.18 g, 28.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl 3-(1-((tert-butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)cyclopropyl)propanoate (21.6, 3.81 g, 47%) as a colorless oil. LC-MS (ESI): m / z 244.2 [M-100+H] + .

[0391] To a solution of ethyl 3-(1-((tert-butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)cyclopropyl)propanoate (21.6, 1.50 g, 4.37 mmol) in tetrahydrofuran (15 mL) was added potassium tert-butoxide (637 mg, 5.68 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The mixture was poured into saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (15 mL×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 4-(tert-butyl)7-ethyl 6-oxo-4-azaspiro[2.5]octane-4,7-dicarboxylate (21.7, 1.20 g, 92%) as a colorless oil. LC-MS(ESI): m / z 198.2[M-100+H] + .

[0392] To a mixture of 4-(tert-butyl)7-ethyl 6-oxo-4-azaspiro[2.5]octane-4,7-dicarboxylate (21.7, 1.20 g, 4.03 mmol) and N,N-diisopropylethylamine (7.03 mL, 40.3 mmol) in dichloromethane (20 mL), trifluoromethanesulfonic anhydride (1.70 mL, 10.1 mmol) was added dropwise at 0° C., and the mixture was stirred for 30 minutes at 0° C. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 4-(tert-butyl)7-ethyl 6-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4,7-dicarboxylate (21.8, 1.34 g, 77%) as a colorless oil. LC-MS(ESI): m / z 330.1 [M-100+H] + .

[0393] To a solution of 4-(tert-butyl)7-ethyl 6-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4,7-dicarboxylate (21.8, 1.34 g, 3.12 mmol) in dioxane (10 mL) and water (2 mL) was added (2-amino-5-chloro-3-fluorophenyl)boronic acid (1.02 g, 3.74 mmol), potassium carbonate (862 mg, 6.24 mmol), and tetrakis(triphenylphosphine)palladium (541 mg, 0.47 mmol). The mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL×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 tert-butyl 9-chloro-7-fluoro-5-oxo-1,4,5,6-tetrahydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.9, 860 mg, 73%) as a white solid. LC-MS (ESI): 323.1 [M-56+H] + .

[0394] To a mixture of tert-butyl 9-chloro-7-fluoro-5-oxo-1,4,5,6-tetrahydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.9, 860 mg, 2.27 mmol) and N,N-diisopropylethylamine (3.95 mL, 22.7 mmol) in dichloromethane (10 mL) was added trifluoromethanesulfonic anhydride (0.95 mL, 5.67 mmol) at 0°C, and the mixture was stirred at 0°C for 45 minutes. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give tert-butyl 9-chloro-7-fluoro-5-(((trifluoromethyl)sulfonyl)oxy)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.10, 730 mg, 63%) as a white solid. LC-MS (ESI): m / z 511.1 [M+H] + .

[0395] To a solution of tert-butyl 9-chloro-7-fluoro-5-(((trifluoromethyl)sulfonyl)oxy)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1′-cyclopropane]-2-carboxylate (21.10, 730 mg, 1.43 mmol) in tetrahydrofuran (10 mL) was added tetrakis(triphenylphosphine)palladium (0.33 g, 0.28 mmol), pyridine (1.15 mL, 14.3 mmol) and triethylsilane (1.66 g, 14.3 mmol).

[0396] The mixture was stirred at 70° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL×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 tert-butyl 9-chloro-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1′-cyclopropane]-2-carboxylate (21.11, 0.43 g, 83%) as a white solid. LC-MS (ESI): m / z 363.2 [M+H] + .

[0397] To a mixture of tert-butyl 9-chloro-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.11, 430 mg, 1.18 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (391 mg, 1.54 mmol), potassium acetate (349 mg, 3.55 mmol), and X-Phos (113 mg, 0.24 mmol) in dioxane (6 mL) was added tris(dibenzylideneacetone)dipalladium (217 mg, 0.24 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give tert-butyl 7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.12, 452 mg, 84%) as a yellow solid. LC-MS (ESI): 455.2 [M+H] + .

[0398] A mixture of tert-butyl 7-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.12, 150 mg, 0.33 mmol), 2,4,5-trichloropyrimidine (1.7, 109 mg, 0.59 mmol), tetrakis(triphenylphosphine)palladium (57.2 mg, 0.05 mmol), and potassium carbonate (91.2 mg, 0.66 mmol) in dioxane (3 mL) and water (0.6 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give tert-butyl 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.13, 144 mg, 92%) as a yellow solid. LC-MS (ESI): m / z 475.2 [M+H] + .

[0399] A mixture of tert-butyl 9-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1′-cyclopropane]-2-carboxylate (21.13, 144 mg, 0.30 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 55.8 mg, 0.36 mmol), potassium carbonate (41.8 mg, 0.30 mmol), 18-crown-6 (16.0 mg, 0.06 mmol), and potassium fluoride (52.8 mg, 0.91 mmol) in dimethyl sulfoxide (2 mL) was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give tert-butyl 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylate (21.14, 0.13 g, 77%) as a white solid. LC-MS (ESI): m / z 556.2 [M+H] + .

[0400] To a solution of tert-butyl 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1′-cyclopropane]-2-carboxylate (21.14, 130 mg, 0.23 mmol) in methanol (1 mL) was added hydrochloric acid (1 mL, 4 M in dioxane) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated aqueous sodium bicarbonate (0.6 mL), and then subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropan]-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (21, 73.0 mg, 68%) as a yellow solid. LC-MS (ESI): m / z 456.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.73(s,1H),8.48(s,1H),8.22(s,1H),7.86(d,J=11.4Hz,1H),7.57(s, 1H),4.94(s,1H),4.29(s,2H),3.92-3.77(m,3H),3.52-3.50(m,1H),3.3 5(td,J=11.7,2.3Hz,1H),3.06(dd,J=11.1,9.6Hz,1H),2.88(s,2H),2.0 1-1.92(m,1H),1.57-1.45(m,1H),0.69-0.62(m,2H),0.55-0.49(m,2H).

[0401] Example 22. Synthesis of (3S,4R)-4-((4-(4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (22) [ka] To a mixture of (4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)boronic acid (17.6, 50.0 mg, 0.17 mmol) and 4-bromo-2-chloro-5-fluoropyrimidine (48.5 mg, 0.23 mmol) in dioxane (1 mL) and water (0.2 mL) was added tetrakis(triphenylphosphine)palladium (30.6 mg, 0.03 mmol) and potassium carbonate (48.7 mg, 0.35 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(4-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-ol (22.1, 50.0 mg, 76%) as a white solid. LC-MS (ESI): m / z 370.0 [M+H] + .

[0402] To a solution of 2-(4-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-3-yl)propan-2-ol (22.1, 50.0 mg, 0.13 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (1.9, 27.0 mg, 0.17 mmol) in anhydrous dimethyl sulfoxide (1.0 mL) was added potassium carbonate (18.6 mg, 0.13 mmol), potassium fluoride (23.5 mg, 0.40 mmol), and 18-crown-6 (7.19 mg, 0.03 mmol). The resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, and then subjected to preparative HPLC to give (3S,4R)-4-((4-(4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (22, 12.0 mg, 19%) as a white solid. LC-MS (ESI): m / z 451.1 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 9.44(s,1H),8.85(s,1H),8.54(d,J=3.7Hz,1H),8.21(d,J=13Hz,1H),7.37(d,J=7.8Hz,1H),5.82(s,1H),4.94(d,J=5.5Hz,1H),3.8 7-3.82(m,3H),3.57-3.50(m,1H),3.38(t,J=11.8Hz,1H),3.09(t,J=10.4Hz,1H),2.07-1.98(m,1H),1.75(s,6H),1.58-1.46(m,1H).

[0403] Example 23. Synthesis of (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (23) [ka] A mixture of 2-(8-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (7.6, 342 mg, 0.99 mmol), 4-bromo-2-chloro-5-fluoropyrimidine (210 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium (115 mg, 0.099 mmol), and potassium carbonate (275 mg, 1.99 mmol) in dioxane (3 mL) and water (0.6 mL) was stirred at 90° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-methylquinolin-3-yl)propan-2-ol (23.1, 220 mg, 63%) as a yellow oil. LC-MS (ESI): m / z 350.1 [M+H] + .

[0404] A mixture of 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-methylquinolin-3-yl)propan-2-ol (23.1, 100 mg, 0.27 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 53.0 mg, 0.34 mmol), potassium fluoride (66.0 mg, 1.14 mmol), 18-crown-6 (75.6 mg, 0.29 mmol), and potassium carbonate (79.0 mg, 0.58 mmol) in dimethyl sulfoxide (2 mL) was stirred at 80° C. for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was subjected to preparative HPLC to give (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (23, 12.4 mg, 10%) as a white solid. LC-MS (ESI): m / z 431.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 9.13(s,1H),8.68(s,1H),8.52(d,J=3.7Hz,1H),8.07(d,J=10.7Hz,1H),7.31(d,J=7.8Hz,1H),5.44(s,1H),4.96(d,J=5.4Hz,1H),3.94 -3.75(m,3H),3.59-3.48(m,1H),3.40-3.30(m,1H),3.13-3.05(m,1H),2.99(s,3H),2.10-1.94(m,1H),1.69(s,6H),1.57-1.47(m,1H).

[0405] Example 24. Synthesis of (3S,4R)-4-((5-fluoro-4-(7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (24) [ka] To a solution of 5,5-dimethyltetrahydropyrrol-2-one (24.1, 10.0 g, 88.4 mmol) and ethyl 2-ethoxy-2-oxoacetate (13.2 mL, 97.2 mmol) in ethanol (100 mL), sodium ethoxide (50.1 mL, 133 mmol, 20% in ethanol) was added dropwise at 0 °C, and the mixture was stirred at 80 °C for 48 h. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and adjusted to pH 3-4 with 2 N hydrochloric acid. The mixture was then extracted with petroleum ether / ethyl acetate (3 / 1, 30 mL) to remove impurities. The remaining suspension was filtered and the filter cake was redissolved in dichloromethane (100 mL), which was subsequently dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 5-hydroxy-2,2-dimethyl-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (24.2, 5.00 g, crude) as a white solid.

[0406] To a solution of ethyl 5-hydroxy-2,2-dimethyl-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (24.2, 5.00 g, crude) and N,N-diisopropylethylamine (11.6 mL, 70.3 mmol) in dichloromethane (100 mL), trifluoromethanesulfonic anhydride (3.95 mL, 23.4 mmol) was added dropwise at −78° C. The mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 2). 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 4-(ethoxycarbonyl)-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate (24.3, 5.00 g) as a white solid. 1 H NMR (500 MHz, chloroform-d3) δ 6.52 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.80 (s, 2H), 1.43-1.31 (m, 9H).

[0407] To a solution of 4-(ethoxycarbonyl)-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate (24.3, 2.00 g, 5.79 mmol) and 4-chloro-6-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.73 g, 6.37 mmol) in dioxane (30 mL) and water (6 mL) was added tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol) and potassium carbonate (2.40 g, 17.4 mmol). The mixture was stirred at 110 °C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure, and the residue was triturated with water (30 mL) and ethyl acetate (30 mL). The suspension was filtered, and the cake was washed successively with water (10 mL) and ethyl acetate (20 mL). The cake was then dried in vacuo to give 9-chloro-7-fluoro-3,3-dimethyl-2,3,4,6-tetrahydrobenzo[c][2,6]naphthyridine-1,5-dione (24.4, 1.40 g, 82%) as an off-white solid. LC-MS (ESI): m / z 295.2 [M+H] + .

[0408] A mixture of 9-chloro-7-fluoro-3,3-dimethyl-2,3,4,6-tetrahydrobenzo[c][2,6]naphthyridin-1,5-dione (24.4, 1.40 g, 4.75 mmol) and phosphorus oxychloride (10 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The residue was quenched with water (20 mL), adjusted to pH 7 with saturated aqueous sodium bicarbonate, and extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5,9-dichloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridin-1(2H)-one (24.5, 1.40 g, crude) as a yellow solid. LC-MS(ESI):m / z 313.3[M+H] + .

[0409] A mixture of 5,9-dichloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridin-1(2H)-one (24.5, 1.20 g, crude), triethylamine (1.60 mL, 11.5 mmol), formic acid (723 μL, 19.2 mmol), and tetrakis(triphenylphosphine)palladium (0.44 g, 0.38 mmol) in dimethylformamide (10 mL) was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and filtered. The filter cake was subjected to silica gel chromatography to obtain the crude product, which was triturated with petroleum ether / ethyl acetate (1 / 1, 2 mL). The suspension was filtered, and the filter cake was washed with petroleum ether / ethyl acetate (1 / 1, 2 mL) and dried in vacuo to give 9-chloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridin-1(2H)-one (24.6, 700 mg) as a yellow solid. LC-MS (ESI): m / z 279.1 [M+H] + .

[0410] To a solution of 9-chloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridin-1(2H)-one (24.6, 100 mg, 0.36 mmol) in tetrahydrofuran (3 mL), bis(cyclopentadienyl)zirconium chloride hydride (463 mg, 1.80 mmol) was added portionwise at 0° C., and the mixture was stirred at 0° C. for 1 hour. Next, methanol (10 mL) was added to the reaction mixture, followed by sodium borohydride (57.0 mg, 1.51 mmol) portionwise at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes and then concentrated under reduced pressure. The residue was diluted with water (5 mL) and saturated aqueous sodium bicarbonate solution (1 mL), and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 9-chloro-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (24.8, 300 mg, 90% yield over two steps) as a yellow solid. LC-MS (ESI): m / z 265.2 [M+H] + .

[0411] A mixture of 9-chloro-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (24.8, 30.0 mg, 0.11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (43.0 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (10.3 mg, 0.01 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (10.8 mg, 0.02 mmol), and potassium acetate (33.3 mg, 0.34 mmol) in dioxane (1 mL) was stirred at 90 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, and water (0.2 mL), 4-bromo-2-chloro-5-fluoropyrimidine (47.5 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (13.0 mg, 0.01 mmol), and potassium carbonate (46.6 mg, 0.34 mmol) were added to the reaction mixture. The resulting mixture was stirred at 90 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (2 mL), and extracted with ethyl acetate (5 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 9-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (24.10, 13.0 mg, 32% yield over two steps) as a brown solid. LC-MS(ESI):m / z 361.2[M+H] + .

[0412] A mixture of 9-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridine (24.10, 10.0 mg, 0.03 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 12.8 mg, 0.08 mmol), potassium fluoride (4.80 mg, 0.08 mmol), 18-crown-6 (0.70 mg, 0.003 mmol), and potassium carbonate (11.5 mg, 0.08 mmol) in dimethyl sulfoxide (100 μL) was stirred at 120° C. for 2 hours. After the reaction mixture was cooled to room temperature, methanol (200 μL) and sodium borohydride (1.00 mg, 0.03 mmol) were added sequentially. The resulting mixture was stirred at room temperature for an additional 10 minutes, then filtered and subjected to preparative HPLC to give (3S,4R)-4-((5-fluoro-4-(7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydrobenzo[c][2,6]naphthyridin-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (24, 3.10 mg, 25% yield over two steps) as a yellow solid. LC-MS (ESI): m / z 442.3 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.73(s,1H),8.52(d,J=3.7Hz,1H),8.39(s,1H),8.05(d,J=12.1Hz,1H),7.33(d,J=7.6Hz,1H),4.96(d,J=5.5Hz,1H),4.34(s,2 H),3.88-3.75(m,4H),3.47-3.44(m,1H),3.08(t,J=9.8Hz,1H),2.76(s,2H),2.10-1.86(m,1H),1.58-1.40(m,1H),1.14(s,6H).

[0413] Example 25. Synthesis of (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (60) [ka] To a solution of ethyl 6-bromo-8-fluoro-2-methylquinoline-3-carboxylate (5.1, 4.00 g, 12.8 mmol) in anhydrous tetrahydrofuran (80 mL) was added dropwise methyl-d3-magnesium iodide (64 mL, 64 mmol, 1.0 M in diethyl ether) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride solution (20 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 2-(6-bromo-8-fluoro-2-methylquinolin-3-yl)propan-1,1,1,3,3,3-d6-2-ol (60.1, 2.5 g, 64%) as a yellow solid. LC-MS(ESI):m / z 304.0[M+H] + .

[0414] A mixture of 2-(6-bromo-8-fluoro-2-methylquinolin-3-yl)propan-1,1,1,3,3,3-d6-2-ol (60.1 g, 2.20 g, 7.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.75 g, 10.8 mmol), potassium acetate (2.13 g, 21.7 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (525 mg, 0.72 mmol) in dioxane (40 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-1,1,1,3,3,3-d6-2-ol (60.2, 2.20 g, 86%) as a yellow solid. LC-MS (ESI): m / z 352.2 [M+H] + .

[0415] A mixture of 2-(8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-1,1,1,3,3,3-d6-2-ol (60.2, 2.00 g, 5.60 mmol), 2,4,5-trichloropyrimidine (1.7, 1.34 g, 7.28 mmol), tetrakis(triphenylphosphine)palladium (650 mg, 0.56 mmol) and potassium carbonate (2.32 g, 16.8 mmol) in dioxane / water (20 mL / 4 mL) was stirred at 90° C. under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2-methylquinolin-3-yl)propan-1,1,1,3,3,3-d6-2-ol (60.3, 1.20 g, 56%) as a yellow solid. LC-MS (ESI): m / z 372.0 [M+H] + .

[0416] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2-methylquinolin-3-yl)propan-1,1,1,3,3,3-d6-2-ol (60.3, 1.00 g, 2.70 mmol), (3S,4R)-4-aminotetrahydropyran-3-ol hydrochloride (1.9, 590 mg, 3.80 mmol), potassium fluoride (620 mg, 10.7 mmol), 18-crown-6 (710 mg, 2.70 mmol) and potassium carbonate (370 mg, 2.70 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120 °C for 2.5 h. The reaction mixture was filtered and the filtrate was subjected to preparative HPLC to give (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (60, 180 mg, 15%) as a white solid. LC-MS (ESI): m / z 453.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.46(s,2H),8.24(s,1H),7.80(d,J=11.5Hz,1H),7.53(s,1H),5.30(d,J=6.8Hz,1H),4.92(d,J=5.4Hz,1H),3.89-3.7 9(m,3H),3.53-3.45(m,1H),3.36-3.33(m,1H),3.08-3.03(m,1H),2.95(s,3H),2.01-1.91(m,1H),1.55-1.45(m,1H).

[0417] Example 26. Synthesis of (3S,4R)-4-((5-chloro-4-(4-ethyl-8-fluoro-3-(2-hydroxypropan-2-yl)cinnolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (61) [ka] A mixtu...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, L １ is an optionally substituted phenylene, an optionally substituted 5- or 6-membered heteroarylene, an optionally substituted 4- to 8-membered heterocyclylene, or an optionally substituted C ３～８ is a carbocyclylene; R １ is hydrogen, OH, NH ２ , NHCH ３ , or N(CH ３ ) ２ and X is N or CR １０ and R ２ is an optionally substituted ring system selected from a 10-membered heteroaryl, a 9-12 membered bicyclic heterocyclic ring, or a 12-16 membered heteroaryl or heterocyclic ring system having three or more rings, said ring system containing at least one phenyl or heteroaryl ring; R ２ is attached to the remainder of Formula I through a ring atom of the phenyl or heteroaryl portion of said ring system, provided that said phenyl or heteroaryl portion is not fused to a 5-membered heteroaryl; R ３ is hydrogen, deuterium, halogen (e.g., F, Cl), CN, OR １１ , N.R. １２ R １３ , C(O)NR １２ R １３ , COOR Ａ , C.O.R. Ｂ , optionally substituted C １～６ Alkyl, optionally substituted C ２～４ Alkenyl, optionally substituted C ２～４ Alkynyl, optionally substituted C １～４ Heteroalkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; R ４ is hydrogen, deuterium, halogen (e.g., F), optionally substituted C １～６ Alkyl, or NR １２ R １３ and During the ceremony, R １０ is hydrogen, halogen (e.g., F), CN, —OH, optionally substituted C １～４ Alkyl, optionally substituted C １～４ Heteroalkyl, optionally substituted C ３～８ carbocyclyl, or optionally substituted 4-10 membered heterocyclyl; R １１ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or an oxygen protecting group; R in each existence １２ and R １３ each independently selected from hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or a nitrogen protecting group; or R １２ and R １３ can be linked to form an optionally substituted 4- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl; R Ａ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or an oxygen protecting group; R Ｂ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted phenyl, optionally substituted 4- to 10-membered heterocyclyl, or optionally substituted heteroaryl (eg, 5- or 6-membered heteroaryl).

2. Formula A: 【Chemistry 2】 (In the formula, Q is, (1) O; (2) NR １４ (In the formula, R １４ is hydrogen, G Ａ , S.O. ２ G Ａ , S.O. ２ NG Ｂ G Ｃ ,S(O)(NH)G Ａ , COG Ａ , COOG Ａ , or C(O)NG Ｂ G Ｃ ); (3) CR １５ R １６ (In the formula, R １５ and R １６ are joined with the carbon atoms to which they are attached to form an optionally substituted 4- to 6-membered heterocyclic ring having 1 or 2 ring heteroatoms independently selected from O and N; or (4) non-existence; r1 is 1, 2, or 3; r2 is 0, 1, or 2; n is 0, 1, 2, 3, or 4, where valency allows; (i) R in each occurrence １００ are independently halogen (e.g., F or Cl), CN, OH, COOH, G Ａ , O.G. Ａ ,NG Ｂ G Ｃ ,NG Ｂ G Ｃ SO ２ G Ａ ,NG Ｂ G Ｃ SO ２ NG 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 , S.O. ２ G Ａ , S.O. ２ NG 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 joined together with the intervening atoms to form an optionally substituted ring, such as an optionally substituted 3- to 6-membered ring, and any remaining R at each occurrence １００ is as defined in (i); During the ceremony, G in each existence Ａ independently represents an optionally substituted C １～６ Alkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), or optionally substituted 4- to 10-membered heterocyclyl; G in each existence Ｂ and G Ｃ each independently selected from hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl), optionally substituted 4- to 10-membered heterocyclyl; or a nitrogen protecting group; or G Ｂ and G Ｃ can be linked to form an optionally substituted 4- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl.

10. The compound of claim 1, characterized as having a structure according to:

3. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein n is 0.

4. n is 1 or 2, and R １００ are independently selected from the group consisting of C optionally substituted with F, Cl, CN, OH, F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, and C optionally substituted with F １～４ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from heteroalkyl.

5. n is 1 and R １００ F, Cl, CN, OH, methyl, CF ３ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a fluorine-substituted methyl, methoxy, or fluorine-substituted methoxy such as:

6. Formula A-1 or A-2: 【Chemistry 3】 (In the formula, R １７ teeth, (1) CHF ２ , C.F. ３ C optionally substituted with 1 to 3 substituents independently selected from deuterium, F, and OH, such as １～４ Alkyl; (2) Phenyl, pyridyl, or pyrimidyl, each of which is optionally substituted with deuterium, halogen, CN, OH, or F. １～３ C optionally substituted with alkyl or F １～３ phenyl, pyridyl, or pyrimidyl optionally substituted with 1 to 3 substituents independently selected from alkoxy; or (3) C optionally substituted with deuterium, halogen, CN, OH, F １～３ C optionally substituted with alkyl or F １～３ and 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from alkoxy.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having:

7. R １７ but, 【Chemistry 4】 7. The compound of claim 6, selected from:

8. L in Formula I １ -R １ but, 【Chemistry 5】 or L in formula I is selected from １ -R １ but, 【Chemistry 6】 2. The compound of claim 1, selected from:

9. 9. The compound according to any one of claims 1 to 8, wherein X is N, or a pharmaceutically acceptable salt thereof.

10. R ２ is a 10-membered bicyclic heteroaryl having 1 to 4 ring nitrogen atoms, such as quinolinyl, naphthyridinyl, etc., which is optionally substituted with halo (e.g., F), CN, G １ , OH, COOH, C(O)-G １ , O-G １ , C(O)-O-G １ , N.H. ２ , NH(G １ ), N(G １ ) (G １ ), C(O)—NH ２ , C(O)-NH(G １ ), C(O)-N(G １ ) (G １ ), G ２ , O-G ２ , NH(G ２ ), N(G １ ) (G ２ ), C(O)-NH(G ２ ), and C(O)-N(G １ ) (G ２ Optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from G in each existence １ are independently F, CN, OH, and C １～４ C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl １～４ Alkyl, or F, CN, OH, and C １～４ C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl ３～６ is cycloalkyl; G in each existence ２ is independently 4-6 membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, each of which is selected from oxo (where applicable), halo (e.g., F), CN, G １ , OH, O-G １ , N.H. ２ , NH(G １ ), and N(G １ ) (G １ Optionally substituted with 1 to 3 substituents independently selected from:

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein two optional substituents of the 10-membered bicyclic heteroaryl group, together with an intervening atom, can optionally be linked to form a fused ring structure.

11. R ２ But, M-1: 【Chemistry 7】 (In the formula, J １ and J ２ are independently N or CR ３０ and R in each occurrence ３０ are independently hydrogen, halogen, C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ is heteroalkyl; R ２０ is hydrogen, halogen (e.g., F or Cl), CN, C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ heteroalkyl or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring, or 5-membered heteroaryl); R ２１ , R ２２ , and R ２３ are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ heteroalkyl, or (6) each independently oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ a 3- to 6-membered ring structure optionally substituted with 1-3 substituents which are heteroalkyl (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or R ２１ and R ２２ are, together with the intervening atoms, independently selected from oxo, deuterium, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ forming a 5-8 membered ring (e.g., a 5-7 membered carbocyclic or heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R ２３ is defined above; or R ２２ and R ２３ are, together with the intervening atoms, independently selected from oxo, deuterium, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ forming a 5-8 membered ring (e.g., a 5-7 membered carbocyclic, aryl, heteroaryl, or heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R ２１ is defined above; Preferably, R ２１ , R ２２ , and R ２３ At least one of R ２１ , R ２２ , and R ２３ contains a hydrogen bond donor, or R ２１ and R ２２ , or R ２２ and R ２３ wherein the ring structure formed by 10. The compound of any one of claims 1 to 9, having a structure according to:

12. J １ is CR ３０ and R ３０ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. J １ is N, or a pharmaceutically acceptable salt thereof.

14. J ２ is CR ３０ and R ３０ The compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

15. J ２ The compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof, wherein

16. R ２ But, M-1-1: 【Chemistry 8】 (In the formula, R ２１ , R ２２ , and R ２３ are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ heteroalkyl, or (6) each independently oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, having a structure with a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocyclic ring, or a 5 membered heteroaryl) optionally substituted with 1-3 substituents that are heteroalkyl.

17. The compound has the formula I-1: 【Chemistry 9】 17. The compound of claim 11 or 16, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

18. R ２０ is hydrogen, halogen, or C １～４ The compound of any one of claims 11 to 17, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

19. R ２０ is hydrogen, F, Cl, methyl, or ethyl, preferably R ２０ The compound according to any one of claims 11 to 17, or a pharmaceutically acceptable salt thereof, wherein

20. R ２１ is hydrogen, deuterium, halogen (e.g., F or Cl), C １～４ alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen １～４ Heteroalkyl, preferably R ２１ The compound according to any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, deuterium, F, or methyl.

21. R ２１ But, OH, NH ２ , or NH(C １～４ C substituted with alkyl １～４ 20. The compound of any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, which is alkyl.

22. R ２１ but, 【Chemistry 10】 20. The compound according to any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, wherein:

23. R ２１ is a 4- to 6-membered heterocyclic ring having one or two ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., and each of the 4- to 6-membered heterocyclic rings independently represents oxo, F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ 20. The compound of any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents which are (alkyl).

24. R ２１ but, 【Chemistry 11】 20. The compound according to any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, which is an azetidinyl or pyrrolidinyl such as:

25. R ２１ is a 5-membered heteroaryl ring having 2 to 4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., and each of the 5-membered heteroaryl rings is independently selected from F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ 20. The compound of any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents which are (alkyl).

26. R ２１ but, 【Chemistry 12】 1 or 2 C such as methyl １～４ 20. The compound of any one of claims 11 to 19, which is imidazolyl or pyrazolyl optionally substituted with alkyl, or a pharmaceutically acceptable salt thereof.

27. R ２２ is hydrogen, halogen (e.g., F or Cl), C １～４ alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen １～４ 27. The compound of any one of claims 11 to 26, or a pharmaceutically acceptable salt thereof, which is heteroalkyl.

28. R ２２ But, OH, NH ２ , or NH(C １～４ C substituted with alkyl １～４ alkyl or R ２２ But, OH, NH ２ , or NH(C １～４ C substituted with alkyl ３～６ 27. The compound of any one of claims 11 to 26, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

29. R ２２ but, 【Chemistry 13】 or R ２２ but, 【Chemistry 14】 or R ２２ but, 【Chemistry 15】 or R ２２ but, 【Chemistry 16】 or R ２２ but, 【Chemistry 17】 27. The compound according to any one of claims 11 to 26, or a pharmaceutically acceptable salt thereof, wherein:

30. R ２２ is a 4- to 6-membered heterocyclic ring having one or two ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, etc., and each of the 4- to 6-membered heterocyclic rings is independently oxo, F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ 27. The compound of any one of claims 11 to 26, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents which are (alkyl).

31. R ２２ but, 【Chemistry 18】 or azetidinyl or pyrrolidinyl such as or R ２２ but, 【Chemistry 19】 27. The compound according to any one of claims 11 to 26, or a pharmaceutically acceptable salt thereof, wherein:

32. R ２２ are 5-membered heteroaryl rings having 2 to 4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., and the 5-membered heteroaryl rings are each independently selected from F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ alkyl), preferably R ２２ but, 【Chemistry 20】 1 or 2 C such as methyl １～４ 27. The compound of any one of claims 11 to 26, which is imidazolyl or pyrazolyl optionally substituted with alkyl, or a pharmaceutically acceptable salt thereof.

33. R ２１ and R ２２ together with the intervening atoms, join together to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, which each independently represent F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ alkyl), and preferably one of the substituents is OH, NH ２ , or NH(C １～４ 20. The compound of any one of claims 11 to 19, or a pharmaceutically acceptable salt thereof, comprising a hydrogen bond donor such as alkyl.

34. R ２３ is hydrogen, deuterium, halogen (e.g., F or Cl), C １～４ alkyl (e.g., methyl or ethyl), or N(CH ３ ) ２ C with one or two heteroatoms that are independently oxygen or nitrogen, such as １～４ Heteroalkyl, preferably R ２３ 34. The compound of any one of claims 11 to 33, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, deuterium, F, Cl, or methyl.

35. R ２３ But, OH, NH ２ , or NH(C １～４ C substituted with alkyl １～４ 34. The compound of any one of claims 11 to 33, or a pharmaceutically acceptable salt thereof, which is alkyl.

36. R ２３ but, 【Chemical 21】 34. The compound according to any one of claims 11 to 33, wherein:

37. R ２３ is a 4- to 6-membered heterocyclic ring having one or two ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, etc., and each of the 4- to 6-membered heterocyclic rings is independently oxo, F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ 34. The compound of any one of claims 11 to 33, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 3 substituents which are (alkyl).

38. R ２３ but, 【Chemical 22】 34. The compound of any one of claims 11 to 33, or a pharmaceutically acceptable salt thereof, which is an azetidinyl or pyrrolidinyl such as:

39. R ２３ are 5-membered heteroaryl rings having 2 to 4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., and the 5-membered heteroaryl rings are each independently selected from F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ alkyl), preferably R ２３ but, 【Chemical 23】 1 or 2 C such as methyl １～４ 34. The compound of any one of claims 11 to 33, which is imidazolyl or pyrazolyl optionally substituted with alkyl, or a pharmaceutically acceptable salt thereof.

40. R ２２ and R ２３ together with the intervening atoms, join together to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, which are each independently selected from F, OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ Alkoxy, or NH(C １～４ alkyl), and preferably one of the substituents is OH, NH ２ , or NH(C １～４ 27. The compound of any one of claims 11 to 26, or a pharmaceutically acceptable salt thereof, comprising a hydrogen bond donor such as alkyl.

41. R ２ However, M-2 or M-5: 【Chemistry 24】 (In the formula, J １ and J ２ are independently N or CR ３０ and R in each occurrence ３０ are independently hydrogen, halogen, C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ is heteroalkyl; Ring C is a heterocyclic or heteroaryl ring, which is １１０ optionally substituted with 1 to 5 instances of R in each existence １１０ are independently (1) oxo, (2) halogen (e.g., F or Cl), or (3) OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), (4) each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ (6) R is heteroalkyl; １１０ Two examples of the following, when joined together with an intervening atom, can each independently be oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ forming a 3-6 membered ring structure optionally substituted with 1-3 substituents which are heteroalkyl (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring); J ３ and J ４ are independently N, NR ３１ , C.R. ３２ R ３３ , or CR ３４ and R in each existence ３１ are independently hydrogen, C optionally substituted with F １～４ alkyl, or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R in each existence ３２ and R ３３ each independently being (1) hydrogen or deuterium, (2) halogen (e.g., F or Cl), or (3) OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), (4) each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or (7) R ３２ and R ３３ are joined together with the carbon atom to which they are both attached to form a carbonyl (CO), or each independently form an oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ form a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4- to 6-membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; or R ３２ Two examples of R ３２ One example of and R １００ One example of is each independently oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ forming a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R in each existence ３４ are independently (1) hydrogen, (2) halogen (e.g., F or Cl), or (3) OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), (4) each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ heteroalkyl, or (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R ２０Ａ and R ２１Ａ are each independently hydrogen, deuterium, halogen (e.g., F or Cl), CN, C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure according to: heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring, or 5 membered heteroaryl).

42. 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein Ring C is a heterocyclic ring having 1 or 2 ring heteroatoms, such as a 5- or 6-membered heterocyclic ring having 1 ring nitrogen atom; or Ring C is a 5-membered heteroaryl having 1 or 2 ring heteroatoms.

43. J １ is CR ３０ and R ３０ 43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

44. J １ 43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein:

45. J ２ is CR ３０ and R ３０ 45. The compound of any one of claims 41 to 44, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

46. J ２ is N, or a pharmaceutically acceptable salt thereof.

47. The compound has the formula I-2: 【Chemistry 25】 42. The compound of claim 41, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

48. R ２０Ａ is hydrogen, halogen, or C １～４ 48. The compound of any one of claims 41 to 47, or a pharmaceutically acceptable salt thereof, which is alkyl.

49. R ２０Ａ is hydrogen, F, Cl, methyl, or ethyl, preferably R ２０Ａ The compound according to any one of claims 41 to 47, or a pharmaceutically acceptable salt thereof, wherein

50. R ２１Ａ is hydrogen, deuterium, halogen, or C １～４ 50. The compound of any one of claims 41 to 49, or a pharmaceutically acceptable salt thereof, which is alkyl.

51. R ２１Ａ is hydrogen, deuterium, F, Cl, methyl, or ethyl, preferably R ２１Ａ 50. The compound of any one of claims 41 to 49, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, deuterium, or methyl.

52. p is 0 or p is 1, and R １１０ But, OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), or C １～４ 52. The compound of any one of claims 41 to 51, or a pharmaceutically acceptable salt thereof, which is alkyl.

53. p is 2 and R １１０ But independently, C １～４ alkyl (e.g., methyl, ethyl); or two R １１０ or a pharmaceutically acceptable salt thereof.

52. The compound of any one of claims 41 to 51, wherein:

54. J ３ NR ３１ and R ３１ is hydrogen or C １～４ 54. The compound of any one of claims 41 to 53, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

55. J ３ The compound of any one of claims 41 to 53, or a pharmaceutically acceptable salt thereof, wherein

56. J ３ is CR ３４ and R ３４ is hydrogen or C １～４ 54. The compound of any one of claims 41 to 53, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

57. J ３ is CR ３２ R ３３ and R ３２ is hydrogen, deuterium, F, or C １～４ alkyl (e.g., methyl or ethyl), and R ３３ is hydrogen, deuterium, F, or C １～４ alkyl (e.g., methyl or ethyl), e.g., J ３ But CH ２ , CDs ２ , C.F. ２ , CH(CH ３ ), or C(CH ３ ) ２ 54. The compound according to any one of claims 41 to 53, wherein:

58. J ３ is CR ３２ R ３３ and R ３２ and R ３３ is taken together with the carbon atom to which they are both attached to form a 3-4 membered ring, such as cyclopropyl, or a pharmaceutically acceptable salt thereof.

59. J ４ NR ３１ and R ３１ is hydrogen or C １～４ 59. The compound of any one of claims 41 to 58, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

60. J ４ is N, or a pharmaceutically acceptable salt thereof.

61. J ４ is CR ３４ and R ３４ is hydrogen or C １～４ 59. The compound of any one of claims 41 to 58, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

62. J ４ But, CR ３２ R ３３ and R ３２ is hydrogen, deuterium, F, or C １～４ alkyl (e.g., methyl or ethyl), and R ３３ is hydrogen, deuterium, F, or C １～４ alkyl (e.g., methyl or ethyl), e.g., J ４ But CH ２ , CDs ２ , C.F. ２ , CH(CH ３ ), or C(CH ３ ) ２ 59. The compound according to any one of claims 41 to 58, or a pharmaceutically acceptable salt thereof, wherein:

63. J ４ But, CR ３２ R ３３ and R ３２ and R ３３ taken together with the carbon atom to which they are both attached form a 3- to 4-membered ring, such as cyclopropyl; or J ４ The compound according to any one of claims 41 to 58, or a pharmaceutically acceptable salt thereof, wherein is C(O).

64. Where applicable, R ２ is of formula F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, F-10, F-11, F-12, F-13, or F-14: 【Chemical 26】 (In the formula, p1 is 0, 1, 2, or 3, where valency allows; R １１１ is hydrogen or R １１０ and Variable element J １ , J ２ , R ２０Ａ , R ２１Ａ , R ３１ , R ３２ , R ３３ , R ３４ , and R １１０ is as defined in any of claims 39 to 60) 64. The compound of any one of claims 41 to 63, characterized as having a structure according to:

65. Where applicable, R ２ Formula F-1-1, F-2-1, F-3-1, F-4-1, F-5-1, F-6-1, F-7-1, F-8-1, F-9-1, F-10-1, F-11-1, F-12-1, F-13-1, or F-14-1: 【Chemical 27】 65. The compound of claim 64, characterized as having a structure according to:

66. In F-1 or F-2 (or a sub-formula thereof), p1 is 0 or p1 is 1, and R １１０ is C １～４ 66. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein:

67. In F-1 or F2 (or a subformula thereof), p is 2 and R １１０ But independently, C １～４ alkyl (e.g., methyl, ethyl); or two R １１０ or a pharmaceutically acceptable salt thereof.

66. The compound of claim 64 or 65, wherein:

68. In F-3, F-4, F-5, F-6, or F-7 (or a subformula thereof), R １１１ is hydrogen or C １～４ 66. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein:

69. In F-4, F-5, F-6, or F-7 (or a subformula thereof), R １１１ But NH ２ or NH(C １～４ 66. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein:

70. R ２ However, M-3 or M-4: 【Chemical 28】 (In the formula, J １ and J ２ are independently N or CR ３０ and R in each occurrence ３０ are independently hydrogen, halogen, C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ is heteroalkyl; Ring C is a heterocyclic or heteroaryl ring, which is １１０ optionally substituted with 1 to 5 instances of R in each existence １１０ are independently (1) oxo, (2) halogen (e.g., F or Cl), or (3) OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), (4) each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ (6) R is heteroalkyl; １１０ Two examples of the following, when joined together with an intervening atom, can each independently be oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ forming a 3-6 membered ring structure optionally substituted with 1-3 substituents which are heteroalkyl (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocyclic ring); U is O or C(=O); W and V are independently C, N, or CR. ３４ and t is 0, 1, 2, or 3; and each Z is independently O, N, NR ３１ , C.R. ３２ R ３３ , or CR ３４ and the bond between W and V, between W and Z, or between two consecutive Z's, is a single or double bond, if valence allows; J ３ and J ４ are independently N, NR ３１ , C.R. ３２ R ３３ , or CR ３４ and R in each existence ３１ are independently hydrogen, C optionally substituted with F １～４ alkyl, or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R in each existence ３２ and R ３３ each independently being (1) hydrogen, (2) halogen (e.g., F or Cl), or (3) OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), (4) each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); or (7) R ３２ and R ３３ are joined together with the carbon atom to which they are both attached to form a carbonyl (CO), or each independently form an oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ C optionally substituted with alkyl or F １～４ forming a 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4- to 6-membered heterocyclic ring) optionally substituted with 1-3 substituents that are heteroalkyl; R in each existence ３４ are independently (1) hydrogen, (2) halogen (e.g., F or Cl), or (3) OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), (4) each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ heteroalkyl, or (6) an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); Or J ３ and R １１０ One example of J ４ and R １１０ An example of is linked together with the intervening atoms to form a ring structure; R ２０Ａ is hydrogen, halogen (e.g., F or Cl), CN, C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ heteroalkyl or an optionally substituted 3- to 6-membered ring structure (e.g., cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic ring, or 5-membered heteroaryl); R ２２Ａ and R ２３Ａ are each independently: (1) hydrogen; (2) halogen (e.g., F or Cl); (3) CN; (4) are each independently F, OH, or NH ２ , 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 C optionally substituted with 1 to 3 substituents that are cycloalkyl １～４ alkyl, (5) C optionally substituted with F １～４ heteroalkyl, or (6) each independently oxo, halo (e.g., F), OH, NH ２ , C optionally substituted with F １～４ alkyl, C optionally substituted with F １～４ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure with a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocyclic ring, or a 5 membered heteroaryl) optionally substituted with 1-3 substituents that are heteroalkyl.

71. 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein Ring C is a heterocyclic ring having one or two ring heteroatoms, such as a 5- or 6-membered heterocyclic ring having one or two ring nitrogen atoms; or Ring C is a 5-membered heteroaryl having one or two ring heteroatoms.

72. J １ is CR ３０ and R ３０ 72. The compound of claim 70 or 71, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

73. J １ 72. The compound of claim 70 or 71, or a pharmaceutically acceptable salt thereof, wherein:

74. J ２ is CR ３０ and R ３０ 74. The compound of any one of claims 70 to 73, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

75. J ２ is N, or a pharmaceutically acceptable salt thereof.

76. The compound has formula I-3 or I-4: 【Chemical 29】 71. The compound of claim 70, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

77. R ２０Ａ is hydrogen, halogen, or C １～４ 77. The compound of any one of claims 70 to 76, or a pharmaceutically acceptable salt thereof, which is alkyl.

78. R ２０Ａ 77. The compound of any one of claims 70 to 76, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, F, Cl, methyl, or ethyl.

79. p is 0 or p is 1, and R １１０ But, OH, NH ２ , NH(C １～４ alkyl), or N(C １～４ alkyl) (C １～４ alkyl), or C １～４ 79. The compound of any one of claims 70 to 78, or a pharmaceutically acceptable salt thereof, which is alkyl.

80. p is 2 and R １１０ But independently, C １～４ alkyl (e.g., methyl, ethyl); or two R １１０ or a pharmaceutically acceptable salt thereof.

79. The compound of any one of claims 70 to 78, wherein:

81. J ３ NR ３１ and R ３１ is hydrogen or C １～４ 81. The compound of any one of claims 70 to 80, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

82. J ３ is N, or a pharmaceutically acceptable salt thereof.

83. J ３ is CR ３４ and R ３４ is hydrogen or C １～４ 81. The compound of any one of claims 70 to 80, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

84. J ３ is CR ３２ R ３３ and R ３２ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), and R ３３ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), e.g., J ３ But CH ２ , CH(CH ３ ), or C(CH ３ ) ２ 81. The compound according to any one of claims 70 to 80, wherein:

85. J ３ is CR ３２ R ３３ and R ３２ and R ３３ is taken together with the carbon atom to which they are both attached to form a 3-4 membered ring, such as cyclopropyl, or a pharmaceutically acceptable salt thereof.

86. J ４ NR ３１ and R ３１ is hydrogen or C １～４ 86. The compound of any one of claims 70 to 85, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

87. J ４ is N, or a pharmaceutically acceptable salt thereof.

88. J ４ is CR ３４ and R ３４ is hydrogen or C １～４ 86. The compound of any one of claims 70 to 85, or a pharmaceutically acceptable salt thereof, which is alkyl (e.g., methyl or ethyl).

89. J ４ is CR ３２ R ３３ and R ３２ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), and R ３３ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), e.g., J ４ But CH ２ , CH(CH ３ ), or C(CH ３ ) ２ 86. The compound according to any one of claims 70 to 85, wherein:

90. J ４ is CR ３２ R ３３ and R ３２ and R ３３ is taken together with the carbon atom to which they are both attached to form a 3-4 membered ring, such as cyclopropyl, or a pharmaceutically acceptable salt thereof.

91. 91. The compound of any one of claims 70 to 90, or a pharmaceutically acceptable salt thereof, wherein U is O.

92. 91. The compound of any one of claims 70 to 90, or a pharmaceutically acceptable salt thereof, wherein U is C(=O).

93. 93. The compound according to any one of claims 70 to 92, or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2.

94. Z at each occurrence independently represents CR ３２ R ３３ and R ３２ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), and R ３３ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), for example, when Z is CH ２ , CH(CH ３ ), or C(CH ３ ) ２ 94. The compound according to any one of claims 70 to 93, wherein:

95. One example of Z is CR ３２ R ３３ and R ３２ and R ３３ taken together with the carbon atoms to which they are both attached form a 3- to 4-membered ring, such as cyclopropyl; any remaining instances of Z are independently selected from CR ３２ R ３３ and R ３２ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl) and R ３３ is hydrogen or C １～４ alkyl (e.g., methyl or ethyl), for example, the remaining instances of Z are independently CH ２ , CH(CH ３ ), or C(CH ３ ) ２ 94. The compound according to any one of claims 70 to 93, wherein:

96. W is C, and Z directly connected to W is CR ３４ and R ３４ is hydrogen or C １～４ 94. The compound of any one of claims 70 to 93, or a pharmaceutically acceptable salt thereof, wherein Z is alkyl (for example, methyl or ethyl) and the bond between Z and W is a double bond.

97. 96. The compound of any one of claims 70 to 95, or a pharmaceutically acceptable salt thereof, wherein W is C or CH.

98. 98. The compound of any one of claims 70 to 97, or a pharmaceutically acceptable salt thereof, wherein V is C or N, or V is CH.

99. R ２ is M-3-A, M-4-A, M-3-B, M-4-B, M-3-C, M-4-C, M-3-D, or M-4-D: 【Chemistry 30】 91. The compound of any one of claims 70-90, having a structure according to:

100. R ２ is M-3-A-1, M-3-A-2, M-3-A-3, M-4-A-1, M-3-B-1, M-3-B-2, or M-3-C-1: 【Chemical 31】 (In the formula, R １１１ is hydrogen or R １１０ is) 100. The compound of claim 99 having a structure according to: or a pharmaceutically acceptable salt thereof.

101. R ２２Ａ But hydrogen, C １～４ alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen １～４ 101. The compound of any one of claims 70 to 100, or a pharmaceutically acceptable salt thereof, which is heteroalkyl.

102. R ２２Ａ But, OH, NH ２ , or NH(C １～４ C substituted with alkyl １～４ 101. The compound of any one of claims 70 to 100, or a pharmaceutically acceptable salt thereof, which is alkyl.

103. R ２３Ａ But hydrogen, C １～４ alkyl (e.g., methyl or ethyl), or C with 1 or 2 heteroatoms that are independently oxygen or nitrogen １～４ 103. The compound of any one of claims 70 to 102, or a pharmaceutically acceptable salt thereof, which is heteroalkyl.

104. R ２３Ａ But, OH, NH ２ , or NH(C １～４ C substituted with alkyl １～４ 103. The compound of any one of claims 70 to 102, or a pharmaceutically acceptable salt thereof, which is alkyl.

105. R ２ but, 【Chemical 32】 or R ２ but, 【Chemical 33】 or R ２ but, 【Chemical 34】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

106. R ２ but, 【Chemistry 35】 or R ２ but, 【Chemical 36】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

107. R ２ but, 【Chemical 37】 or R ２ but, 【Chemical 38】 or R ２ but, 【Chemical 39】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

108. R ２ but, 【Chemistry 40】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

109. R ２ but, 【Chemistry 41】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

110. R ２ but, 【Chemistry 42】 or R ２ but, 【Chemistry 43】 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

111. R ３ is optionally substituted with hydrogen, F, Cl, Br, F and / or deuterium; １～４ Alkyl (e.g., methyl, CD ３ , ethyl, CHF ２ , C.F. ２ CH ３ , C.F. ２ CF ３ , C.H. ２ CH ２ F, CH ２ CF ２ H or CF ３ ) or CN, or a pharmaceutically acceptable salt thereof.

112. R ３ But C ３～６ cycloalkyl, 4- to 6-membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O, and S, or 5- to 6-membered heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S, each of which is independently selected from oxo (if applicable), deuterium, F, CN, G １ , OH, O-G １ , N.H. ２ , NH(G １ ), N(G １ ) (G １ ), C(O)—NH ２ , C(O)-NH(G １ ), and C(O)-N(G １ ) (G １ Optionally substituted with 1 to 3 substituents independently selected from: １ are independently deuterium, F, CN, OH, and C １～４ C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl １～４ Alkyl, or deuterium, F, CN, OH, and C １～４ C optionally substituted with 1 to 3 substituents independently selected from heteroalkyl ３～６ 111. The compound of any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

113. R ３ but, 【Chemical 44】 111. The compound of any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof, selected from:

114. R ４ The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or deuterium.

115. A compound selected from Examples 1-111 or a compound set forth in Table 1 herein, a stereoisomer thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof.

116. 116. A pharmaceutical composition comprising a compound according to any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

117. 117. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 116.

118. 118. The method of claim 117, wherein 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, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric (i.e., stomach) cancer and thyroid cancer.

119. 118. The method of claim 117, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

120. 118. The method of claim 117, wherein the cancer is a breast cancer 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.

121. 118. The method of claim 117, wherein the cancer is a breast cancer selected from endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits inherent or acquired resistance to CDK4 / CDK6 inhibition.

122. 118. The method of claim 117, wherein the cancer is advanced or metastatic breast cancer.

123. 118. The method of claim 117, wherein the cancer is ovarian cancer.

124. 124. The method of any one of claims 117 to 123, wherein the cancer is mediated by a CDK, such as CDK4.

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